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Occupational Exposure to Hexavalent Chromium

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Start Preamble Start Printed Page 10100

AGENCY:

Occupational Safety and Health Administration (OSHA), Department of Labor.

ACTION:

Final rule.

SUMMARY:

The Occupational Safety and Health Administration (OSHA) is amending the existing standard which limits occupational exposure to hexavalent chromium (Cr(VI)). OSHA has determined based upon the best evidence currently available that at the current permissible exposure limit (PEL) for Cr(VI), workers face a significant risk to material impairment of their health. The evidence in the record for this rulemaking indicates that workers exposed to Cr(VI) are at an increased risk of developing lung cancer. The record also indicates that occupational exposure to Cr(VI) may result in asthma, and damage to the nasal epithelia and skin.

The final rule establishes an 8-hour time-weighted average (TWA) exposure limit of 5 micrograms of Cr(VI) per cubic meter of air (5 μg/m3). This is a considerable reduction from the previous PEL of 1 milligram per 10 cubic meters of air (1 mg/10 m3, or 100 μg/m3) reported as CrO3, which is equivalent to a limit of 52 μg/m3 as Cr(VI). The final rule also contains ancillary provisions for worker protection such as requirements for exposure determination, preferred exposure control methods, including a compliance alternative for a small sector for which the new PEL is infeasible, respiratory protection, protective clothing and equipment, hygiene areas and practices, medical surveillance, recordkeeping, and start-up dates that include four years for the implementation of engineering controls to meet the PEL.

The final standard separately regulates general industry, construction, and shipyards in order to tailor requirements to the unique circumstances found in each of these sectors.

The PEL established by this rule reduces the significant risk posed to workers by occupational exposure to Cr(VI) to the maximum extent that is technologically and economically feasible.

DATES:

This final rule becomes effective on May 30, 2006. Start-up dates for specific provisions are set in § 1910.1026(n) for general industry; § 1915.1026(l) for shipyards; and § 1926.1126(l) for construction. However, affected parties do not have to comply with the information collection requirements in the final rule until the Department of Labor publishes in the Federal Register the control numbers assigned by the Office of Management and Budget (OMB). Publication of the control numbers notifies the public that OMB has approved these information collection requirements under the Paperwork Reduction Act of 1995.

ADDRESSES:

In compliance with 28 U.S.C. 2112(a), the Agency designates the Associate Solicitor for Occupational Safety and Health, Office of the Solicitor, Room S-4004, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210, as the recipient of petitions for review of these standards.

Start Further Info

FOR FURTHER INFORMATION CONTACT:

Mr. Kevin Ropp, Director, OSHA Office of Communications, Room N-3647, U.S. Department of Labor, 200 Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-1999.

End Further Info End Preamble Start Supplemental Information

SUPPLEMENTARY INFORMATION:

The following table of contents lays out the structure of the preamble to the final standards. This preamble contains a detailed description of OSHA's legal obligations, the analyses and rationale supporting the Agency's determination, including a summary of and response to comments and data submitted during the rulemaking.

I. General

II. Pertinent Legal Authority

III. Events Leading to the Final Standard

IV. Chemical Properties and Industrial Uses

V. Health Effects

A. Absorption, Distribution, Metabolic Reduction and Elimination

1. Deposition and Clearance of Inhaled Cr(VI) From the Respiratory Tract

2. Absorption of Inhaled Cr(VI) Into the Bloodstream

3. Dermal Absorption of Cr(VI)

4. Absorption of Cr(VI) by the Oral Route

5. Distribution of Cr(VI) in the Body

6. Metabolic Reduction of Cr(VI)

7. Elimination of Cr(VI) From the Body

8. Physiologically-Based Pharmacokinetic Modeling

9. Summary

B. Carcinogenic Effects

1. Evidence From Chromate Production Workers

2. Evidence From Chromate Pigment Production Workers

3. Evidence From Workers in Chromium Plating

4. Evidence From Stainless Steel Welders

5. Evidence From Ferrochromium Workers

6. Evidence From Workers in Other Industry Sectors

7. Evidence From Experimental Animal Studies

8. Mechanistic Considerations

C. Non-Cancer Respiratory Effects

1. Nasal Irritation, Nasal Tissue Ulcerations and Nasal Septum Perforations

2. Occupational Asthma

3. Bronchitis

4. Summary

D. Dermal Effects

E. Other Health Effects

VI. Quantitative Risk Assessment

A. Introduction

B. Study Selection

1. Gibb Cohort

2. Luippold Cohort

3. Mancuso Cohort

4. Hayes Cohort

5. Gerin Cohort

6. Alexander Cohort

7. Studies Selected for the Quantitative Risk Assessment

C. Quantitative Risk Assessments Based on the Gibb Cohort

1. Environ Risk Assessments

2. National Institute for Occupational Safety and Health (NIOSH) Risk Assessment

3. Exponent Risk Assessment

4. Summary of Risk Assessments Based on the Gibb Cohort

D. Quantitative Risk Assessments Based on the Luippold Cohort

E. Quantitative Risk Assessments Based on the Mancuso, Hayes, Gerin, and Alexander Cohorts

1. Mancuso Cohort

2. Hayes Cohort

3. Gerin Cohort

4. Alexander Cohort

F. Summary of Risk Estimates Based on Gibb, Luippold, and Additional Cohorts

G. Issues and Uncertainties

1. Uncertainty With Regard to Worker Exposure to Cr(VI)

2. Model Uncertainty, Exposure Threshold, and Dose Rate Effects

3. Influence of Smoking, Race, and the Healthy Worker Survivor Effect

4. Suitability of Risk Estimates for Cr(VI) Exposures in Other Industries

H. Conclusions

VII. Significance of Risk

A. Material Impairment of Health

1. Lung Cancer

2. Non-Cancer Impairments

B. Risk Assessment

1. Lung Cancer Risk Based on the Gibb Cohort

2. Lung Cancer Risk Based on the Luippold Cohort

3. Risk of Non-Cancer Impairments

C. Significance of Risk and Risk Reduction

VIII. Summary of the Final Economic Analysis and Regulatory Flexibility Analysis

IX. OMB Review Under the Paperwork Reduction Act of 1995

X. Federalism

XI. State Plans Start Printed Page 10101

XII. Unfunded Mandates

XIII. Protecting Children from Environmental Health and Safety Risks

XIV. Environmental Impacts

XV. Summary and Explanation of the Standards

(a) Scope

(b) Definitions

(c) Permissible Exposure Limit (PEL)

(d) Exposure Determination

(e) Regulated Areas

(f) Methods of Compliance

(g) Respiratory Protection

(h) Protective Work Clothing and Equipment

(i) Hygiene Areas and Practices

(j) Housekeeping

(k) Medical Surveillance

(l) Communication of Chromium (VI) Hazards to Employees

(m) Recordkeeping

(n) Dates

XVI. Authority and Signature

XVII. Final Standards

I. General

This final rule establishes a permissible exposure limit (PEL) of 5 micrograms of Cr(VI) per cubic meter of air (5 μg/m3) as an 8-hour time-weighted average for all Cr(VI) compounds. After consideration of all comments and evidence submitted during this rulemaking, OSHA has made a final determination that a PEL of 5 μg/m3 is necessary to reduce the significant health risks posed by occupational exposures to Cr(VI); it is the lowest level that is technologically and economically feasible for industries impacted by this rule. A full explanation of OSHA's rationale for establishing this PEL is presented in the following preamble sections: V (Health Effects), VI (Quantitative Risk Assessment), VII (Significance of Risk), VIII (Summary of the Final Economic Analysis and Regulatory Flexibility Analysis), and XV (Summary and Explanation of the Standard, paragraph (c), Permissible Exposure Limit).

OSHA is establishing three separate standards covering occupational exposures to Cr(VI) for: general industry (29 CFR 1910.1026); shipyards (29 CFR 1915.1026), and construction (29 CFR 1926.1126). In addition to the PEL, these three standards include ancillary provisions for exposure determination, methods of compliance, respiratory protection, protective work clothing and equipment, hygiene areas and practices, medical surveillance, communication of Cr(VI) hazards to employees, recordkeeping, and compliance dates. The general industry standard has additional provisions for regulated areas and housekeeping. The Summary and Explanation section of this preamble (Section XV, paragraphs (d) through (n)) includes a full discussion of the basis for including these provisions in the final standards.

Several major changes were made to the October 4, 2004 proposed rule as a result of OSHA's analysis of comments and data received during the comment periods and public hearings. The major changes are summarized below and are fully discussed in the Summary and Explanation section of this preamble (Section XV)

Scope. As proposed, the standards apply to occupational exposures to Cr(VI) in all forms and compounds with limited exceptions. OSHA has made a final determination to exclude from coverage of these final standards exposures that occur in the application of pesticides containing Cr(VI) (e.g., the treatment of wood with preservatives). These exposures are already covered by the Environmental Protection Agency. OSHA is also excluding exposures to portland cement and exposures in work settings where the employer has objective data demonstrating that a material containing chromium or a specific process, operation, or activity involving chromium cannot release dusts, fumes, or mists of Cr(VI) in concentrations at or above 0.5 μg/m3 under any expected conditions of use. OSHA believes that the weight of evidence in this rulemaking demonstrates that the primary risk in these two exposure scenarios can be effectively addressed through existing OSHA standards for personal protective equipment, hygiene, hazard communication and the PELs for portland cement or particulates not otherwise regulated (PNOR).

Permissible Exposure Limit. OSHA proposed a PEL of 1 μg/m3 but has now determined that a PEL 5 μg/m3 is the lowest level that is technologically and economically feasible.

Exposure Determination. OSHA did not include a provision for exposure determination in the proposed shipyard and construction standards, reasoning that the obligation to meet the proposed PEL would implicitly necessitate performance-based monitoring by the employer to ensure compliance with the PEL. However, OSHA was convinced by arguments presented during the rulemaking that an explicit requirement for exposure determination is necessary to ensure that employee exposures are adequately characterized. Therefore OSHA has included a provision for exposure determination for general industry, shipyards and construction in the final rule. In order to provide additional flexibility in characterizing employee exposures, OSHA is allowing employers to choose between a scheduled monitoring option and a performance-based option for making exposure determinations.

Methods of Compliance. Under the proposed rule employers were to use engineering and work practice controls to achieve the proposed PEL unless the employer could demonstrate such controls are not feasible. In the final rule, OSHA has retained this exception but has added a provision that only requires employers to use engineering and work practice controls to reduce or maintain employee exposures to 25 μg/m3 when painting aircraft or large aircraft parts in the aerospace industry to the extent such controls are feasible. The employer must then supplement those engineering controls with respiratory protection to achieve the PEL. As discussed more fully in the Summary of the Final Economic Analysis and Regulatory Flexibility Analysis (Section VIII) and the Summary and Explanation (Section XV) OSHA has determined that this is the lowest level achievable through the use of engineering and work practice controls alone for these limited operations.

Housekeeping. In the proposed rule, cleaning methods such as shoveling, sweeping, and brushing were prohibited unless they were the only effective means available to clean surfaces contaminated with Cr(VI). The final standard has modified this prohibition to make clear only dry shoveling, sweeping and brushing are prohibited so that effective wet shoveling, sweeping, and brushing would be allowed. OSHA is also adding a provision that allows the use of compressed air to remove Cr(VI) when no alternative method is feasible.

Medical Surveillance. As proposed and continued in these final standards, medical surveillance is required to be provided to employees experiencing signs or symptoms of the adverse health effects associated with Cr(VI) exposure or exposed in an emergency. In addition, for general industry, employees exposed above the PEL for 30 or more days a year were to be provided medical surveillance. In the final standard, OSHA has changed the trigger for medical surveillance to exposure above the action level (instead of the PEL) for 30 days a year to take into account the existing risks at the new PEL. This provision has also been extended to the standards for shipyards and construction since those employers now will be required to perform an exposure determination and thus will be able to determine which employees are exposed above the action level 30 or more days a year. Start Printed Page 10102

Communication of Hazards. In the proposed standard, OSHA specified the sign for the demarcation of regulated areas in general industry and the label for contaminated work clothing or equipment and Cr(VI) contaminated waste and debris. The proposed standard also listed the various elements to be covered for employee training. In order to simplify requirements under this section of the final standard and reduce confusion between this standard and the Hazard Communication Standard, OSHA has removed the requirement for special signs and labels and the specification of employee training elements. Instead, the final standard requires that signs, labels and training be in accordance with the Hazard Communication Standard (29 CFR 1910.1200). The only additional training elements required in the final rule are those related specifically to the contents of the final Cr(VI) standards. While the final standards have removed language in the communication of hazards provisions to make them more consistent with OSHA's existing Hazard Communication Standard, the employers obligation to mark regulated areas (where regulated areas are required), to label Cr(VI) contaminated clothing and wastes, and to train on the hazards of Cr(VI) have not changed.

Recordkeeping. In the proposed standards for shipyards and construction there were no recordkeeping requirements for exposure records since there was not a requirement for exposure determination. The final standard now requires exposure determination for shipyards and construction and therefore, OSHA has also added provisions for exposure records to be maintained in these final standards. In keeping with its intent to be consistent with the Hazard Communication Standard, OSHA has removed the requirement for training records in the final standards.

Dates. In the proposed standard, the effective date of the standard was 60 days after the publication date; the start-up date for all provisions except engineering controls was 90 days after the effective date; and the start-up date for engineering controls was two years after the effective date. OSHA believes that it is appropriate to allow additional time for employers, particularly small employers, to meet the requirements of the final rule. The effective and start-up dates have been extended as follows: the effective date for the final rule is changed to 90 days after the publication date; the start-up date for all provisions except engineering controls is changed to 180 days after the effective date for employers with 20 or more employees; the start-up date for all provisions except engineering controls is changed to one year after the effective date for employers with 19 or fewer employees; and the start-up date for engineering controls is changed to four years after the effective date for all employers.

II. Pertinent Legal Authority

The purpose of the Occupational Safety and Health Act, 29 U.S.C. 651 et seq. (“the Act”) is to,

* * * assure so far as possible every working man and woman in the nation safe and healthful working conditions and to preserve our human resources. 29 U.S.C. 651(b).

To achieve this goal Congress authorized the Secretary of Labor (the Secretary) to promulgate and enforce occupational safety and health standards. 29 U.S.C. 654(b) (requiring employers to comply with OSHA standards), 655(a) (authorizing summary adoption of existing consensus and federal standards within two years of the Act's enactment), and 655(b) (authorizing promulgation, modification or revocation of standards pursuant to notice and comment).

The Act provides that in promulgating health standards dealing with toxic materials or harmful physical agents, such as this standard regulating occupational exposure to Cr(VI), the Secretary,

* * * shall set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life. 29 U.S.C. § 655(b)(5).

The Supreme Court has held that before the Secretary can promulgate any permanent health or safety standard, she must make a threshold finding that significant risk is present and that such risk can be eliminated or lessened by a change in practices. Industrial Union Dept., AFL-CIO v. American Petroleum Institute, 448 U.S. 607, 641-42 (1980) (plurality opinion) (“The Benzene case”). The Court further observed that what constitutes “significant risk” is “not a mathematical straitjacket” and must be “based largely on policy considerations.” The Benzene case, 448 U.S. at 655. The Court gave the example that if,

* * * the odds are one in a billion that a person will die from cancer * * * the risk clearly could not be considered significant. On the other hand, if the odds are one in one thousand that regular inhalation of gasoline vapors that are 2% benzene will be fatal, a reasonable person might well consider the risk significant. * * * Id.

OSHA standards must be both technologically and economically feasible. United Steelworkers v. Marshall, 647 F.2d 1189, 1264 (D.C. Cir. 1980) (“The Lead I case”). The Supreme Court has defined feasibility as “capable of being done.” American Textile Mfrs. Inst. v. Donovan, 425 U.S. 490, 509 (1981) (“The Cotton dust case”). The courts have further clarified that a standard is technologically feasible if OSHA proves a reasonable possibility,

* * * within the limits of the best available evidence * * * that the typical firm will be able to develop and install engineering and work practice controls that can meet the PEL in most of its operations. See The Lead I case, 647 F.2d at 1272.

With respect to economic feasibility, the courts have held that a standard is feasible if it does not threaten massive dislocation to or imperil the existence of the industry. See The Lead case, 647 F.2d at 1265. A court must examine the cost of compliance with an OSHA standard “in relation to the financial health and profitability of the industry and the likely effect of such costs on unit consumer prices.” Id.

[The] practical question is whether the standard threatens the competitive stability of an industry, * * * or whether any intra-industry or inter-industry discrimination in the standard might wreck such stability or lead to undue concentration. Id. (citing Industrial Union Dept., AFL-CIO v. Hodgson, 499 F.2d 467 (D.C. Cir. 1974)).

The courts have further observed that granting companies reasonable time to comply with new PEL's may enhance economic feasibility. Id. While a standard must be economically feasible, the Supreme Court has held that a cost-benefit analysis of health standards is not required by the Act because a feasibility analysis is. The Cotton dust case, 453 U.S. at 509. Finally, unlike safety standards, health standards must eliminate risk or reduce it to the maximum extent that is technologically and economically feasible. See International Union, United Automobile, Aerospace & Agricultural Implement Workers of America, UAW v. OSHA, 938 F.2d 1310, 1313 (D.C. Cir. 1991); Control of Hazardous Energy Sources (Lockout/Tagout), Final rule; supplemental statement of reasons, (58 FR 16612, March 30, 1993).

III. Events Leading to the Final Standard

OSHA's previous standards for workplace exposure to Cr(VI) were adopted in 1971, pursuant to section 6(a) of the Act, from a 1943 American National Standards Institute (ANSI) recommendation originally established to control irritation and damage to nasal Start Printed Page 10103tissues (36 FR at 10466, 5/29/71; Ex. 20-3). OSHA's general industry standard set a permissible exposure limit (PEL) of 1 mg chromium trioxide per 10 m3 air in the workplace (1 mg/10 m3 CrO3) as a ceiling concentration, which corresponds to a concentration of 52 μg/m3 Cr(VI). A separate rule promulgated for the construction industry set an eight-hour time-weighted-average PEL of 1 mg/10 m3 CrO3, also equivalent to 52 μg/m3 Cr(VI), adopted from the American Conference of Governmental Industrial Hygienists (ACGIH) 1970 Threshold Limit Value (TLV) (36 FR at 7340, 4/17/71).

Following the ANSI standard of 1943, other occupational and public health organizations evaluated Cr(VI) as a workplace and environmental hazard and formulated recommendations to control exposure. The ACGIH first recommended control of workplace exposures to chromium in 1946, recommending a time-weighted average Maximum Allowable Concentration (later called a Threshold Limit Value) of 100 μg/m3 for chromic acid and chromates as Cr2 O3 (Ex. 5-37), and later classified certain Cr(VI) compounds as class A1 (confirmed human) carcinogens in 1974. In 1975, the NIOSH Criteria for a Recommended Standard recommended that occupational exposure to Cr(VI) compounds should be limited to a 10-hour TWA of 1 μg/m3, except for some forms of Cr(VI) then believed to be noncarcinogenic (Ex. 3-92). The National Toxicology Program's First Annual Report on Carcinogens identified calcium chromate, chromium chromate, strontium chromate, and zinc chromate as carcinogens in 1980 (Ex. 35-157).

During the 1980s, regulatory and standards organizations came to recognize Cr(VI) compounds in general as carcinogens. The Environmental Protection Agency (EPA) Health Assessment Document of 1984 stated that,

* * * using the IARC [International Agency for Research on Cancer] classification scheme, the level of evidence available for the combined animal and human data would place hexavalent chromium (Cr VI) compounds into Group 1, meaning that there is decisive evidence for the carcinogenicity of those compounds in humans (Ex. 19-1, p. 7-107).

In 1988 IARC evaluated the available evidence regarding Cr(VI) carcinogenicity, concluding in 1990 that

* * * [t]here is sufficient evidence in humans for the carcinogenicity of chromium[VI] compounds as encountered in the chromate production, chromate pigment production and chromium plating industries, [and] sufficient evidence in experimental animals for the carcinogenicity of calcium chromate, zinc chromates, strontium chromate and lead chromates (Ex. 18-3, p. 213).

In September 1988, NIOSH advised OSHA to consider all Cr(VI) compounds as potential occupational carcinogens (Ex. 31-22-22). ACGIH now classifies water-insoluble and water-soluble Cr(IV) compounds as class A1 carcinogens (Ex. 35-207). Current ACGIH standards include specific 8-hour time-weighted average TLVs for calcium chromate (1 μg/m3), lead chromate (12 μg/m3), strontium chromate (0.5 μg/m3), and zinc chromates (10 μg/m3), and generic TLVs for water soluble (50 μg/m3) and insoluble (10 μg/m3) forms of hexavalent chromium not otherwise classified, all measured as chromium (Ex. 35-207).

In July 1993, OSHA was petitioned for an emergency temporary standard to reduce occupational exposures to Cr(VI) compounds (Ex. 1). The Oil, Chemical, and Atomic Workers International Union (OCAW) and Public Citizen's Health Research Group (Public Citizen), citing evidence that occupational exposure to Cr(VI) increases workers' risk of lung cancer, petitioned OSHA to promulgate an emergency temporary standard to lower the PEL for Cr(VI) compounds to 0.5 μg/m3 as an eight-hour time-weighted average (TWA). Upon review of the petition, OSHA agreed that there was evidence of increased cancer risk from exposure to Cr(VI) at the existing PEL, but found that the available data did not show the “grave danger” required to support an emergency temporary standard (Ex. 1-C). The Agency therefore denied the request for an emergency temporary standard, but initiated Section 6(b)(5) rulemaking and began performing preliminary analyses relevant to the rule.

In 1997, Public Citizen petitioned the United States Court of Appeals for the Third Circuit to compel OSHA to complete rulemaking lowering the standard for occupational exposure to Cr(VI). The Court denied Public Citizen's request, concluding that there was no unreasonable delay and dismissed the suit. Oil, Chemical and Atomic Workers Union and Public Citizen Health Research Group v. OSHA, 145 F.3d 120 (3rd Cir. 1998). Afterwards, the Agency continued its data collection and analytic efforts on Cr(VI) (Ex. 35-208, p. 3). In 2002, Public Citizen again petitioned the Court to compel OSHA to commence rulemaking to lower the Cr(VI) standard (Ex. 31-24-1). Meanwhile on August 22, 2002, OSHA published a Request for Information on Cr(VI) to solicit additional information on key issues related to controlling exposures to Cr(VI) (FR 67 at 54389), and on December 4, 2002 announced its intent to proceed with developing a proposed standard (Ex. 35-306). On December 24, 2002, the Court granted Public Citizen's petition, and ordered the Agency to proceed expeditiously with a Cr(VI) standard. See Public Citizen Health Research Group v. Chao, 314 F.3d 143 (3rd Cir. 2002)). In a subsequent order, the Court established a compressed schedule for completion of the rulemaking, with deadlines of October 4, 2004 for publication of a proposed standard and January 18, 2006 for publication of a final standard (Ex. 35-304).

In 2003, as required by the Small Business Regulatory Enforcement Act (SBREFA), OSHA initiated SBREFA proceedings, seeking the advice of small business representatives on the proposed rule. The SBREFA panel, including representatives from OSHA, the Small Business Administration (SBA), and the Office of Management and Budget (OMB), was convened on December 23, 2003. The panel conferred with representatives from small entities in chemical, alloy, and pigment manufacturing, electroplating, welding, aerospace, concrete, shipbuilding, masonry, and construction on March 16-17, 2004, and delivered its final report to OSHA on April 20, 2004. The Panel's report, including comments from the small entity representatives (SERS) and recommendations to OSHA for the proposed rule, is available in the Cr(VI) rulemaking docket (Ex. 34). The SBREFA Panel made recommendations on a variety of subjects. The most important recommendations with respect to alternatives that OSHA should consider included: A higher PEL than the PEL of 1; excluding cement from the scope of the standard; the use of SECALs for some industries; different PELS for different Hexavalent chromium compounds; a multi-year phase-in to the standards; and further consideration to approaches suited to the special conditions of the maritime and construction industries. OSHA has adapted many of these recommendations: The PEL is now 5; cement has been excluded from the scope of the standard; a compliance alternative, similar to a SECAL, has been used in aerospace industry; the standard allows four years to phase in engineering controls; and a new performance based monitoring approach for all industries, among other changes, all of which should make it easier for all Start Printed Page 10104industries with changing work place conditions to meet the standard in a cost effective way. A full discussion of all of the recommendations, and OSHA's responses to them, is provided in Section VIII of this Preamble.

In addition to undertaking SBREFA proceedings, in early 2004, OSHA provided the Advisory Committee on Construction Safety and Health (ACCSH) and the Maritime Advisory Committee on Occupational Safety and Health (MACOSH) with copies of the draft proposed rule for review. OSHA representatives met with ACCSH in February 2004 and May 2004 to discuss the rulemaking and receive their comments and recommendations. On February 13, 2004, ACCSH recommended that portland cement should be included within the scope of the proposed standard (Ex. 35-307, pp. 288-293) and that identical PELs should be set for construction, maritime, and general industry (Ex. 35-307, pp. 293-297). On May 18, 2004, ACCSH recommended that the construction industry should be included in the current rulemaking, and affirmed its earlier recommendation regarding portland cement. OSHA representatives met with MACOSH in March 2004. On March 3, 2004, MACOSH collected and forwarded additional exposure monitoring data to OSHA to help the Agency better evaluate exposures to Cr(VI) in shipyards (Ex. 35-309, p. 208). MACOSH also recommended a separate Cr(VI) standard for the maritime industry, arguing that maritime involves different exposures and requires different means of exposure control than general industry and construction (Ex. 35-309, p. 227).

In accordance with the Court's rulemaking schedule, OSHA published the proposed standard for hexavalent chromium on October 4, 2004 (69 FR at 59306). The proposal included a notice of public hearing in Washington, DC (69 FR at 59306, 59445-59446). The notice also invited interested persons to submit comments on the proposal until January 3, 2005. In the proposal, OSHA solicited public input on 65 issues regarding the human health risks of Cr(VI) exposure, the impact of the proposed rule on Cr(VI) users, and other issues of particular interest to the Agency (69 FR at 59306-59312).

OSHA convened the public hearing on February 1, 2005, with Administrative Law Judges John M. Vittone and Thomas M. Burke presiding. At the conclusion of the hearing on February 15, 2005, Judge Burke set a deadline of March 21, 2005, for the submission of post hearing comments, additional information and data relevant to the rulemaking, and a deadline of April 20, 2005, for the submission of additional written comments, arguments, summations, and briefs. A wide range of employees, employers, union representatives, trade associations, government agencies and other interested parties participated in the public hearing or contributed written comments. Issues raised in their comments and testimony are addressed in the relevant sections of this preamble (e.g., comments on the risk assessment are discussed in section VI; comments on the benefits analysis in section VIII). On December 22, 2005, OSHA filed a motion with the U.S. Court of Appeals for the Third Circuit requesting an extension of the court-mandated deadline for the publication of the final rule by six weeks, to February 28, 2006 (Ex. 48-13). The Court granted the request on January 17, 2006 (Ex. 48-15).

As mandated by the Act, the final standard on occupational exposure to hexavalent chromium is based on careful consideration of the entire record of this proceeding, including materials discussed or relied upon in the proposal, the record of the hearing, and all written comments and exhibits received.

OSHA has developed separate final standards for general industry, shipyards, and the construction industry. The Agency has concluded that excess exposure to Cr(VI) in any form poses a significant risk of material impairment to the health of workers, by causing or contributing to adverse health effects including lung cancer, non-cancer respiratory effects, and dermal effects. OSHA determined that the TWA PEL should not be set above 5 μg/m3 based on the evidence in the record and its own quantitative risk assessment. The TWA PEL of 5 μg/m3 reduces the significant risk posed to workers by occupational exposure to Cr(VI) to the maximum extent that is technologically and economically feasible. (See discussion of the PEL in Section XV below.)

IV. Chemical Properties and Industrial Uses

Chromium is a metal that exists in several oxidation or valence states, ranging from chromium (−II) to chromium (+VI). The elemental valence state, chromium (0), does not occur in nature. Chromium compounds are very stable in the trivalent state and occur naturally in this state in ores such as ferrochromite, or chromite ore (FeCr2 O4). The hexavalent, Cr(VI) or chromate, is the second most stable state. It rarely occurs naturally; most Cr(VI) compounds are man made.

Chromium compounds in higher valence states are able to undergo “reduction” to lower valence states; chromium compounds in lower valence states are able to undergo “oxidation” to higher valence states. Thus, Cr(VI) compounds can be reduced to Cr(III) in the presence of oxidizable organic matter. Chromium can also be reduced in the presence of inorganic chemicals such as iron.

Chromium does exist in less stable oxidation (valence) states such as Cr(II), Cr(IV), and Cr(V). Anhydrous Cr(II) salts are relatively stable, but the divalent state (II, or chromous) is generally relatively unstable and is readily oxidized to the trivalent (III or chromic) state. Compounds in valence states such as (IV) and (V) usually require special handling procedures as a result of their instability. Cr(IV) oxide (CrO2) is used in magnetic recording and storage devices, but very few other Cr(IV) compounds have industrial use. Evidence exists that both Cr(IV) and Cr(V) are formed as transient intermediates in the reduction of Cr(VI) to Cr(III) in the body.

Chromium (III) is also an essential nutrient that plays a role in glucose, fat, and protein metabolism by causing the action of insulin to be more effective. Chromium picolinate, a trivalent form of chromium combined with picolinic acid, is used as a dietary supplement, because it is claimed to speed metabolism.

Elemental chromium and the chromium compounds in their different valence states have various physical and chemical properties, including differing solubilities. Most chromium species are solid. Elemental chromium is a steel gray solid, with high melting and boiling points (1857 °C and 2672 °C, respectively), and is insoluble in water and common organic solvents. Chromium (III) chloride is a violet or purple solid, with high melting and sublimation points (1150 °C and 1300 °C, respectively), and is slightly soluble in hot water and insoluble in common organic solvents. Ferrochromite is a brown-black solid; chromium (III) oxide is a green solid; and chromium (III) sulfate is a violet or red solid, insoluble in water and slightly soluble in ethanol. Chromium (III) picolinate is a ruby red crystal soluble in water (1 part per million at 25 °C). Chromium (IV) oxide is a brown-black solid that decomposes at 300 °C and is insoluble in water.

Cr(VI) compounds have mostly lemon yellow to orange to dark red hues. They are typically crystalline, granular, or powdery although one compound (chromyl chloride) exists in liquid form. For example, chromyl chloride is a dark Start Printed Page 10105red liquid that decomposes into chromate ion and hydrochloric acid in water. Chromic acids are dark red crystals that are very soluble in water. Other examples of soluble chromates are sodium chromate (yellow crystals) and sodium dichromate (reddish to bright orange crystals). Lead chromate oxide is typically a red crystalline powder. Zinc chromate is typically seen as lemon yellow crystals which decompose in hot water and are soluble in acids and liquid ammonia. Other chromates such as barium, calcium, lead, strontium, and zinc chromates vary in color from light yellow to greenish yellow to orange-yellow and exist in solid form as crystals or powder.

The Color Pigments Manufacturers Association (CPMA) provided additional information on lead chromate and some other chromates used in their pigments (Ex. 38-205, pp. 12-13). CPMA describes two main lead chromate color groups: the chrome yellow pigments and the orange to red varieties known as molybdate orange pigments. The chrome yellow pigments are solid solution crystal compositions of lead chromate and lead sulfate. Molybdate orange pigments are solid solution crystal compositions of lead chromate, lead sulfate, and lead molybdate (Ex. 38-205, p. 12). CPMA also describes a basic lead chromate called “chrome orange,” and a lead chromate precipitated “onto a core” of silica (Ex. 38-205, p. 13).

OSHA re-examined available information on solubility values in light of comments from the CPMA and Dominion Color Corporation (DCC) on qualitative solubility designations and CPMA's claim of low bioavailability of lead chromate due to its extremely low solubility (Exs. 38-201-1, p. 4; 38-205, p. 95). There was not always agreement or consistency with the qualitative assignments of solubilities. Quantitative values for the same compound also differ depending on the source of information.

The Table IV-1 is the result of OSHA's re-examination of quantitative water solubility values and qualitative designations. Qualitative designations as well as quantitative values are listed as they were provided by the source. As can be seen by the Table IV-1, qualitative descriptions vary by the descriptive terminology chosen by the source.

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OSHA has made some generalizations to describe the water solubilities of chromates in subsequent sections of this Federal Register notice. OSHA has divided Cr(VI) compounds and mixtures into three categories based on solubility values. Compounds and mixtures with water solubilities less than 0.01 g/l are referred to as water insoluble. Compounds and mixtures between 0.01 g/l and 500 g/l are referred to as slightly Start Printed Page 10108soluble. Compounds and mixtures with water solubility values of 500 g/l or greater are referred to as highly water soluble. It should be noted that these boundaries for insoluble, slightly soluble, and highly soluble are arbitrary designations for the sake of further description elsewhere in this document. Quantitative values take precedence over qualitative designations. For example, zinc chromates would be slightly soluble where their solubility values exceed 0.01 g/l.

Some major users of chromium are the metallurgical, refractory, and chemical industries. Chromium is used by the metallurgical industry to produce stainless steel, alloy steel, and nonferrous alloys. Chromium is alloyed with other metals and plated on metal and plastic substrates to improve corrosion resistance and provide protective coatings for automotive and equipment accessories. Welders use stainless steel welding rods when joining metal parts.

Cr(VI) compounds are widely used in the chemical industry in pigments, metal plating, and chemical synthesis as ingredients and catalysts. Chromates are used as high quality pigments for textile dyes, paints, inks, glass, and plastics. Cr(VI) can be produced during welding operations even if the chromium was originally present in another valence state. While Cr(VI) is not intentionally added to portland cement, it is often present as an impurity.

Occupational exposures to Cr(VI) can occur from inhalation of mists (e.g., chrome plating, painting), dusts (e.g., inorganic pigments), or fumes (e.g., stainless steel welding), and from dermal contact (e.g., cement workers).

There are about thirty major industries and processes where Cr(VI) is used. These include producers of chromates and related chemicals from chromite ore, electroplating, welding, painting, chromate pigment production and use, steel mills, and iron and steel foundries. A detailed discussion of the uses of Cr(VI) in industry is found in Section VIII of this preamble.

V. Health Effects

This section summarizes key studies of adverse health effects resulting from exposure to hexavalent chromium (Cr(VI)) in humans and experimental animals, as well as information on the fate of Cr(VI) in the body and laboratory research that relates to its toxic mode of action. The primary health impairments from workplace exposure to Cr(VI) are lung cancer, asthma, and damage to the nasal epithelia and skin. While this chapter on health effects does not describe all of the many studies that have been conducted on Cr(VI) toxicity, it includes a selection of those that are relevant to the rulemaking and representative of the scientific literature on Cr(VI) health effects.

A. Absorption, Distribution, Metabolic Reduction and Elimination

Although chromium can exist in a number of different valence states, Cr(VI) is the form considered to be the greatest health risk. Cr(VI) enters the body by inhalation, ingestion, or absorption through the skin. For occupational exposure, the airways and skin are the primary routes of uptake. The following discussion summarizes key aspects of Cr(VI) uptake, distribution, metabolism, and elimination.

1. Deposition and Clearance of Inhaled Cr(VI) From the Respiratory Tract

Various anatomical, physical and physiological factors determine both the fractional and regional deposition of inhaled particulate matter. Due to the airflow patterns in the lung, more particles tend to deposit at certain preferred regions in the lung. It is therefore possible to have a buildup of chromium at certain sites in the bronchial tree that could create areas of very high chromium concentration. A high degree of correspondence between the efficiency of particle deposition and the frequency of bronchial tumors at sites in the upper bronchial tree was reported in research by Schlesinger and Lippman that compared the distribution of cancer sites in published reports of primary bronchogenic tumors with experimentally determined particle deposition patterns (Ex. 35-102).

Large inhaled particles (>5 μm) are efficiently removed from the air-stream in the extrathoracic region (Ex. 35-175). Particles greater than 2.5 μm are generally deposited in the tracheobronchial regions, whereas particles less than 2.5 μm are generally deposited in the pulmonary region. Some larger particles (>2.5 μm) can reach the pulmonary region. The mucociliary escalator predominantly clears particles that deposit in the extrathoracic and the tracheobronchial region of the lung. Individuals exposed to high particulate levels of Cr(VI) may also have altered respiratory mucociliary clearance. Particulates that reach the alveoli can be absorbed into the bloodstream or cleared by phagocytosis.

2. Absorption of Inhaled Cr(VI) Into the Bloodstream

The absorption of inhaled chromium compounds depends on a number of factors, including physical and chemical properties of the particles (oxidation state, size, solubility) and the activity of alveolar macrophages (Ex. 35-41). The hexavalent chromate anions (CrO4)2− enter cells via facilitated diffusion through non-specific anion channels (similar to phosphate and sulfate anions). As demonstrated in research by Suzuki et al., a portion of water soluble Cr(VI) is rapidly transported to the bloodstream in rats (Ex. 35-97). Rats were exposed to 7.3-15.9 mg Cr(VI)/m3 as potassium dichromate for 2-6 hours. Following exposure to Cr(VI), the ratio of blood chromium/lung chromium was 1.44±0.30 at 0.5 hours, 0.81±0.10 at 18 hours, 0.85±0.20 at 48 hours, and 0.96±0.22 at 168 hours after exposure.

Once the Cr(VI) particles reach the alveoli, absorption into the bloodstream is greatly dependent on solubility. More soluble chromates are absorbed faster than water insoluble chromates, while insoluble chromates are poorly absorbed and therefore have longer resident time in the lungs. This effect has been demonstrated in research by Bragt and van Dura on the kinetics of three Cr(VI) compounds: highly soluble sodium chromate, slightly soluble zinc chromate and water insoluble lead chromate (Ex. 35-56). They instilled51 chromium-labeled compounds (0.38 mg Cr(VI)/kg as sodium chromate, 0.36 mg Cr(VI)/kg as zinc chromate, or 0.21 mg Cr(VI)/kg as lead chromate) intratracheally in rats. Peak blood levels of51 chromium were reached after 30 minutes for sodium chromate (0.35 μg chromium/ml), and after 24 hours for zinc chromate (0.60 μg chromium/ml) and lead chromate (0.007 μg chromium/ml). At 30 minutes after administration, the lungs contained 36, 25, and 81% of the respective dose of the sodium, zinc, and lead chromate. On day six, >80% of the dose of all three compounds had been cleared from the lungs, during which time the disappearance from lungs followed linear first-order kinetics. The residual amount left in the lungs on day 50 or 51 was 3.0, 3.9, and 13.9%, respectively. From these results authors concluded that zinc chromate, which is less soluble than sodium chromate, is more slowly absorbed from the lungs. Lead chromate was more poorly and slowly absorbed, as indicated by very low levels in blood and greater retention in the lungs. The authors also noted that the kinetics of sodium and zinc chromates were very similar. Zinc chromate, which is less soluble than sodium chromate, was slowly absorbed from the lung, but the maximal blood levels were higher than those resulting from an equivalent dose of sodium chromate. The authors Start Printed Page 10109believe that this was probably the result of hemorrhages macroscopically visible in the lungs of zinc chromate-treated rats 24 hours following intratracheal administration. Boeing Corporation commented that this study does not show that the highly water soluble sodium chromate is cleared more rapidly or retained in the lung for shorter periods than the less soluble zinc chromate (Ex. 38-106-2, p. 18-19). This comment is addressed in the Carcinogenic Effects Conclusion Section V.B.9 dealing with the carcinogenicity of slightly soluble Cr(VI) compounds.

Studies by Langard et al. and Adachi et al. provide further evidence of absorption of chromates from the lungs (Exs. 35-93; 189). In Langard et al., rats exposed to 2.1 mg Cr(VI)/m3 as zinc chromate for 6 hours/day achieved steady state concentrations in the blood after 4 days of exposure (Ex. 35-93). Adachi et al. studied rats that were subject to a single inhalation exposure to chromic acid mist generated from electroplating at a concentration of 3.18 mg Cr(VI)/m3 for 30 minutes which was then rapidly absorbed from the lungs (Ex. 189). The amount of chromium in the lungs of these rats declined from 13.0 mg immediately after exposure to 1.1 mg after 4 weeks, with an overall half-life of five days.

Several other studies have reported absorption of chromium from the lungs after intratracheal instillation (Exs. 7-9; 9-81; Visek et al. 1953 as cited in Ex. 35-41). These studies indicated that 53-85% of Cr(VI) compounds (particle size <5 μm) were cleared from the lungs by absorption into the bloodstream or by mucociliary clearance in the pharynx; the rest remained in the lungs. Absorption of Cr(VI) from the respiratory tract of workers has been shown in several studies that identified chromium in the urine, serum and red blood cells following occupational exposure (Exs. 5-12; 35-294; 35-84).

Evidence indicates that even chromates encapsulated in a paint matrix may be released in the lungs (Ex. 31-15, p. 2). In a study of chromates in aircraft spray paint, LaPuma et al. measured the mass of Cr(VI) released from particles into water originating from three types of paint particles: solvent-borne epoxy (25% strontium chromate (SrCrO4)), water-borne epoxy (30% SrCrO4) and polyurethane (20% SrCrO4) (Ex. 31-2-1). The mean fraction of Cr(VI) released into the water after one and 24 hours for each primer averaged: 70% and 85% (solvent epoxy), 74% and 84% (water epoxy), and 94% and 95% (polyurethane). Correlations between particle size and the fraction of Cr(VI) released indicated that smaller particles (<5 μm) release a larger fraction of Cr(VI) versus larger particles (>5 μm). This study demonstrates that the paint matrix only modestly hinders Cr(VI) release into a fluid, especially with smaller particles. Larger particles, which contain the majority of Cr(VI) due to their size, appear to release proportionally less Cr(VI) (as a percent of total Cr(VI)) than smaller particles. Some commenters suggested that the above research shows that the slightly soluble Cr(VI) from aircraft spray paint is less likely to reach and be absorbed in the bronchoalveolar region of the lung than a highly soluble Cr(VI) form, such as chromic acid aerosol (Exs. 38-106-2; 39-43, 44-33). This issue is further discussed in the Carcinogenic Effects Conclusion Section V.B.9.a and in the Quantitative Risk Assessment Section VI.G.4.a.

A number of questions remain unanswered regarding encapsulated Cr(VI) and bioavailability from the lung. There is a lack of detailed information on the efficiency of encapsulation and whether all of the chromate molecules are encapsulated. The stability of the encapsulated product in physiological and environmental conditions over time has not been demonstrated. Finally, the fate of inhaled encapsulated Cr(VI) in the respiratory tract and the extent of distribution in systemic tissues has not been thoroughly studied.

3. Dermal Absorption of Cr(VI)

Both human and animal studies demonstrate that Cr(VI) compounds are absorbed after dermal exposure. Dermal absorption depends on the oxidation state of chromium, the vehicle and the integrity of the skin. Cr(VI) readily traverses the epidermis to the dermis (Exs. 9-49; 309). The histological distribution of Cr(VI) within intact human skin was studied by Liden and Lundberg (Ex. 35-80). They applied test solutions of potassium dichromate in petrolatum or in water as occluded circular patches of filter paper to the skin. Results with potassium dichromate in water revealed that Cr(VI) penetrated beyond the dermis and penetration reached steady state with resorption by the lymph and blood vessels by 5 hours. About 10 times more chromium penetrated when potassium dichromate was applied in petrolatum than when applied in water, indicating that organic solvents facilitate the absorption of Cr(VI) from the skin. Research by Baranowska-Dutkiewicz also demonstrated that the absorption rates of sodium chromate solutions from the occluded forearm skin of volunteers increase with increasing concentration (Ex. 35-75). The rates were 1.1 μg Cr(VI)/cm2/hour for a 0.01 molar solution, 6.4 μg Cr(VI)/cm2/hour for a 0.1 molar solution, and 10 μg Cr(VI)/cm2/hour for a 0.2 molar solution.

Additional studies have demonstrated that the absorption of Cr(VI) compounds can take place through the dermal route. Using volunteers, Mali found that potassium dichromate penetrates the intact epidermis (Exs. 9-49; 35-41). Wahlberg and Skog demonstrated the presence of chromium in the blood, spleen, bone marrow, lymph glands, urine and kidneys of guinea pigs dermally exposed to51 chromium labeled Cr(VI) compounds (Ex. 35-81).

4. Absorption of Cr(VI) by the Oral Route

Inhaled Cr(VI) can enter the digestive tract as a result of mucocilliary clearance and swallowing. Studies indicate Cr(VI) is absorbed from the gastrointestinal tract. For example, in a study by Donaldson and Barreras, the six-day fecal and 24-hour urinary excretion patterns of radioactivity in groups of six volunteers given Cr(VI) as sodium chromate labeled with51 chromium indicated that at least 2.1% of the Cr(VI) was absorbed. After intraduodenal administration at least 10% of the Cr(VI) compound was absorbed. These studies also demonstrated that Cr(VI) compounds are reduced to Cr(III) compounds in the stomach, thereby accounting for the relatively poor gastrointestinal absorption of orally administered Cr(VI) compounds (Exs. 35-96; 35-41). In the gastrointestinal tract, Cr(VI) can be reduced to Cr(III) by gastric juices, which is then poorly absorbed (Underwood, 1971 as cited in Ex. 19-1; Ex. 35-85).

In a study conducted by Clapp et al., treatment of rats by gavage with an unencapsulated lead chromate pigment or with a silica-encapsulated lead chromate pigment resulted in no measurable blood levels of chromium (measured as Cr(III), detection limit = 10 μg/L) after two or four weeks of treatment or after a two-week recovery period. However, kidney levels of chromium (measured as Cr(III)) were significantly higher in the rats that received the unencapsulated pigment when compared to the rats that received the encapsulated pigment, indicating that silica encapsulation may reduce the gastrointestinal bioavailability of chromium from lead chromate pigments (Ex. 11-5). This study does not address the bioavailability of encapsulated chromate pigments from the lung where residence time could be different. Start Printed Page 10110

5. Distribution of Cr(VI) in the Body

Once in the bloodstream, Cr(VI) is taken up into erythrocytes, where it is reduced to lower oxidation states and forms chromium protein complexes during reduction (Ex. 35-41). Once complexed with protein, chromium cannot leave the cell and chromium ions are unable to repenetrate the membrane and move back into the plasma (Exs. 7-6; 7-7; 19-1; 35-41; 35-52). Once inside the blood cell, the intracellular Cr(VI) reduction to Cr(III) depletes Cr(VI) concentration in the red blood cell (Ex. 35-89). This serves to enhance diffusion of Cr(VI) from the plasma into the erythrocyte resulting in very low plasma levels of Cr(VI). It is also believed that the rate of uptake of Cr(VI) by red blood cells may not exceed the rate at which they reduce Cr(VI) to Cr(III) (Ex. 35-99). The higher tissue levels of chromium after administration of Cr(VI) than after administration of Cr(III) reflect the greater tendency of Cr(VI) to traverse plasma membranes and bind to intracellular proteins in the various tissues, which may explain the greater degree of toxicity associated with Cr(VI) (MacKenzie et al. 1958 as cited in 35-52; Maruyama 1982 as cited in 35-41; Ex. 35-71).

Examination of autopsy tissues from chromate workers who were occupationally exposed to Cr(VI) showed that the highest chromium levels were in the lungs. The liver, bladder, and bone also had chromium levels above background. Mancuso examined tissues from three individuals with lung cancer who were exposed to chromium in the workplace (Ex. 124). One was employed for 15 years as a welder, the second and third worked for 10.2 years and 31.8 years, respectively, in ore milling and preparations and boiler operations. The cumulative chromium exposures for the three workers were estimated to be 3.45, 4.59, and 11.38 mg/m3-years, respectively. Tissues from the first worker were analyzed 3.5 years after last exposure, the second worker 18 years after last exposure, and the third worker 0.6 years after last exposure. All tissues from the three workers had elevated levels of chromium, with the possible exception of neural tissues. Levels were orders of magnitude higher in the lungs when compared to other tissues. Similar results were also reported in autopsy studies of people who may have been exposed to chromium in the workplace as well as chrome platers and chromate refining workers (Exs. 35-92; 21-1; 35-74; 35-88).

Animal studies have shown similar distribution patterns after inhalation exposure. For example, a study by Baetjer et al. investigated the distribution of Cr(VI) in guinea pigs after intratracheal instillation of slightly soluble potassium dichromate (Ex. 7-8). At 24 hours after instillation, 11% of the original dose of chromium from potassium dichromate remained in the lungs, 8% in the erythrocytes, 1% in plasma, 3% in the kidney, and 4% in the liver. The muscle, skin, and adrenal glands contained only a trace. All tissue concentrations of chromium declined to low or nondetectable levels in 140 days, with the exception of the lungs and spleen.

6. Metabolic Reduction of Cr(VI)

Cr(VI) is reduced to Cr(III) in the lungs by a variety of reducing agents. This serves to limit uptake into lung cells and absorption into the bloodstream. Cr(V) and Cr(IV) are transient intermediates in this process. The genotoxic effects produced by the Cr(VI) are related to the reduction process and are further discussed in the section V.B.8 on Mechanistic Considerations.

In vivo and in vitro experiments in rats indicated that, in the lungs, Cr(VI) can be reduced to Cr(III) by ascorbate and glutathione. A study by Suzuki and Fukuda showed that the reduction of Cr(VI) by glutathione is slower than the reduction by ascorbate (Ex. 35-65). Other studies have reported the reduction of Cr(VI) to Cr(III) by epithelial lining fluid (ELF) obtained from the lungs of 15 individuals by bronchial lavage. The average overall reduction capacity was 0.6 μg Cr(VI)/mg of ELF protein. In addition, cell extracts made from pulmonary alveolar macrophages derived from five healthy male volunteers were able to reduce an average of 4.8 μg Cr(VI)/106 cells or 14.4 μg Cr(VI)/mg protein (Ex. 35-83). Postmitochondrial (S12) preparations of human lung cells (peripheral lung parenchyma and bronchial preparations) were also able to reduce Cr(VI) to Cr(III) (De Flora et al. 1984 as cited in Ex. 35-41).

7. Elimination of Cr(VI) From the Body

Excretion of chromium from Cr(VI) compounds is predominantly in the urine, although there is some biliary excretion into the feces. In both urine and feces, the chromium is present as low molecular weight Cr(III) complexes. Absorbed chromium is excreted from the body in a rapid phase representing clearance from the blood and at least two slower phases representing clearance from tissues. Urinary excretion accounts for over 50% of eliminated chromium (Ex. 35-41). Although chromium is excreted in urine and feces, the intestine plays only a minor part in chromium elimination, representing only about 5% of elimination from the blood (Ex. 19-1). Normal urinary levels of chromium in humans have been reported to range from 0.24-1.8 μg/L with a median level of 0.4 μg/L (Ex. 35-79). Humans exposed to 0.01-0.1 mg Cr(VI)/m3 as potassium dichromate (8-hour time-weighted average) had urinary excretion levels from 0.0247 to 0.037 mg Cr(III)/L. Workers exposed mainly to Cr(VI) compounds had higher urinary chromium levels than workers exposed primarily to Cr(III) compounds. An analysis of the urine did not detect Cr(VI), indicating that Cr(VI) was rapidly reduced before excretion (Exs. 35-294; 5-48).

A half-life of 15-41 hours has been estimated for chromium in urine for four welders using a linear one-compartment kinetic model (Exs. 35-73; 5-52; 5-53). Limited work on modeling the absorption and deposition of chromium indicates that adipose and muscle tissue retain chromium at a moderate level for about two weeks, while the liver and spleen store chromium for up to 12 months. The estimated half-life for whole body chromium retention is 22 days for Cr(VI) (Ex. 19-1). The half-life of chromium in the human lung is 616 days, which is similar to the half-life in rats (Ex. 7-5).

Elimination of chromium was shown to be very slow in rats exposed to 2.1 mg Cr(VI)/m3 as zinc chromate six hours/day for four days. Urinary levels of chromium remained almost constant for four days after exposure and then decreased (Ex. 35-93). After intratracheal administration of sodium dichromate to rats, peak urinary chromium concentrations were observed at six hours, after which the urinary concentrations declined rapidly (Ex. 35-94). The more prolonged elimination of the moderately soluble zinc chromate as compared to the more soluble sodium dichromate is consistent with the influence of Cr(VI) solubility on absorption from the respiratory tract discussed earlier.

Information regarding the excretion of chromium in humans after dermal exposure to chromium or its compounds is limited. Fourteen days after application of a salve containing water soluble potassium chromate, which resulted in skin necrosis and sloughing at the application site, chromium was found at 8 mg/L in the urine and 0.61 mg/100 g in the feces of one individual (Brieger 1920 as cited in Ex. 19-1). A slight increase over background levels of urinary chromium was observed in four Start Printed Page 10111subjects submersed in a tub of chlorinated water containing 22 mg Cr(VI)/L as potassium dichromate for three hours (Ex. 31-22-6). For three of the four subjects, the increase in urinary chromium excretion was less than 1 μg/day over the five-day collection period. Chromium was detected in the urine of guinea pigs after radiolabeled sodium chromate solution was applied to the skin (Ex. 35-81).

8. Physiologically-Based Pharmacokinetic Modeling

Physiologically-based pharmacokinetic (PBPK) models have been developed that simulate absorption, distribution, metabolism, and excretion of Cr(VI) and Cr(III) compounds in humans (Ex. 35-95) and rats (Exs. 35-86; 35-70). The original model (Ex. 35-86) evolved from a similar model for lead, and contained compartments for the lung, GI tract, skin, blood, liver, kidney, bone, well-perfused tissues, and slowly perfused tissues. The model was refined to include two lung subcompartments for chromium, one of which allowed inhaled chromium to enter the blood and GI tract and the other only allowed chromium to enter the GI tract (Ex. 35-70). Reduction of Cr(VI) to Cr(III) was considered to occur in every tissue compartment except bone.

The model was developed from several data sets in which rats were dosed with Cr(VI) or Cr(III) intravenously, orally or by intratracheal instillation, because different distribution and excretion patterns occur depending on the route of administration. In most cases, the model parameters (e.g., tissue partitioning, absorption, reduction rates) were estimated by fitting model simulations to experimental data. The optimized rat model was validated against the 1978 Langard inhalation study (Ex. 35-93). Chromium blood levels were overpredicted during the four-day inhalation exposure period, but blood levels during the post-exposure period were well predicted by the model. The model-predicted levels of liver chromium were high, but other tissue levels were closely estimated.

A human PBPK model recently developed by O'Flaherty et al. is able to predict tissue levels from ingestion of Cr(VI) (Ex. 35-95). The model incorporates differential oral absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in major body fluids and tissues, and concentration-dependent urinary clearance. The model does not include a physiologic lung compartment, but can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions of soluble Cr(III) or Cr(VI).

PBPK models are increasingly used in risk assessments, primarily to predict the concentration of a potentially toxic chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species. Further development of the respiratory tract portion of the model, specific Cr(VI) rate data on extracellular reduction and uptake into lung cells, and more precise understanding of critical pathways inside target cells would improve the model value for risk assessment purposes.

9. Summary

Based on the studies presented above, evidence exists in the literature that shows Cr(VI) can be systemically absorbed by the respiratory tract. The absorption of inhaled chromium compounds depends on a number of factors, including physical and chemical properties of the particles (oxidation state, size, and solubility), the reduction capacity of the ELF and alveolar macrophages and clearance by the mucocliary escalator and phagocytosis. Highly water soluble Cr(VI) compounds (e.g. sodium chromate) enter the bloodstream more readily than highly insoluble Cr(VI) compounds (e.g. lead chromate). However, insoluble compounds may have longer residence time in lung. Absorption of Cr(VI) can also take place after oral and dermal exposure, particularly if the exposures are high.

The chromate (CrO4) 2− enters cells via facilitated diffusion through non-specific anion channels (similar to phosphate and sulfate anions). Following absorption of Cr(VI) compounds from various exposure routes, chromium is taken up by the blood cells and is widely distributed in tissues as Cr(VI). Inside blood cells and tissues, Cr(VI) is rapidly reduced to lower oxidation states and bound to macromolecules which may result in genotoxic or cytotoxic effects. However, in the blood a substantial proportion of Cr(VI) is taken up into erythrocytes, where it is reduced to Cr(III) and becomes bound to hemoglobin and other proteins.

Inhaled Cr(VI) is reduced to Cr(III) in vivo by a variety of reducing agents. Ascorbate and glutathione in the ELF and macrophages have been shown to reduce Cr(VI) to Cr(III) in the lungs. After oral exposure, gastric juices are also responsible for reducing Cr(VI) to Cr(III). This serves to limit the amount of Cr(VI) systemically absorbed.

Absorbed chromium is excreted from the body in a rapid phase representing clearance from the blood and at least two slower phases representing clearance from tissues. Urinary excretion is the primary route of elimination, accounting for over 50% of eliminated chromium. Although chromium is excreted in urine and feces, the intestine plays only a minor part in chromium elimination representing only about 5% of elimination from the blood.

B. Carcinogenic Effects

There has been extensive study on the potential for Cr(VI) to cause carcinogenic effects, particularly cancer of the lung. OSHA reviewed epidemiologic data from several industry sectors including chromate production, chromate pigment production, chromium plating, stainless steel welding, and ferrochromium production. Supporting evidence from animal studies and mechanistic considerations are also evaluated in this section.

1. Evidence from Chromate Production Workers

The epidemiologic literature of workers in the chromate production industry represents the earliest and best-documented relationship between exposure to chromium and lung cancer. The earliest study of chromate production workers in the United States was reported by Machle and Gregorius in 1948 (Ex. 7-2). In the United States, two chromate production plants, one in Baltimore, MD, and one in Painesville, OH, have been the subject of multiple studies. Both plants were included in the 1948 Machle and Gregorius study and again in the study conducted by the Public Health Service and published in 1953 (Ex. 7-3). Both of these studies reported the results in aggregate. The Baltimore chromate production plant was studied by Hayes et al. (Ex. 7-14) and more recently by Gibb et al. (Ex. 31-22-11). The chromate production plant in Painesville, OH, has been followed since the 1950s by Mancuso with his most recent follow-up published in 1997. The most recent study of the Painesville plant was published by Luippold et al. (Ex. 31-18-4). The studies by Gibb and Luippold present historical exposure data for the time periods covered by their respective studies. The Gibb exposure data are especially interesting since the industrial hygiene data were collected on a routine basis and not for compliance purposes. These routine air Start Printed Page 10112measurements may be more representative of those typically encountered by the exposed workers. In Great Britain, three plants have been studied repeatedly, with reports published between 1952 and 1991. Other studies of cohorts in the United States, Germany, Italy and Japan are also reported. The elevated lung cancer mortality reported in the great majority of these cohorts and the significant upward trends with duration of employment and cumulative exposure provide some of the strongest evidence that Cr(VI) is carcinogenic to workers. A summary of selected human epidemiologic studies in chromate production workers is presented in Table V-1.

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The basic hexavalent chromate production process involves milling and mixing trivalent chromite ore with soda ash, sometimes in the presence of lime (Exs. 7-103; 35-61). The mixture is ‘roasted’ at a high temperature, which oxidizes much of the chromite to hexavalent sodium chromate. Depending on the lime content used in the process, the roast also contains other chromate species, especially calcium Start Printed Page 10115chromate under high lime conditions. The highly water-soluble sodium chromate is water-extracted from the water-insoluble trivalent chromite and the less water-soluble chromates (e.g., calcium chromate) in the ‘leaching’ process. The sodium chromate leachate is reacted with sulfuric acid and sodium bisulfate to form sodium dichromate. The sodium dichromate is prepared and packaged as a crystalline powder to be sold as final product or sometimes used as the starting material to make other chromates such as chromic acid and potassium dichromate.

a. Cohort Studies of the Baltimore Facility. The Hayes et al. study of the Baltimore, Maryland chromate production plant was designed to determine whether changes in the industrial process at one chromium chemical production facility were associated with a decreased risk of cancer, particularly cancer of the respiratory system (Ex. 7-14). Four thousand two hundred and seventeen (4,217) employees were identified as newly employed between January 1, 1945 and December 31, 1974. Excluded from this initial enumeration were employees who: (1) were working as of 1945, but had been hired prior to 1945 and (2) had been hired since 1945 but who had previously been employed at the plant. Excluded from the final cohort were those employed less than 90 days; women; those with unknown length of employment; those with no work history; and those of unknown age. The final cohort included 2,101 employees (1,803 hourly and 298 salaried).

Hayes divided the production process into three departments: (1) The mill and roast or “dry end” department which consists of grinding, roasting and leaching processes; (2) the bichromate department which consists of the acidification and crystallization processes; and (3) the special products department which produces secondary products including chromic acid. The bichromate and special products departments are referred to as the “wet end”.

The construction of a new mill and roast and bichromate plant that opened during 1950 and 1951 and a new chromic acid and special products plant that opened in 1960 were cited by Hayes as “notable production changes” (Ex. 7-14). The new facilities were designed to “obtain improvements in process technique and in environmental control of exposure to chromium bearing dusts * * *” (Ex. 7-14).

Plant-related work and health histories were abstracted for each employee from plant records. Each job on the employee's work history was characterized according to whether the job exposure occurred in (1) a newly constructed facility, (2) an old facility, or (3) could not be classified as having occurred in the new or the old facility. Those who ever worked in an old facility or whose work location(s) could not be distinguished based upon job title were considered as having a high or questionable exposure. Only those who worked exclusively in the new facility were defined for study purposes as “low exposure”. Data on cigarette smoking were abstracted from plant records, but were not utilized in any analyses since the investigators thought them “not to be of sufficient quality to allow analysis.”

One thousand one hundred and sixty nine (1,169) cohort members were identified as alive, 494 not individually identified as alive and 438 as deceased. Death certificates could not be located for 35 reported decedents. Deaths were coded to the 8th revision of the International Classification of Diseases.

Mortality analysis was limited to the 1,803 hourly employees calculating the standardized mortality ratios (SMRs) for specific causes of death. The SMR is a ratio of the number of deaths observed in the study population to the number that would be expected if that study population had the same specific mortality rate as a standard reference population (e.g., age-, gender-, calendar year adjusted U.S. population). The SMR is typically multiplied by 100, so a SMR greater than 100 represents an elevated mortality in the study cohort relative to the reference group. In the Hayes study, the expected number of deaths was based upon Baltimore, Maryland male mortality rates standardized for age, race and time period. For those where race was unknown, the expected numbers were derived from mortality rates for whites. Cancer of the trachea, bronchus and lung accounted for 69% of the 86 cancer deaths identified and was statistically significantly elevated (O=59; E=29.16; SMR=202; 95% CI: 155-263).

Analysis of lung cancer deaths among hourly workers by year of initial employment (1945-1949; 1950-1959 and 1960-1974), exposure category (low exposure or questionable/high exposure) and duration of employment (short term defined as 90 days-2 years; long term defined as 3 years +) was also conducted. For those workers characterized as having questionable/high exposure, the SMRs were significantly elevated for the 1945-1949 and the 1950-1959 hire periods and for both short- and long-term workers (not statistically significant for the short-term workers initially hired 1945-1949). For those characterized as low exposure, there was an elevated SMR for the long-term workers hired between 1950 and 1959, but based only on three deaths (not statistically significant). No lung cancer cases were observed for workers hired 1960-1974.

Case-control analyses of (1) a history of ever having been employed in selected jobs or combinations of jobs or (2) a history of specified morbid conditions and combinations of conditions reported on plant medical records were conducted. Cases were defined as decedents (both hourly and salaried were included in the analyses) whose underlying or contributing cause of death was lung cancer. Controls were defined as deaths from causes other than malignant or benign tumors. Cases and controls were matched on race (white/non-white), year of initial employment (+/−3 years), age at time of initial employment (+/−5 years) and total duration of employment (90 days-2 years; 3-4 years and 5 years +). An odds ratio (OR) was determined where the ratio is the odds of employment in a job involving Cr(VI) exposure for the cases relative to the controls.

Based upon matched pairs, analysis by job position showed significantly elevated odds ratios for special products (OR=2.6) and bichromate and special products (OR=3.3). The relative risk for bichromate alone was also elevated (OR=2.1, not statistically significant).

The possible association of lung cancer and three health conditions (skin ulcers, nasal perforation and dermatitis) as recorded in the plant medical records was also assessed. Of the three medical conditions, only the odds ratio for dermatitis was statistically significant (OR=3.0). When various combinations of the three conditions were examined, the odds ratio for having all three conditions was statistically significantly elevated (OR=6.0).

Braver et al. used data from the Hayes study discussed above and the results of 555 air samples taken during the period 1945-1950 by the Baltimore City Health Department, the U.S. Public Health Service, and the companies that owned the plant, in an attempt to examine the relationship between exposure to Cr(VI) and the occurrence of lung cancer (Ex. 7-17). According to the authors, methods for determining the air concentrations of Cr(VI) have changed since the industrial hygiene data were collected at the Baltimore plant between 1945 and 1959. The authors asked the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Start Printed Page 10116Administration (OSHA) to review the available documents on the methods of collecting air samples, stability of Cr(VI) in the sampling media after collection and the methods of analyzing Cr(VI) that were used to collect the samples during that period.

Air samples were collected by both midget impingers and high volume samplers. According to the NIOSH/OSHA review, high volume samplers could have led to a “significant” loss of Cr(VI) due to the reduction of Cr(VI) to Cr(III) by glass or cellulose ester filters, acid extraction of the chromate from the filter, or improper storage of samples. The midget impinger was “less subject” to loss of Cr(VI) according to the panel since neither filters nor acid extraction from filters was employed. However, if iron was present or if the samples were stored for too long, conversion from Cr(VI) to Cr(III) may have occurred. The midget impinger can only detect water soluble Cr(VI). The authors noted that, according to a 1949 industrial hygiene survey by the U.S. Public Health Service, very little water insoluble Cr(VI) was found at the Baltimore plant. One NIOSH/OSHA panel member characterized midget impinger results as “reproducible” and “accuracy * * * fairly solid unless substantial reducing agents (e.g., iron) are present” (Ex. 7-17, p. 370). Based upon the panel's recommendations, the authors used the midget impinger results to develop their exposure estimates even though the panel concluded that the midget impinger methods “tend toward underestimation” of Cr(VI).

The authors also cite other factors related to the industrial hygiene data that could have potentially influenced the accuracy of their exposure estimates (either overestimating or underestimating the exposure). These include: Measurements may have been taken primarily in “problem” areas of the plant; the plants may have been cleaned or certain processes shut down prior to industrial hygiene monitoring by outside groups; respirator use; and periodic high exposures (due to infrequent maintenance operations or failure of exposure control equipment) which were not measured and therefore not reflected in the available data.

The authors estimated exposure indices for cohorts rather than for specific individuals using hire period (1945-1949 or 1950-1959) and duration of exposure, defined as short (at least 90 days but less than three years) and long (three years or more). The usual exposure to Cr(VI) for both the short- and long-term workers hired 1945-1949 was calculated as the average of the mean annual air concentration for 1945-1947 and 1949 (data were missing for 1948). This was estimated to be 413 μg/m3. The usual exposure to Cr(VI) was estimated to be 218 μg/m3 for the short and long employees hired between 1950 and 1959 based on air measurements in the older facility in the early 1950s.

Cumulative exposure was calculated as the usual exposure level times average duration. Short-term workers, regardless of length of employment, were assumed to have received 1.6 years of exposure regardless of hire period. For long-term workers, the average length of exposure was 12.3 years. Those hired 1945-1949 were assigned five years at an exposure of 413 μg/m3 and 7.3 years at an exposure of 218 μg/m3. For the long-term workers hired between 1950 and 1959, the average length of exposure was estimated to be 13.4 years. The authors estimated that the cumulative exposures at which “significant increases in lung cancer mortality” were observed in the Hayes study were 0.35, 0.67, 2.93 and 3.65 mg/m3—years. The association seen by the authors appears more likely to be the result of duration of employment rather than the magnitude of exposure since the variation in the latter was small.

Gibb et al. relied upon the Hayes study to investigate mortality in a second cohort of the Baltimore plant (Ex. 31-22-11). The Hayes cohort was composed of 1,803 hourly and 298 salaried workers newly employed between January 1, 1945 and December 31, 1974. Gibb excluded 734 workers who began work prior to August 1, 1950 and included 990 workers employed after August 1, 1950 who worked less than 90 days, resulting in a cohort of 2,357 males followed for the period August 1, 1950 through December 31, 1992. Fifty-one percent (1,205) of the cohort was white; 36% (848) nonwhite. Race was unknown for 13% (304) of the cohort. The plant closed in 1985.

Deaths were coded according to the 8th revision of the International Classification of Diseases. Person years of observation were calculated from the beginning of employment until death or December 31, 1992, whichever came earlier. Smoking data (yes/no) were available for 2,137 (93.3%) of the cohort from company records.

Between 1950 and 1985, approximately 70,000 measurements of airborne Cr(VI) were collected utilizing several different sampling methods. The program of routine air sampling for Cr(VI) was initiated to “characterize ‘typical/usual exposures’ of workers” (Ex. 31-22-11, p. 117). Area samples were collected during the earlier time periods, while both area and personal samples were collected starting in 1977. Exposure estimates were derived from the area sampling systems and were adjusted to “an equivalent personal exposure estimate using job-specific ratios of the mean area and personal sampling exposure estimates for the period 1978-1985 * * *” (Ex. 31-22-11, p. 117). According to the author, comparison of the area and personal samples showed “no significant differences” for about two-thirds of the job titles. For several job titles with a “significant point source of contamination” the area sampling methods “significantly underestimated” personal exposure estimates and were adjusted “by the ratio of the two” (Ex. 31-22-11, p. 118).

A job exposure matrix (JEM) was constructed, where air sampling data were available, containing annual average exposure for each job title. Data could not be located for the periods 1950-1956 and 1960-1961. Exposures were modeled for the missing data using the ratio of the measured exposure for a job title to the average of all measured job titles in the same department. For the time periods where “extensive” data were missing, a simple straight line interpolation between years with known exposures was employed.

To estimate airborne Cr(III) concentrations, 72 composite dust samples were collected at or near the fixed site air monitoring stations about three years after the facility closed. The dust samples were analyzed for Cr(VI) content using ion chromatography. Cr(III) content was determined through inductively coupled plasma spectroscopic analysis of the residue. The Cr(III):Cr(VI) ratio was calculated for each area corresponding to the air sampling zones and the measured Cr(VI) air concentration adjusted based on this ratio. Worker exposures were calculated for each job title and weighted by the fraction of time spent in each air-monitoring zone. The Cr(III):Cr(VI) ratio was derived in this manner for each job title based on the distribution of time spent in exposure zones in 1978. Cr(VI) exposures in the JEM were multiplied by this ratio to estimate Cr(III) exposures.

Information on smoking was collected at the time of hire for approximately 90% of the cohort. Of the 122 lung cancer cases, 116 were smokers and four were non smokers at the time of hire. Smoking status was unknown for two lung cancer cases. As discussed below, these data were used by the study authors to adjust for smoking in their proportional hazards regression models used to determine whether lung cancer mortality in the worker cohort increased Start Printed Page 10117with increasing cumulative Cr(VI) exposure.

A total of 855 observed deaths (472 white; 323 nonwhite and 60 race unknown) were reported. SMRs were calculated using U.S. rates for overall mortality. Maryland rates (the state in which the plant was located) were used to analyze lung cancer mortality in order to better account for regional differences in disease fatality. SMRs were not adjusted for smoking. In the public hearing, Dr. Gibb explained that it was more appropriate to adjust for smoking in the proportional hazards models than in the SMRs, because the analyst must make more assumptions to adjust the SMRs for smoking than to adjust the regression model (Tr. 124).

A statistically significant lung cancer SMR, based on the national rate, was found for whites (O=71; SMR=186; 95% CI: 145-234); nonwhites (O=47; SMR=188; 95% CI: 138-251) and the total cohort (O=122; SMR=180; 95% CI: 149-214). The ratio of observed to expected lung cancer deaths (O/E) for the entire cohort stratified by race and cumulative exposure quartile were computed. Cumulative exposure was lagged five years (only exposure occurring five years before a given age was counted). The cut point for the quartiles divided the cohort into four equal groups based upon their cumulative exposure at the end of their working history (0-0.00149 mgCrO3/m3-yr; 0.0015-0.0089 mgCrO3/m3-yr; 0.009-0.0769 mgCrO3/m3-yr; and 0.077-5.25 mgCrO3/m3-yr). For whites, the relative risk of lung cancer was significantly elevated for the second through fourth exposure quartiles with O/E values of 0.8, 2.1, 2.1 and 1.7 for the four quartiles, respectively. For nonwhites, the O/E values by exposure quartiles were 1.1, 0.9, 1.2 and 2.9, respectively. Only the highest exposure quartile was significantly elevated. For the total cohort, a significant exposure-response trend was observed such that lung cancer mortality increased with increasing cumulative Cr(VI) exposure.

Proportional hazards models were used to assess the relationship between chromium exposure and the risk of lung cancer. The lowest exposure quartile was used as the reference group. The median exposure in each quartile was used as the measure of cumulative Cr(VI) exposure. When smoking status was included in the model, relative lung cancer risks of 1.83, 2.48 and 3.32 for the second, third and fourth exposure quartiles respectively were estimated. Smoking, Cr(III) exposure, and work duration were also significant predictors of lung cancer risk in the model.

The analysis attempted to separate the effects into two multivariate proportionate hazards models (one model incorporated the log of cumulative Cr(VI) exposure, the log of cumulative Cr(III) exposure and smoking; the second incorporated the log of cumulative Cr(VI), work duration and smoking). In either regression model, lung cancer mortality remained significantly associated (p < .05) with cumulative Cr(VI) exposure even after controlling for the combination of smoking and Cr(III) exposure or the combination of smoking and work duration. On the other hand, lung cancer mortality was not significantly associated with cumulative Cr(III) or work duration in the multivariate analysis indicating lung cancer risk was more strongly correlated with cumulative Cr(VI) exposure than the other variables.

Exponent, as part of a larger submission from the Chrome Coalition, submitted comments on the Gibb paper prior to the publication of the proposed rule. These comments asked that OSHA review methodological issues believed by Exponent to impact upon the usefulness of the Gibb data in a risk assessment analysis. While Exponent states that the Gibb study offers data that “are substantially better for cancer risk than the Mancuso study * * * they believe that further scrutiny of some of the methods and analytical procedures is necessary (Ex. 31-18-15-1, p. 5).

The issues raised by Exponent and the Chrome Coalition (Ex. 31-18-14) concerning the Gibb paper are: selection of the appropriate reference population for compilation of expected numbers for use in the SMR analysis; inclusion of short term workers (< 1 year); expansion of the number of exposure groupings to evaluate dose response trends; analyzing dose response by peak JEM exposure levels; analyzing dose-response at exposures above and below the current PEL and calculating smoking-adjusted SMRs for use in dose-response assessments. Exponent obtained the original data from the Gibb study. The data were reanalyzed to address the issues cited above. Exponent's findings are presented in Exhibit 31-18-15-1 and are discussed below.

Exponent suggested that Gibb's use of U.S. and Maryland mortality rates for developing expectations for the SMR analysis was inappropriate. It suggested that Baltimore city mortality rates would have been the appropriate standard to select since those mortality rates would more accurately reflect the mortality experience of those who worked at the plant. Exponent reran the SMR analysis to compare the SMR values reported by Gibb (U.S. mortality rates for SMR analysis) with the results of an SMR analysis using Maryland mortality rates and Baltimore mortality rates. Gibb reported a lung cancer SMR of 1.86 (95% CI: 1.45-2.34) for white males based upon 71 lung cancer deaths using U.S. mortality rates. Reanalysis of the data produced a lung cancer SMR of 1.85 (95% CI: 1.44-2.33) for white males based on U.S. mortality rates, roughly the same value obtained by Gibb. When Maryland and Baltimore rates are used, the SMR drops to 1.70 and 1.25 respectively.

Exponent suggested conducting sensitivity analysis that excludes short-term workers (defined as those with one year of employment) since the epidemiologic literature suggests that the mortality of short-term workers is different than long-term workers. Short-term workers in the Gibb study comprise 65% of the cohort and 54% of the lung cancers. The Coalition also suggested that data pertaining to short-term employees' information are of “questionable usefulness for assessing the increased cancer risk from chronic occupational exposure to Cr(VI)” (Ex. 31-18-15-1, p. 5).

Lung cancer SMRs were calculated for those who worked for less than one year and for those who worked one year or more. Exponent defined short-term workers as those who worked less than one year “because it is consistent with the inclusion criteria used by others studying chromate chemical production worker cohorts” (Ex. 31-18-15-1, p. 12). Exponent also suggested that Gibb's breakdown of exposure by quartile was not the most “appropriate” way of assessing dose-response since cumulative Cr(VI) exposures remained near zero until the 50th to 60th percentile, “so there was no real distinction between the first two quartiles * * * (Ex. 31-18-15-1, p. 24). They also suggested that combining “all workers together at the 75th quartile * * * does not properly account for the heterogeneity of exposure in this group” (Ex. 31-18-15-1, p. 24). The Exponent reanalysis used six cumulative exposure levels of Cr(VI) compared with the four cumulative exposure levels of Cr(VI) in the Gibb analysis. The lower levels of exposure were combined and “more homogeneous” categories were developed for the higher exposure levels.

Using these re-groupings and excluding workers with less than one year of employment, Exponent reported that the highest SMRs are seen in the highest exposure group (1.5-<5.25 mg Start Printed Page 10118CrO3/m3-years) for both white and nonwhite, based on either the Maryland or the Baltimore mortality rates. The authors did not find “that the inclusion of short-term workers had a significant impact on the results, especially if Baltimore rates are used in the SMR calculations' (Ex. 31-18-15-1, p. 28).

Analysis of length of employment and “peak” (i.e., highest recorded mean annual) exposure level to Cr(VI) was conducted. Exponent reported that approximately 50% of the cohort had “only very low” peak exposure levels (<7.2 μg CrO3/m3 or approximately 3.6 μg/m3 of Cr(VI)). The majority of the short-term workers had peak exposures of <100 μg CrO3/m3. There were five peak Cr(VI) exposure levels (<7.2 μg CrO3/m3; 7.2-<19.3 μg CrO3/m3; 19.3-<48.0 μg CrO3/m3; 48.0-<105 μg CrO3/m3; 105-<182 μg CrO3/m3; and 182-<806 μg CrO3/m3) included in the analyses. Overall, the lung cancer SMRs for the entire cohort grouped according to the six peak exposure categories were slightly higher using Maryland reference rates compared to Baltimore reference rates.

The Exponent analysis of workers who were ever exposed above the current PEL versus those never exposed above the current PEL produced slightly higher SMRs for those ever exposed, with the SMRs higher using the Maryland standard rather than the Baltimore standard. The only statistically significant result was for all lung cancer deaths combined.

Assessment was made of the potential impact of smoking on the lung cancer SMRs since Gibb did not adjust the SMRs for smoking. Exponent stated that the smoking-adjusted SMRs are more appropriate for use in the risk assessment than the unadjusted SMRs. It should be noted that smoking adjusted SMRs could not be calculated using Baltimore reference rates. As noted by the authors, the smoking adjusted SMRs produced using Maryland reference rates are, by exposure, “reasonably consistent with the Baltimore-referenced SMRs” (Ex. 31-18-15-1, p. 41).

Gibb et al. included workers regardless of duration of employment, and the cohort was heavily weighted by those individuals who worked less than 90 days. In an attempt to clarify this issue, Exponent produced analyses of short-term workers, particularly with respect to exposures. Exponent redefined short-term workers as those who worked less than one year, to be consistent with the definition used in other studies of chromate producers. OSHA finds this reanalysis excluding short-term workers to be useful. It suggests that including cohort workers employed less than one year did not substantively alter the conclusions of Gibb et al. with regard to the association between Cr(VI) exposure and lung cancer mortality. It should be noted that in the Hayes study of the Baltimore plant, the cohort is defined as anyone who worked 90 days or more.

Hayes et al. used Baltimore mortality rates while Gibb et al. used U.S. mortality rates to calculate expectations for overall SMRs. To calculate expectations for the analysis of lung cancer mortality and exposure, Gibb et al. used Maryland state mortality rates. The SMR analyses provided by Exponent using both Maryland and Baltimore rates are useful. The data showed that using Baltimore rates raised the expected number of lung cancer deaths and, thus, lowered the SMRs. However, there remained a statistically significant increase in lung cancer risk among the exposed workers and a significant upward trend with cumulative Cr(VI) exposure. The comparison group should be as similar as possible with respect to all other factors that may be related to the disease except the determinant under study. Since the largest portion of the cohort (45%) died in the city of Baltimore, and even those whose deaths occurred outside of Baltimore (16%) most likely lived in proximity to the city, the use of Baltimore mortality rates as an external reference population is preferable.

Gibb's selection of the cut points for the exposure quartiles was accomplished by dividing the workers in the cohort into four equal groups based on their cumulative exposure at the end of their working history. Using the same method but excluding the short-term workers would have resulted in slightly different cumulative exposure quartiles. Exponent expressed a preference for a six-tiered exposure grouping. The impact of using different exposure groupings is further discussed in section VI.C of the quantitative risk assessment.

The exposure matrix of Gibb et al. utilizes an unusually high-quality set of industrial hygiene data. Over 70,000 samples taken to characterize the “typical/usual” working environment is more extensive industrial hygiene data then is commonly available for most exposure assessments. However, there are several unresolved issues regarding the exposure assessment, including the impact of the different industrial hygiene sampling techniques used over the sampling time frame, how the use of different sampling techniques was taken into account in developing the exposure assessment and the use of area vs. personal samples.

Exponent and the Chrome Coalition also suggested that the SMRs should have been adjusted for smoking. According to Exponent, smoking adjusted SMRs based upon the Maryland mortality rates produced SMRs similar to the SMRs obtained using Baltimore mortality rates (Ex. 31-18-15-1). The accuracy of the smoking data is questionable since it represents information obtained at the time of hire. Hayes abstracted the smoking data from the plant medical records, but “found it not to be of sufficient quality to allow analysis.” One advantage to using the Baltimore mortality data may be to better control for the potential confounding of smoking.

The Gibb study is one of the better cohort mortality studies of workers in the chromium production industry. The quality of the available industrial hygiene data and its characterization as “typical/usual” makes the Gibb study particularly useful for risk assessment.

b. Cohort Studies of the Painesville Facility. The Ohio Department of Health conducted epidemiological and environmental studies at a plant in Painesville that manufactured sodium bichromate from chromite ore. Mancuso and Hueper (Ex. 7-12) reported an excess of respiratory cancer among chromate workers when compared to the county in which the plant was located. Among the 33 deaths in males who had worked at the plant for a minimum of one year, 18.2% were from respiratory cancer. In contrast, the expected frequency of respiratory cancer among males in the county in which the plant was located was 1.2%. Although the authors did not include a formal statistical comparison, the lung cancer mortality rate among the exposed workers would be significantly greater than the county rate.

Mancuso (Ex. 7-11) updated his 1951 study of 332 chromate production workers employed during the period 1931-1937. Age adjusted mortality rates were calculated by the direct method using the distribution of person years by age group for the total chromate population as the standard. Vital status follow-up through 1974 found 173 deaths. Of the 66 cancer deaths, 41 (62.1%) were lung cancers. A cluster of lung cancer deaths was observed in workers with 27-36 years since first employment.

Mancuso used industrial hygiene data collected in 1949 to calculate weighted average exposures to water-soluble (presumed to be Cr(VI)), insoluble (presumed to be principally Cr(III)) and Start Printed Page 10119total chromium (Ex. 7-98). The age-adjusted lung cancer death rate increased from 144.6 (based upon two deaths) to 649.6 (based upon 14 deaths) per 100,000 in five exposure categories ranging from a low of 0.25-0.49 to a high of 4.0+ mg/m3-years for the insoluble Cr(III) exposures. For exposure to soluble Cr(VI), the age adjusted lung cancer rates ranged from 80.2 (based upon three deaths) to 998.7 (based upon 12 deaths) in five exposure categories ranging from <0.25 to 2.0+ mg/m3-years. For total chromium, the age-adjusted death rates ranged from 225.7 (based upon three deaths) to 741.5 (based upon 16 deaths) for exposures ranging from 0.50-0.99 mg/m3-years to 6.0+ mg/m3-years.

Age-adjusted lung cancer death rates also were calculated by classifying workers by the levels of insoluble Cr(III) and total chromium exposure. From the data presented, it appears that for a fixed level of insoluble Cr(III), the lung cancer risk appears to increase as the total chromium increases (Ex. 7-11).

Mancuso (Ex. 23) updated the 1975 study. As of December 31, 1993, 283 (85%) cohort members had died and 49 could not be found. Of the 102 cancer deaths, 66 were lung cancers. The age-adjusted lung cancer death rate per 100,000 ranged from 187.9 (based upon four deaths) to 1,254.1 (based upon 15 deaths) for insoluble Cr(III) exposure categories ranging from 0.25-0.49 to 4.00-5.00 mg/m3 years. For the highest exposure to insoluble Cr(III) (6.00+ mg/m3 years) the age-adjusted lung cancer death rate per 100,000 fell slightly to 1,045.5 based upon seven deaths.

The age-adjusted lung cancer death rate per 100,000 ranged from 99.7 (based upon five deaths) to 2,848.3 (based upon two deaths) for soluble Cr(VI) exposure categories ranging from <0.25 to 4.00+ mg/m3 years. For total chromium, the age-adjusted lung cancer death rate per 100,000 ranged from 64.7 (based upon two deaths) to 1,106.7 (based upon 21 deaths) for exposure categories ranging from <0.50 to 6.00+ mg/m3 years.

To investigate whether the increase in the lung cancer death rate was due to one form of chromium compound (presumed insoluble Cr(III) or soluble Cr(VI)), age-adjusted lung cancer mortality rates were calculated by classifying workers by the levels of exposure to insoluble Cr(III) and total chromium. For a fixed level of insoluble Cr(III), the lung cancer rate appears to increase as the total chromium increases for each of the six total chromium exposure categories, except for the 1.00-1.99 mg/m3-years category. For the fixed exposure categories for total chromium, increasing exposures to levels of insoluble Cr(III) showed an increased age-adjusted death rate from lung cancer in three of the six total chromium exposure categories.

For a fixed level of soluble Cr(VI), the lung cancer death rate increased as total chromium categories of exposure increased for three of the six gradients of soluble Cr(VI). For the fixed exposure categories of total chromium, the increasing exposure to specific levels of soluble Cr(VI) led to an increase in two of the six total chromium exposure categories. Mancuso concluded that the relationship of lung cancer is not confined solely to either soluble or insoluble chromium. Unfortunately, it is difficult to attribute these findings specifically to Cr(III) [as insoluble chromium] and Cr(VI) [as soluble chromium] since it is likely that some slightly soluble and insoluble Cr(VI) as well as Cr(III) contributed to the insoluble chromium measurement.

Luippold et al. conducted a retrospective cohort study of 493 former employees of the chromate production plant in Painesville, Ohio (Ex. 31-18-4). This Painesville cohort does not overlap with the Mancuso cohort and is defined as employees hired beginning in 1940 who worked for a minimum of one year at Painesville and did not work at any other facility owned by the same company that used or produced Cr(VI). An exception to the last criterion was the inclusion of workers who subsequently were employed at a company plant in North Carolina (number not provided). Four cohort members were identified as female. The cohort was followed for the period January 1, 1941 through December 31, 1997. Thirty-two percent of the cohort worked for 10 or more years.

Information on potential confounders was limited. Smoking status (yes/no) was available for only 35% of the cohort from surveys administered between 1960 and 1965 or from employee medical files. For those employees where smoking data were available, 78% were smokers (responded yes on at least one survey or were identified as smokers from the medical file). Information on race also was limited, the death certificate being the primary source of information.

Results of the vital status follow-up were: 303 deaths; 132 presumed alive and 47 vital status unknown. Deaths were coded to the 9th revision of the International Classification of Diseases. Cause of death could not be located for two decedents. For five decedents the cause of death was only available from data collected by Mancuso and was recoded from the 7th to the 9th revision of the ICD. There were no lung cancer deaths among the five recoded deaths.

SMRs were calculated based upon two reference populations: The U.S. (white males) and the state of Ohio (white males). Lung cancer SMRs stratified by year of hire, duration of exposure, time since first employment and cumulative exposure group also were calculated.

Proctor et al. analyzed airborne Cr(VI) levels throughout the facility for the years 1943 to 1971 (the plant closed April 1972) from 800 area air sampling measurements from 21 industrial hygiene surveys (Ex. 35-61). A job exposure matrix (JEM) was constructed for 22 exposure areas for each month of plant operation. Gaps in the matrix were completed by computing the arithmetic mean concentration from area sampling data, averaged by exposure area over three time periods (1940-1949; 1950-1959 and 1960-1971) which coincided with process changes at the plant (Ex. 31-18-1)

The production of water-soluble sodium chromate was the primary operation at the Painesville plant. It involved a high lime roasting process that produced a water insoluble Cr(VI) residue (calcium chromate) as byproduct that was transported in open conveyors and likely contributed to worker exposure until the conveyors were covered during plant renovations in 1949. The average airborne soluble Cr(VI) from industrial hygiene surveys in 1943 and 1948 was 0.72 mg/m3 with considerable variability among departments. During these surveys, the authors believe the reported levels may have underestimated total Cr(VI) exposure by 20 percent or less for some workers due to the presence of insoluble Cr(VI) dust.

Reductions in Cr(VI) levels over time coincided with improvements in the chromate production process. Industrial hygiene surveys over the period from 1957 to 1964 revealed average Cr(VI) levels of 270 μg/m3. Another series of plant renovations in the early 1960s lowered average Cr(VI) levels to 39 μg/m3 over the period from 1965 to 1972. The highest Cr(VI) concentrations generally occurred in the shipping, lime and ash, and filtering operations while the locker rooms, laboratory, maintenance shop and outdoor raw liquor storage areas had the lowest Cr(VI) levels.

The average cumulative Cr(VI) exposure (mg/m3-yrs) for the cohort was 1.58 mg/m3-yrs and ranged from 0.006 to 27.8 mg/m3-yrs. For those who died from lung cancer, the average Cr(VI) exposure was 3.28 mg/m3-yrs and ranged from 0.06 to 27.8 mg/m3-yrs. Start Printed Page 10120According to the authors, 60% of the cohort accumulated an estimated Cr(VI) exposure of 1.00 mg/m3-yrs or less.

Sixty-three per cent of the study cohort was reported as deceased at the end of the follow-up period (December 31, 1997). There was a statistically significant increase for the all causes of death category based on both the national and Ohio state standard mortality rates (national: O=303; E=225.6; SMR=134; 95% CI: 120-150; state: O=303; E=235; SMR=129; 95% CI: 115-144). Fifty-three of the 90 cancer deaths were cancers of the respiratory system with 51 coded as lung cancer. The SMR for lung cancer is statistically significant using both reference populations (national O= 51; E=19; SMR 268; 95% CI: 200-352; state O=51; E=21.2; SMR 241; 95% CI: 180-317).

SMRs also were calculated by year of hire, duration of employment, time since first employment and cumulative Cr(VI) exposure, mg/m3-years. The highest lung cancer SMRs were for those hired during the earliest time periods. For the period 1940-1949, the lung cancer SMR was 326 (O=30; E=9.2; 95% CI: 220-465); for 1950-1959, the lung cancer SMR was 275 (O=15; E=5.5; 95% CI: 154-454). For the period 1960-1971, the lung cancer SMR was just under 100 based upon six deaths with 6.5 expected.

Lung cancer SMRs based upon duration of employment (years) increased as duration of employment increased. For those with one to four years of employment, the lung cancer SMR was 137 based upon nine deaths (E=6.6; 95% CI: 62-260); for five to nine years of employment, the lung cancer SMR was 160 (O=8; E=5.0; 95% CI: 69-314). For those with 10-19 years of employment, the lung cancer SMR was 169 (O=7; E=4.1; 95% CI: 68-349), and for those with 20 or more years of employment, the lung cancer SMR was 497 (O=27; E=5.4; 95% CI: 328-723).

Analyses of cumulative Cr(VI) exposure found the lung cancer SMR (based upon the Ohio standard) in the highest exposure group (2.70-27.80 mg/m3-yrs) was 463 (O=20; E=4.3; 95% CI: 183-398). In the 1.05-2.69 mg/m3-yrs cumulative exposure group, the lung cancer SMR was 365 based upon 16 deaths (E=4.4; 95% CI: 208-592). For the cumulative exposure groups 0.49-1.04, 0.20-0.48 and 0.00-0.19, the lung cancer SMRs were 91 (O=4; E=4.4; 95% CI: 25-234; 184 (O=8; E=4.4; 95% CI: 79-362) and 67 (O=3; E=4.5; 95% CI: 14-196). A test for trend showed a strong relationship between lung cancer mortality and cumulative Cr(VI) exposure (p=0.00002). The authors claim that the SMRs are also consistent with a threshold effect since there was no statistically significant trend for excess lung cancer mortality with cumulative Cr(VI) exposures less than about 1 mg/m3-yrs. The issue of whether the cumulative Cr(VI) exposure-lung cancer response is best represented by a threshold effect is discussed further in preamble section VI on the quantitative risk assessment.

The Painesville cohort is small (482 employees). Excluded from the cohort were six employees who worked at other chromate plants after Painesville closed. However, exceptions were made for employees who subsequently worked at the company's North Carolina plant (number not provided) because exposure data were available from the North Carolina plant. Subsequent exposure to Cr(VI) by other terminated employees is unknown and not taken into account by the investigators. Therefore, the extent of the bias introduced is unknown.

The 10% lost to follow-up (47 employees) in a cohort of this size is striking. Four of the forty-seven had “substantial” follow-up that ended in 1997 just before the end date of the study. For the remaining 43, most were lost in the 1950s and 1960s (most is not defined). Since person-years are truncated at the time individuals are lost to follow up, the potential implication of lost person years could impact the width of the confidence intervals.

The authors used U.S. and Ohio mortality rates for the standards to compute the expectations for the SMRs, stating that the use of Ohio rates minimizes bias that could occur from regional differences in mortality. It is unclear why county rates were not used to address the differences in regional mortality.

c. Other Cohort Studies. The first study of cancer of the respiratory system in the U.S. chromate producing industry was reported by Machle and Gregorius (Ex. 7-2). The study involved a total of 11,000 person-years of observation between 1933 and 1947. There were 193 deaths; 42 were due to cancer of the respiratory system. The proportion of respiratory cancer deaths among chromate workers was compared with proportions of respiratory cancer deaths among Metropolitan Life Insurance industrial policyholders. A non-significant excess respiratory cancer among chromate production workers was found. No attempt was made to control for confounding factors (e.g., age). While some exposure data are presented, the authors state that one cannot associate tumor rates with tasks (and hence specific exposures) because of “shifting of personnel” and the lack of work history records.

Baetjer reported the results of a case-control study based upon records of two Baltimore hospitals (Ex. 7-7). A history of working with chromates was determined from these hospital records and the proportion of lung cancer cases determined to have been exposed to chromates was compared with the proportion of controls exposed. Of the lung cancer cases, 3.4% had worked in a chromate manufacturing plant, while none of the controls had such a history recorded in the medical record. The results were statistically significant and Baetjer concluded that the data confirmed the conclusions reached by Machle and Gregorius that “the number of deaths due to cancer of the lung and bronchi is greater in the chromate-producing industry than would normally be expected” (Ex. 7-7, p. 516).

As a part of a larger study carried out by the U.S. Public Health Service, the morbidity and mortality of male workers in seven U.S. chromate manufacturing plants during the period 1940-1950 was reported (Exs. 7-1; 7-3). Nearly 29 times as many deaths from respiratory cancer (excluding larynx) were found among workers in the chromate industry when compared to mortality rates for the total U.S. for the period 1940-1948. The lung cancer risk was higher at the younger ages (a 40-fold risk at ages 15-45; a 30-fold risk at ages 45-54 and a 20-fold risk at ages 55-74). Analysis of respiratory cancer deaths (excluding larynx) by race showed an observed to expected ratio of 14.29 for white males and 80 for nonwhite males.

Taylor conducted a mortality study in a cohort of 1,212 chromate workers followed over a 24 year (1937-1960) period (Ex. 7-5). The workers were from three chromate plants that included approximately 70% of the total population of U.S. chromate workers in 1937. In addition, the plants had been in continuous operation for the study period (January 1, 1937 to December 31, 1960). The cohort was followed utilizing records of Old Age and Survivors Disability Insurance (OASDI). Results were reported both in terms of SMRs and conditional probabilities of survival to various ages comparing the mortality experience of chromate workers to the U.S. civilian male population. No measures of chromate exposure were reported although results are provided in terms of duration of employment. Taylor concluded that not only was there an excess in mortality from respiratory cancer, but from other causes as well, especially as duration of employment increased. Start Printed Page 10121

In a reanalysis of Taylor's data, Enterline excluded those workers born prior to 1889 and analyzed the data by follow-up period using U.S. rates (Ex. 7-4). The SMR for respiratory cancer for all time periods showed a nine-fold excess (O=69 deaths; E=7.3). Respiratory cancer deaths comprised 28% of all deaths. Two of the respiratory cancer deaths were malignant neoplasms of the maxillary sinuses, a number according to Enterline, “greatly in excess of that expected based on the experience of the U.S. male population.” Also slightly elevated were cancers of the digestive organs (O=16; E=10.4) and non-malignant respiratory disease (O=13; E=8.9).

Pastides et al. conducted a cohort study of workers at a North Carolina chromium chemical production facility (Ex. 7-93). Opened in 1971, this facility is the largest chromium chemical production facility in the United States. A low-lime process was used since the plant began operation. Three hundred and ninety eight workers employed for a minimum of one year between September 4, 1971 and December 31, 1989 comprised the study cohort. A self-administered employee questionnaire was used to collect data concerning medical history, smoking, plant work history, previous employment and exposure to other potential chemical hazards. Personal air monitoring results for Cr(VI) were available from company records for the period February 1974 through April 1989 for 352 of the 398 cohort members. A job matrix utilizing exposure area and calendar year was devised. The exposure means from the matrix were linked to each employee's work history to produce the individual exposure estimates by multiplying the mean Cr(VI) value from the matrix by the duration (time) in a particular exposure area (job). Annual values were summed to estimate total cumulative exposure.

Personal air monitoring indicated that TWA Cr(VI) air concentrations were generally very low. Roughly half the samples were less than 1 μg/m3, about 75 percent were below 3 μg/m3, and 96 percent were below 25 μg/m3. The average worker's age was 42 years and mean duration of employment was 9.5 years. Two thirds of the workers had accumulated less than 0.01 μg/m3-yr cumulative Cr(VI) exposure. SMRs were computed using National, State (not reported) and county mortality rates (eight adjoining North Carolina counties, including the county in which the plant is located). Two of the 17 recorded deaths in the cohort were from lung cancers. The SMRs for lung cancer were 127 (95% CI: 22-398) and 97 (95% CI: 17-306) based on U.S. and North Carolina county mortality rates, respectively. The North Carolina cohort is still relatively young and not enough time has elapsed to reach any conclusions regarding lung cancer risk and Cr(VI) exposure.

In 2005, Luippold et al. published a study of mortality among two cohorts of chromate production workers with low exposures (Ex. 47-24-2). Luippold et al. studied a total of 617 workers with at least one year of employment, including 430 at the North Carolina plant studied by Pastides et al. (1994) (“Plant 1”) and 187 hired after the 1980 institution of exposure-reducing process and work practice changes at a second U.S. plant (“Plant 2”). A high-lime process was never used at Plant 1, and workers drawn from Plant 2 were hired after the institution of a low lime process, so that exposures to calcium chromate in both cohorts were likely minimal. Personal air-monitoring measures available from 1974 to 1988 for the first plant and from 1981 to 1998 for the second plant indicated that exposure levels at both plants were low, with overall geometric mean concentrations below 1.5 μg/m3 and area-specific average personal air sampling values not exceeding 10 μg/m3 for most years (Ex. 47-24-2, p. 383).

Workers were followed through 1998. By the end of follow-up, which lasted an average of 20.1 years for workers at Plant 1 and 10.1 years at Plant 2, 27 cohort members (4%) were deceased. There was a 41% deficit in all-cause mortality when compared to all-cause mortality from age-specific state reference rates, suggesting a strong healthy worker effect. Lung cancer was 16% lower than expected based on three observed vs. 3.59 expected cases, also using age-specific state reference rates (Ex. 47-24-2, p. 383). The authors stated that “[t]he absence of an elevated lung cancer risk may be a favorable reflection of the postchange environment”, but cautioned that longer follow-up allowing an appropriate latency for the entire cohort would be required to confirm this conclusion (Ex. 47-24-2, p. 381). OSHA received several written testimony regarding this cohort during the post-hearing comment period. These are discussed in section VI.B.7 on the quantitative risk assessment.

A study of four chromate producing facilities in New Jersey was reported by Rosenman (Ex. 35-104). A total of 3,408 individuals were identified from the four facilities over different time periods (plant A from 1951-1954; plant B from 1951-1971; plant C from 1937-1964 and plant D 1937-1954). No Cr(VI) exposure data was collected for this study. Proportionate mortality ratios (PMRs) and proportionate cancer mortality ratios (PCMRs), adjusted by race, age, and calendar year, were calculated for the three companies (plants A and B are owned by one company). Unlike SMRs, PMRs are not based on the expected mortality rates in a standardized population but, instead, merely represent the proportional distribution of deaths in the cohort relative to the general U.S. population. Analyses were done evaluating duration of work and latency from first employment.

Significantly elevated PMRs were seen for lung cancer among white males (170 deaths, PMR=1.95; 95% CI: 1.67-2.27) and black males (54 deaths, PMR=1.88; 95% CI: 1.41-2.45). PMRs were also significantly elevated (regardless of race) for those who worked 1-10, 11-20 and >20 years and consistently higher for white and black workers 11-20 years and >20 years since first hire. The results were less consistent for those with 10 or fewer years since first hire.

Bidstrup and Case reported the mortality experience of 723 workers at three chromate producing factories in Great Britain (Ex. 7-20). Lung cancer mortality was 3.6 times that expected (O=12; E=3.3) for England and Wales. Alderson et al. conducted a follow-up of workers from the three plants in the U.K. (Bolton, Rutherglen and Eaglescliffe) originally studied by Bidstrup (Ex. 7-22). Until the late 1950s, all three plants operated a “high-lime” process. This process potentially produced significant quantities of calcium chromate as a by-product as well as the intended sodium dichromate. Process changes occurred during the 1940s and 1950s. The major change, according to the author, was the introduction of the “no-lime” process, which eliminated unwanted production of calcium chromate. The no-lime process was introduced at Eaglescliffe 1957-1959 and by 1961 all production at the plant was by this process. Rutherglen operated a low-lime process from 1957/1959 until it closed in 1967. Bolton never changed to the low lime process. The plant closed in 1966. Subjects were eligible for entry into the study if they had received an X-ray examination at work and had been employed for a minimum of one year between 1948 and 1977. Of the 3,898 workers enumerated at the three plants, 2,715 met the cohort entrance criteria, (alive: 1,999; deceased: 602; emigrated: 35; and lost to follow-up: 79). Those lost to follow-up were not included in the analyses. Eaglescliffe contributed the greatest number of subjects to the study (1,418). Rutherglen contributed the Start Printed Page 10122largest number of total deaths (369, or 61%). Lung cancer comprised the majority of cancer deaths and was statistically significantly elevated for the entire cohort (O=116; E=47.96; SMR= 240; p <0.001). Two deaths from nasal cancer were observed, both from Rutherglen.

SMRs were computed for Eaglescliffe by duration of employment, which was defined based upon plant process updates (those who only worked before the plant modification, those who worked both before and after the modifications, or those who worked only after the modifications were completed). Of the 179 deaths at the Eaglescliffe plant, 40 are in the pre-change group; 129 in the pre-/post-change and 10 in the post-change. A total of 36 lung cancer deaths occurred at the plant, in the pre-change group O=7; E=2.3; SMR=303; in the pre-/post-change group O=27; E=13; SMR=2.03 and in the post-change group O=2; E=1.07; SMR=187.

In an attempt to address several potential confounders, regression analysis examined the contributions of various risk factors to lung cancer. Duration of employment, duration of follow-up and working before or after plant modification appear to be greater risk factors for lung cancer, while age at entry or estimated degree of chromate exposure had less influence.

Davies updated the work of Alderson, et al. concerning lung cancer in the U.K. chromate producing industry (Ex. 7-99). The study cohort included payroll employees who worked a minimum of one year during the period January 1, 1950 and June 30, 1976 at any of the three facilities (Bolton, Eaglescliffe or Rutherglen). Contract employees were excluded unless they later joined the workforce, in which case their contract work was taken into account.

Based upon the date of hire, the workers were assigned to one of three groups. The first, or “early” group, consists of workers hired prior to January 1945 who are considered long term workers, but do not comprise a cohort since those who left or died prior to 1950 are excluded. The second group, “pre-change” workers, were hired between January 1, 1945 to December 31, 1958 at Rutherglen or to December 31, 1960 at Eaglescliffe. Bolton employees starting from 1945 are also termed pre-change. The cohort of pre-change workers is considered incomplete since those leaving 1946-1949 could not be included and because of gaps in the later records. For those who started after 1953 and for all men staying 5+ years, this subcohort of pre-change workers is considered complete. The third group, “post-change” workers, started after the process changes at Eaglescliffe and Rutherglen became fully effective and are considered a “complete” cohort. A “control” group of workers from a nearby fertilizer facility, who never worked in or near the chromate plant, was assembled.

A total of 2,607 employees met the cohort entrance criteria. As of December 31, 1988, 1,477 were alive, 997 dead, 54 emigrated and 79 could not be traced (total lost to follow-up: 133). SMRs were calculated using the mortality rates for England and Wales and the mortality rates for Scotland. Causes of death were ascertained for all but three decedents and deaths were coded to the revision of the International Classification of Diseases in effect at the time of death. Lung cancer in this study is defined as those deaths where the underlying cause of death is coded as 162 (carcinoma of the lung) or 239.1 (lung neoplasms of unspecified nature) in the 9th revision of the ICD. Two deaths fell into the latter category. The authors attempted to adjust the national mortality rates to allow for differences based upon area and social class.

There were 12 lung cancer deaths at Bolton, 117 at Rutherglen, 75 at Eaglescliffe and one among staff for a total of 205 lung cancer deaths. A statistically significant excess of lung cancer deaths (175 deaths) among early and pre-change workers is seen at Rutherglen and Eaglescliffe for both the adjusted and unadjusted SMRs. For Rutherglen, for the early period based upon 68 observed deaths, the adjusted SMR was 230 while the unadjusted SMR was 347 (for both SMRs p<0.001). For the 41 pre-change lung cancer deaths at Rutherglen, the adjusted SMR was 160 while the unadjusted SMR was 242 (for both SMRs p<0.001). At Eaglescliffe, there were 14 lung cancer deaths in the early period resulting in an adjusted SMR of 196 and an unadjusted SMR of 269 (for both SMRs p<0.05). For the pre-change period at Eaglescliffe, the adjusted SMR was 195 and the unadjusted was 267 (p<0.001 for both SMRs). At Bolton there is a non-significant excess among pre-change men. There are no apparent excesses in the post-change groups, the staff groups or in the non-exposed fertilizer group.

There is a highly significant overall excess of nasal cancers with two cases at Eaglescliffe and two cases at Rutherglen (O=4, Eadjusted=0.26; SMR=1538). All four men with nasal cancer had more than 20 years of exposure to chromates.

Aw reported on two case-control studies conducted at the previously studies Eaglescliffe plant (Ex. 245). In 1960, the plant, converted from a “high-lime” to a “no-lime” process, reducing the likelihood of calcium chromate formation. As of March 1996, 2,672 post-change workers had been employed, including 891 office personnel. Of the post-change plant personnel, 56% had been employed for more than one year. Eighteen lung cancer cases were identified among white male post-change workers (13 deceased; five alive). Duration of employment for the cases ranged from 1.5 to 25 years with a mean of 14.4. Sixteen of the lung cancer cases were smokers.

In the first case-control study reported, the 15 lung cancer cases identified up to September 1991 were matched to controls by age and hire date (five controls per case). Cases and controls were compared based upon their job categories within the plant. The results showed that cases were more likely to have worked in the kiln area than the controls. Five of the 15 cases had five or more years in the kiln area where Cr(VI) exposure occurred vs. six of the 75 controls. A second case-control study utilized the 18 lung cancer cases identified in post change workers up to March 1996. Five controls per case were matched by age (+/−5 years), gender and hire date. Both cases and controls had a minimum of one year of employment. A job exposure matrix was being constructed that would allow the investigators to “estimate exposure to hexavalent chromates for each worker in the study for all the jobs done since the start of employment at the site until 1980.” Starting in 1970 industrial hygiene sampling was performed to determine exposure for all jobs at the plant. Cr(VI) exposure levels for the period between 1960 and 1969 were being estimated based on the recall of employees regarding past working conditions relative to current conditions from a questionnaire. The author stated that preliminary analysis suggests that the maximum recorded or estimated level of exposure to Cr(VI) for the cases was higher than that of the controls. However, specific values for the estimated Cr(VI) exposures were not reported.

Korallus et al. conducted a study of 1,140 active and retired workers with a minimum of one year of employment between January 1, 1948 and March 31, 1979 at two German chromate production plants (Ex. 7-26). Workers employed prior to January 1, 1948 (either active or retired) and still alive at that date were also included in the cohort. The primary source for determining cause of death was medical Start Printed Page 10123records. Death certificates were used only when medical records could not be found. Expected deaths were calculated using the male population of North Rhineland-Westphalia. Elevated SMRs for cancer of the respiratory system (50 lung cancers and one laryngeal cancer) were seen at both plants (O=21; E=10.9; SMR=192 and O=30; E=13.4; SMR=224).

Korallus et al. reported an update of the study. The cohort definition was expanded to include workers with one year of employment between January 1, 1948 and December 31, 1987 (Ex. 7-91). One thousand four hundred and seventeen workers met the cohort entrance criteria and were followed through December 31, 1988. While death certificates were used, where possible, to obtain cause of death, a majority of the cause of death data was obtained from hospital, surgical and general practitioner reports and autopsies because of Germany's data protection laws. Smoking data for the cohort were incomplete.

Process modifications at the two plants eliminated the high-lime process by January 1, 1958 at one location and January 1, 1964 at the second location. In addition, technical measures were introduced which led to reductions in the workplace air concentrations of chromate dusts. Cohort members were divided into pre- and post-change cohorts, with subcohorts in the pre-change group. SMRs were computed with the expected number of deaths derived from the regional mortality rates (where the plants are located). One plant had 695 workers (279 in the pre-change group and 416 in the post change group). The second plant had 722 workers (460 in the pre-change group and 262 in the post-change group). A total of 489 deaths were ascertained (225 and 264 deaths). Of the cohort members, 6.4% were lost to follow-up.

Lung cancer is defined as deaths coded 162 in the 9th revision of the International Classification of Diseases. There were 32 lung cancer deaths at one plant and 43 lung cancer deaths at the second plant. Lung cancer SMRs by date of entry (which differ slightly by plant) show elevated but declining SMRs for each plant, possibly due to lower Cr(VI) exposure as a result of improvements in production process. The lung cancer SMR for those hired before 1948 at Plant 1 is statistically significant (O=13; SMR=225; 95% CI: 122-382). The overall lung cancer SMR for Plant 1 is also statistically significantly elevated based upon 32 deaths (SMR=175; 95% CI: 120-246). At Plant 2, the only lung cancer SMR that is not statistically significant is for those hired after 1963 (based upon 1 death). Lung cancer SMRs for those hired before 1948 (O=23; SMR=344; 95% CI: 224-508) and for those hired between 1948 and 1963 (O=19; SMR=196; 95% CI: 1.24-2.98) are statistically significantly elevated. The overall lung cancer SMR at Plant 2 based upon 43 deaths is 239 (95% CI: 177-317). No nasal cavity neoplasms were found. A statistically significant SMR for stomach cancer was observed at Plant 2 (O=12; SMR=192; 95% CI: 104-324).

Recently, the mortality experience of the post-change workers identified by Korallus et al. was updated in a study by Birk et al. (Ex. 48-4). The study cohort consisted of 901 post-change male workers from two German chromate production plants (i.e. 472 workers and 262 workers, respectively) employed for at least one year. Review of employment records led to the addition of employees to the previous Korallus cohort. Mortality experience of the cohort was evaluated through 1998. A total of 130 deaths were ascertained, of which 22 were due to cancer of the lung. Four percent of the cohort was lost to follow-up. Specific cause of death could not be determined for 14 decedents. The mean duration of Cr(VI) exposure was 10 years and the mean time since first exposure was 17 years. The proportion of workers who ever smoked was 65 percent.

The cohort lacked sufficient job history information and air monitoring data to develop an adequate job-exposure matrix required to estimate individual airborne exposures (Ex. 48-1-2). Instead, the researchers used the over 12,000 measurements of urinary chromium from routine biomonitoring of plant employees collected over the entire study period to derive individual cumulative urinary chromium estimates as an exposure surrogate. The approximate geometric average of all urinary chromium measurements in the two German plants from 1960 to 1998 was 7-8 μg/dl (Ex. 48-1-2, Table 5). There was a general plant-wide decline in average urinary chromium over time from 30 to 50 μg/dl in the 1960s to less than 5 μg/dl in the 1990s (Ex. 48-4, Figure 1). However, there was substantial variation in urinary chromium by work location and job group.

The study reported a statistically significant deficit in all cause mortality (SMR=80 95% CI: 67-95) and mortality due to heart disease (SMR=66 95% CI: 45-93) based on the age- and calendar year-adjusted German national population rates indicating a healthy worker population. However, the SMR for lung cancer mortality was elevated (SMR=148 95% CI: 93-225) against the same reference population (Ex. 48-4, Table 2). There was a statistically significant two-fold excess lung cancer mortality (SMR=209; 95% CI: 108-365; 12 observed lung cancer deaths) among workers in the highest cumulative exposure grouping (i.e. >200 μg Cr/L-yr). There was no increase in lung cancer mortality in the lower exposure groups, but the number of lung cancer deaths was small (i.e. ≤5 deaths) and the confidence intervals were wide.

There were no obvious trends in lung cancer mortality with employment duration or time since first employed, but the results were, again, limited by the small number of study subjects per group. Logistic regression analysis showed that cumulative urinary chromium ≥ 200 μg Cr/L-yr was associated with a significantly higher risk of lung cancer death (OR=6.9; 95% CI: 2.6-18.2) when compared against workers exposed to lower cumulative urinary chromium exposures. This risk was unchanged after controlling for smoking status indicating that the elevated risks were unlikely to be confounded by smoking. Including a peak exposure score to the regression analysis did not result in additional risk beyond that associated with cumulative exposure alone. Some commenters felt this German post-change cohort provided evidence for an exposure threshold below which there is no risk of lung cancer. This issue is addressed in Section VI.B.7 of the quantitative risk assessment.

DeMarco et al. conducted a cohort study of chromate production workers in northern Italy to assess the existence of excess risk of respiratory cancer, specifically lung cancer (Ex. 7-54). The cohort was defined as males who worked for a minimum of one year from 1948 to 1985 and had at least 10 years of follow-up. Five hundred forty workers met the cohort definition. Vital status follow-up, carried out through June 30, 1985, found 427 cohort members alive, 110 dead and three lost to follow-up. Analysis utilizing SMRs based on Italian national rates was conducted. Of the 110 deaths, 42 were cancer deaths. The statistically significant SMR for lung cancer based upon 14 observed deaths with 6.46 expected was 217 (95% CI: 118-363).

Exposure estimates were based upon the duration of cumulative exposure and upon a risk score (low, medium, high and not assessed) assigned to the department in which the worker was primarily employed. A committee assigned the scores, based upon knowledge of the production process or on industrial hygiene surveys taken in Start Printed Page 101241974, 1982 and 1984. The risk score is a surrogate for the workplace concentrations of Cr(VI) in the different plant departments. Since no substantial changes had been made since World War II, the assumption was made that exposures remained relatively stable. Lung cancer SMRs based upon type of exposure increased with level of exposure (Low: O=1; E=1.43; SMR=70; Medium: O=5; E=202; SMR=2.48; High: O=6; E=1.4; SMR=420; Not Assessed: O=2; E=1.6; SMR=126). Only the SMR for those classified as having worked in departments characterized as high exposure was statistically significant at the p<0.05 level.

A cohort study of workers at a chromium compounds manufacturing plant in Tokyo, Japan by Satoh et al. included males employed between 1918 and 1975 for a minimum of one year and for whom the necessary data were available (Ex. 7-27). Date and cause of death data were obtained from the death certificate (85%) or from other “reliable” written testimony (15%). Of the 1,061 workers identified, 165 were excluded from the study because information was missing. A total of 896 workers met the cohort inclusion criteria and were followed through 1978. The causes of 120 deaths were ascertained. SMRs based on age-cause specific mortality for Japanese males were calculated for four different time periods (1918-1949; 1950-1959; 1960-1969 and 1970-1978) and for the entire follow-up period (1918-1978). An elevated SMR for lung cancer is seen for the entire follow-up period (O=26; E=2.746; SMR=950). A majority of the lung cancer deaths (20) occurred during the 1970-1978 interval.

Results from the many studies of chromate production workers from different countries indicate a relationship between exposure to chromium and malignant respiratory disease. The epidemiologic studies done between 1948 and 1952 by Machle and Gregorius (Ex. 7-2), Mancuso and Hueper (Ex. 7-12) and Brinton, et al. (Ex. 7-1) suggest a risk for respiratory cancer among chromate workers between 15 and 29 times expectation. Despite the potential problems with the basis for the calculations of the expectations or the particular statistical methods employed, the magnitude of the difference between observed and expected is powerful enough to overcome these potential biases.

It is worth noting that the magnitude of difference in the relative risks reported in a mortality study among workers in three chromate plants in the U.K. (Ex.7-20) were lower than the relative risks reported for chromate workers in the U.S. during the 1950s and 1960s. The observed difference could be the result of a variety of factors including different working conditions in the two countries, a shorter follow-up period in the British study, the larger lost-to-follow-up in the British study or the different statistical methods employed. While the earlier studies established that there was an excess risk for respiratory cancer from exposure to chromium, they were unable to specify either a specific chromium compound responsible or an exposure level associated with the risk. Later studies were able to use superior methodologies to estimate standardized lung cancer mortality ratios between chromate production cohorts and appropriate reference populations (Exs. 7-14; 7-22; 7-26; 7-99; 7-91). These studies generally found statistically increased lung cancer risk of around two-fold. The studies usually found trends with duration of employment, year of hire, or some production process change that tended to implicate chromium exposure as the causative agent.

Some of the most recent studies were able to use industrial hygiene data to reconstruct historical Cr(VI) exposures and show statistically significant associations between cumulative airborne Cr(VI) and lung cancer mortality (Exs. 23; 31-22-11; Ex. 31-18-4). Gibb et al. found the significant association between Cr(VI) and lung cancer was evident in models that accounted for smoking. The exposure'response relationship from these chromate production cohorts provide strong evidence that occupational exposure to Cr(VI) dust can increase cancer in the respiratory tract of workers.

The Davies, Korallus, (German cohort), Luippold (2003), and Luippold (2005) studies examine mortality patterns at chromate producing facilities where one production process modification involved conversion from a high-lime to a low-lime or a lime-free process (Exs. 7-99; 7-91; 31-18-4). In addition to process modification, technical improvements also were implemented that lowered Cr(VI) exposure. One of the plants in the Davies study retained the high-lime process and is not discussed. The lung cancer SMRs for one British plant and both of the German plants decline from early, to pre-change to post change time periods. In the remaining British plants, the lung cancer SMR is basically identical for the early and pre-change period, but does decline in the post-change time period. The lung cancer SMR in the Luippold 2003 cohort also declined over time as the amount of lime was reduced in the roasting process. Other modifications at the Painesville plant that reduced airborne Cr(VI) exposure, such as installation of covered conveyors and conversion from batch to continuous process, occurred at the same time (Ex. 35-61). The workers in the Luippold (2005) study were not exposed to Cr(VI) in facilities using a high-lime process. This study did not show excess risk; however, this may be a consequence of short follow-up time (< 20 years for most workers) or the small size of the study (< 4 expected lung cancers), as discussed further in Section VI.B.7. In general, it is not clear whether reduced levels of the high-lime byproduct, calcium chromate, or the roasting/leaching end product, sodium dichromate, that resulted from the various process changes is the reason for the decrease in lung cancer SMRs in these cohorts. It should be noted that increased lung cancer risk was experienced by workers at the Baltimore plant (e.g., Hayes and Gibb cohorts) even though early air monitoring studies suggest that a high lime process was probably not used at this facility (Ex. 7-17).

2. Evidence From Chromate Pigment Production Workers

Chromium compounds are used in the manufacture of pigments to produce a wide range of vivid colors. Lead and zinc chromates have historically been the predominant hexavalent chromium pigments, although others such as strontium and barium chromate have also been produced. These chromates vary considerably in their water solubility with lead and barium chromates being the most water insoluble. All of the above chromates are less water-soluble than the highly water-soluble sodium chromate and dichromate that usually serve as the starting material for chromium pigment production. The reaction of sodium chromate or dichromate with the appropriate zinc or lead compound to form the corresponding lead or zinc chromate takes place in solution. The chromate pigment is then precipitated, separated, dried, milled, and packaged. Worker exposures to chromate pigments are greatest during the milling and packaging stages.

There have been a number of cohort studies of chromate pigment production workers from the United States, the United Kingdom, France, Germany, the Netherlands, Norway and Japan. Most of the studies found significantly elevated lung cancers in workers exposed to Cr(VI) pigments over many years when compared against standardized reference populations. In general, the Start Printed Page 10125studies of chromate pigment workers lack the historical exposure data found in some of the chromate production cohorts. The consistently higher lung cancers across several worker cohorts exposed to the less water-soluble Cr(VI) compounds complements the lung cancer findings from the studies of workers producing highly water soluble chromates and adds to the further evidence that occupational exposure to Cr(VI) compounds should be regarded as carcinogenic. A summary of selected human epidemiologic studies in chromate production workers is presented in Table V-2.

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Langard and Vigander updated a cohort study of lung cancer incidence in 133 workers employed by a chromium pigment production company in Norway (Ex. 7-36). The cohort was originally studied by Langard and Norseth (Ex. 7-33). Twenty four men had more than three years of exposure to chromate dust. From 1948, when the company was founded, until 1951, only lead chromate pigment was produced. Start Printed Page 10127From 1951 to 1956, both lead chromate and zinc chromate pigments were produced and from 1956 to the end of the study period in 1972 only zinc chromate was produced. Workers were exposed to chromates both as the pigment and its raw material, sodium dichromate.

The numbers of expected lung cancers in the workers were calculated using the age-adjusted incidence rates for lung cancer in the Norwegian male population for the period 1955-1976. Follow-up using the Norwegian Cancer Registry through December 1980, found the twelve cancers of which seven were lung cancers. Six of the seven lung cancers were observed in the subcohort of 24 workers who had been employed for more than three years before 1973. There was an increased lung cancer incidence in the subcohort based on an observed to expected ratio of 44 (O=6; E=0.135). Except for one case, all lung cancer cases were exposed to zinc chromates and only sporadically to other chromates. Five of the six cases were known to be smokers or ex-smokers. Although the authors did not report any formal statistical comparisons, the extremely high age-adjusted standardized incidence ratio suggests that the results would likely be statistically significant.

Davies reported on a cohort study of English chromate pigment workers at three factories that produced chromate pigments since the 1920s or earlier (Ex. 7-41). Two of the factories produced both zinc and lead chromate. Both products were made in the same sheds and all workers had mixed exposure to both substances. The only product at the third factory was lead chromate.

Cohort members are defined as males with a minimum of one year of employment first hired between 1933 and 1967 at plant A; 1948 and 1967 at plant B and 1946-1961 at plant C. The analysis excludes men who entered employment later than 1967 because of the short follow-up period. Three hundred and ninety six (396) men from Factory A, 136 men from Factory B and 114 men from Factory C were followed to mid-1977. Ninety-four workers with 3-11 months employment during 1932-1945 at Factory A were also included. Expectations were based upon calendar time period-, gender- and age-specific national cancer death rates for England and Wales. The author adjusted the death rates for each factory for local differences, but the exact methods of adjustment were not explicit.

Exposure to chromates was assigned as high for those in the dry departments where pigments were ground, blended and packed; medium for those in the wet departments where precipitates were washed, pressed and stove dried and in maintenance or cleaning which required time in various departments; or low for those jobs which the author states involved “slight exposure to chromates such as most laboratory jobs, boiler stoking, painting and bricklaying” (Ex. 7-41, p. 159). The high and medium exposure categories were combined for analytical purposes.

For those entering employment from 1932 to 1954 at Factory A, there were 18 lung cancer deaths in the high/medium exposure group, with 8.2 deaths expected. The difference is significant at p<.01. In the low exposure group, the number of observed and expected lung cancer deaths was equal (two deaths). There were no lung cancer deaths at Factory A for those hired between 1955-1960 and 1961-1967.

For those entering employment between 1948 and 1967 at Factory B, there were seven observed lung cancer deaths in the high/medium exposure group with 1.4 expected which is statistically significant at p<.001. At Factory C (which manufactured only lead chromate), there was one death in the high/medium exposure group and one death in the low exposure group for those beginning employment between 1946 and 1967.

The author points out that:

There has been no excess lung cancer mortality amongst workers with chromate exposure rated as “low”, nor among those exposed only to lead chromate. High and medium exposure-rated workers who in the past had mixed exposure to both lead and zinc chromate have experienced a marked excess of lung cancer deaths, even if employed for as little as one year (Ex. 7-41, p. 157).

It is the author's opinion that the results “suggest that the manufacture of zinc chromate may involve a lung cancer hazard” (Ex. 7-41, p. 157).

Davies updated the lung cancer mortality at the three British chromate pigment production factories (Ex. 7-42). The follow-up was through December 31, 1981. The cohort was expanded to include all male workers completing one year of service by June 30, 1975 but excluded office workers.

Among workers at Factory A with high and medium exposure, mortality was statistically significantly elevated over the total follow-up period among entrants hired from 1932 to 1945 (O/E=2.22). A similar, but not statistically significant, excess was seen among entrants hired from 1946 to 1954 (O/E=2.23). The results for Factory B showed statistically significantly elevated lung cancer mortality among workers classified with medium exposures entering service during the period from 1948 to 1960 (O/E=3.73) and from 1961 to 1967 (O/E=5.62). There were no lung cancer deaths in the high exposure group in either time period. At Factory C, analysis by entry date (early entrant and the period 1946-1960) produced no meaningful results since the number of deaths was small. When the two periods are combined, the O/E was near unity. The author concluded that in light of the apparent absence of risk at Factory C, “it seems reasonable to suggest that the hazard affecting workers with mixed exposures at factories A and B * * * is attributable to zinc chromates” (Ex. 7-42, p. 166). OSHA disagrees with this conclusion, as discussed in section V.9.

Davies also studied a subgroup of 57 chromate pigment workers, mostly employed between 1930 and 1945, who suffered clinical lead poisoning (Ex. 7-43). Followed through 1981, there was a statistically significantly elevated SMR for lung cancer based upon four cases (O=4; E=2.8; SMR=145).

Haguenoer studied 251 French zinc and lead chromate pigment workers employed for six months or more between January 1, 1958 and December 31, 1977 (Ex. 7-44). As of December 31, 1977, 50 subjects were identified as deceased. Cause of death was obtained for 30 of the 50 deaths (60%). Lung cancer mortality was significantly elevated based on 11 fatalities (SMR=461; 95% CI: 270-790). The mean time from first employment until detection of cancer was 17 years. The mean duration of employment among cases was 15 years.

The Haguenoer cohort was followed up in a study by Deschamps et al. (Ex. 234). Both lead and zinc chromate pigments were produced at the plant until zinc chromate production ceased in 1986. The cohort consisted of 294 male workers employed for at least six months between 1958 and 1987. At the end of the follow-up, 182 cohort members were alive, 16 were lost to follow-up and 96 were dead. Because of French confidentiality rules, the cause of death could not be obtained from the death certificate; instead physicians and hospital records were utilized. Using cause of death data from sources other than death certificates raises the potential for misclassification bias. Cause of death could not be obtained for five decedents. Data on smoking habits was not available for a number of workers and was not used in the analysis.

Since individual work histories were not available, the authors made the assumption that the exposure level was the same for all workers during their Start Printed Page 10128employment at the plant. Duration of employment was used as a surrogate for exposure. Industrial hygiene measurements taken in 1981 provide some idea of the exposure levels at the plant. In the filtration department, Cr(VI) levels were between 2 and 3 μg/m3; in the grinding department between 6 and 165 μg/m3; in the drying and sacking department between 6 and 178 μg/m3; and in the sacks marking department more than 2000 μg/m3.

The expected number of deaths for the SMR analysis was computed from age-adjusted death rates in the northern region of France where the plant was located. There was a significant increase in lung cancer deaths based on 18 fatalities with five expected (SMR=360; 95% CI: 213-568). Using duration of employment as a surrogate for exposure, statistically significant SMRs were seen for the 10-15 years of exposure (O=6, SMR=720, 95% CI: 264-1568), 15-20 years (O=4, SMR=481, 95% CI: 131-1231), and 20+ years (O=6, SMR=377, 95% CI: 1.38-8.21) time intervals. There was a significantly elevated SMR for brain cancer based upon two deaths (SMR=844, 95% CI: 102-3049). There was a non-statistically significant increase for digestive tract cancer (O=9, SMR=130) consisting of three esophageal cancers, two stomach cancers and four colon cancers.

Equitable Environmental Health, Inc., on behalf of the Dry Color Manufacturers Association, undertook a historical prospective mortality study of workers involved in the production of lead chromate (Exs. 2-D-3; 2-D-1). The cohort was defined as male employees who had been exposed to lead chromate for a minimum of six months prior to December 1974 at one of three facilities in West Virginia, Kentucky or New Jersey. The New Jersey facility had a unit where zinc chromate was produced dating back to 1947 (Ex. 2-D-3). Most workers rotated through this unit and were exposed to both lead and zinc chromates. Two men were identified at the New Jersey facility with exposure solely to lead chromate; no one with exposure only to zinc chromate was identified.

Subsequent review of the data found that the Kentucky plant also produced zinc chromates from the late 1930s to early 1964. During the period 1961-1962, zinc chromates accounted for approximately 12% of chromate production at the plant. In addition, strontium chromate and barium chromate also were produced at the plant.

The cohort consisted of 574 male employees from all three plants (Ex. 2-D-1). Eighty-five deaths were identified with follow up through December 1979. Six death certificates were not obtained. SMRs were reported based on U.S. white male death rates. There were 53 deaths from the New Jersey plant including a statistically significant SMR for cancer of the trachea, bronchus and lung based upon nine deaths (E=3.9; SMR=231; 95% CI: 106-438). One lung cancer decedent worked solely in the production of lead chromates. Three of the lung cancer deaths were black males. In addition, there were six deaths from digestive system cancers, five of which were stomach cancers reported at the New Jersey plant. The SMR for stomach cancer was statistically significantly elevated (O=5; E=0.63; SMR=792; 99% CI: 171-2243). There were 21 deaths from the West Virginia plant, three of which were cancer of the trachea, bronchus and lung (E=2.3; SMR=130; 95% CI: 27-381). There were 11 deaths at the Kentucky plant, two of which were cancer of the trachea, bronchus and lung (E=0.9; SMR=216; 95% CI: 26-780).

Sheffet et al. examined the lung cancer mortality among 1,946 male employees in a chromate pigment factory in Newark, NJ, who were exposed to both lead chromate and zinc chromate pigments (Ex. 7-48). The men worked for a minimum of one month between January 1, 1940 and December 31, 1969. As of March 31, 1979, a total of 321 cohort members were identified as deceased (211 white males and 110 non-white males). Cause of death could not be ascertained for 37 white males and 12 non-white males. The proportion of the cohort lost to follow up was high (15% of white males and 20% of non-white males).

Positions at the plant were classified into three categories according to intensity of exposure: high (continuous exposure to chemical dust), moderate (occasional exposure to chemical dust or to dry or wet pigments) and low (infrequent exposure by janitors or office workers). Positions were also classified by type of chemical exposure: chromates, other inorganic substances, and organics. The authors state that in almost all positions individuals “who were exposed to any chemicals were also exposed to hexavalent chromium in the form of airborne lead and zinc chromates (Ex. 7-48, p. 46).” The proportion of lead chromate to zinc chromate was approximately nine to one. Calculations, based upon air samples during later years, give an estimate for the study period of more than 2000 μg airborne chromium/m3 for the high exposure category, between 500 and 2000 μg airborne chromium/m3 and less than 100 μg airborne chromium/m3 for the low exposure category. Other suspected carcinogens present in the workplace air at much lower levels were nickel sulfate and nickel carbonate.

Because of the large proportion of workers lost to follow-up (15% of white males and 20% of non-white males) and the large numbers of unknown cause of death (21% of white males and 12% of non-white males), the authors calculated three separate mortality expectations based upon race-, gender-, age-, and time-specific U.S. mortality ratios. The first expectation was calculated upon the assumption that those lost to follow-up were alive at the end of the study follow-up period. The second expectation was calculated on the assumption that those whose vital status was unknown were lost to follow-up as of their employment termination date. The third expectation was calculated excluding those of unknown vital status from the cohort. Deaths with unknown cause were distributed in the appropriate proportions among known causes of death which served as an adjustment to the observed deaths. The adjusted deaths were used in all of the analyses.

A statistically significant ratio for lung cancer deaths among white males (O/E=1.6) was observed when using the assumption that either the lost to follow-up were assumed lost as of their termination date or were excluded from the cohort (assumptions two and three above). The ratio for lung cancer deaths for non-white males results in an identical O/E of 1.6 for all three of the above scenarios, none of which was statistically significant.

In addition, the authors also conducted Proportionate Mortality Ratio (PMR) and Proportionate Cancer Mortality Ratio (PCMR) analyses. For white males, the lung cancer PMR was 200 and the lung cancer PCMR was 160 based upon 25.5 adjusted observed deaths (21 actual deaths). Both were statistically significantly elevated at the p<.05 level. For non-white males, the lung cancer PMR was 200 and the lung cancer PCMR was 150 based upon 11.2 adjusted observed deaths (10 actual deaths). The lung cancer PMR for non-white males was statistically significantly elevated at the p<.05 level. Statistically significantly elevated PMRs and PCMRs for stomach cancer in white males were reported (PMR=280; PCMR=230) based upon 6.1 adjusted observed deaths (five actual).

The Sheffet cohort was updated in a study by Hayes et al. (Ex. 7-46). The follow up was through December 31, 1982. Workers employed as process operators or in other jobs which involved direct exposure to chromium Start Printed Page 10129dusts were classified as having exposure to chromates. Airborne chromium concentrations taken in “later years” were estimated to be >500 μg g/m3 for “exposed” jobs and >2000 μg/m3 for “highly exposed” jobs.

The cohort included 1,181 white and 698 non-white males. Of the 453 deaths identified by the end of the follow-up period, 41 were lung cancers. For the entire study group, no statistically significant excess was observed for lung cancer (SMR=116) or for cancer at any other site. Analysis by duration of employment found a statistically significant trend (p=.04) for lung cancer SMRs (67 for those employed <1 year; 122 for those employed 1-9 years and 151 for those employed 10+ years).

Analysis of lung cancer deaths by duration of employment in chromate dust associated jobs found no elevation in risk for subjects who never worked in these jobs (SMR=92) or for subjects employed less than one year in these jobs (SMR=93). For those with cumulative employment of 1-9 and 10+ years in jobs with chromate dust exposure, the SMRs were 176 (nine deaths) and 194 (eight deaths) respectively.

Frentzel-Beyme studied the mortality experience of 1,396 men employed for more than six months in one of five factories producing lead and zinc chromate pigments located in Germany and the Netherlands (Ex. 7-45). The observed deaths from the five factories were compared with the expected deaths calculated on the basis of mortality figures for the region in which the plant was located. Additional analysis was conducted on relevant cohorts which included workers with a minimum of 10 years exposure, complete records for the entire staff, and exclusion of foreign nationals. Jobs were assigned into one of three exposure categories: High (drying and milling of the filtered pigment paste), medium (wet processes including precipitation of the pigment, filtering and maintenance, craftsmen and cleaning) and low or trivial exposure (storage, dispatch, laboratory personnel and supervisors).

There were 117 deaths in the entire cohort of which 19 were lung cancer deaths (E=9.3). The lung cancer SMRs in the relevant cohort analyses were elevated at every plant; however, in only one instance was the increased lung cancer SMR statistically significant, based upon three deaths (SMR=386, p<0.05). Analysis by type of exposure is not meaningful due to the small number of lung cancer deaths per plant per exposure classification.

Kano et al. conducted a study of five Japanese manufacturers who produced lead chromates, zinc chromate, and/or strontium chromate to assess if there was an excess risk of lung cancer (Ex. 7-118). The cohort consisted of 666 workers employed for a minimum of one year between 1950 and 1975. At the end of 1989, 604 subjects were alive, five lost to follow-up and 57 dead. Three lung cancer deaths were observed in the cohort with 2.95 expected (SMR=102; 95% CI: 0.21-2.98). Eight stomach cancer deaths were reported with a non-statistically significant SMR of 120.

Following the publication of the proposed rule, the Color Pigment Manufacturers Association requested that OSHA reconsider its preliminary conclusions with respect to the health effects of lead chromate color pigments (Ex. 38-205). They relied on the Davies (Ex. 7-43), Cooper [Equitable Environmental Health, Inc] (Ex. 2-D-1) and Kano (Ex. 14-1-B) epidemiologic studies as the only available data on worker cohorts exposed to lead chromate in the absence of other chromates commonly found in pigment production (e.g., zinc chromate). The CPMA's comments regarding the Davies, Cooper and Kano studies and OSHA's response to them are discussed in section V.B.9.a.

3. Evidence from Workers in Chromium Plating

Chrome plating is the process of depositing chromium metal onto the surface of an item using a solution of chromic acid. The items to be plated are suspended in a diluted chromic acid bath. A fine chromic acid mist is produced when gaseous bubbles, released by the dissociation of water, rise to the surface of the plating bath and burst. There are two types of chromium electroplating. Decorative or “bright” involves depositing a thin (0.5-1 μm) layer of chromium over nickel or nickel-type coatings to provide protective, durable, non-tarnishable surface finishes. Decorative chrome plating is used for automobile and bicycle parts. Hard chromium plating produces a thicker (exceeding 5 μm) coating which makes it resistant and solid where friction is usually greater, such as in crusher propellers and in camshafts for ship engines. Limited air monitoring indicates that Cr(VI) levels are five to ten times higher during hard plating than decorative plating (Ex. 35-116).

There are fewer studies that have examined the lung cancer mortality of chrome platers than of soluble chromate production and chromate pigment production workers. The largest and best described cohort studies investigated chrome plating cohorts in the United Kingdom (Exs. 7-49; 7-57; 271; 35-62). They generally found elevated lung cancer mortality among the chrome platers, especially those engaged in chrome bath work, when compared to various reference populations. The studies of British chrome platers are summarized in Table V-3.

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Cohort studies of chrome platers in Italy, the United States, and Japan are also discussed in this subsection. Co-exposure to nickel, another suspected carcinogen, during plating operations can complicate evaluation of an association between Cr(VI) and an increased risk of lung cancer in chrome platers. Despite this, the International Agency for Research on Cancer concluded that the epidemiological Start Printed Page 10131studies provide sufficient evidence for carcinogenicity of Cr(VI) as encountered in the chromium plating industry; the same conclusion reached for chromate production and chromate pigment production (Exs. 18-1; 35-43). The findings implicate the highly water-soluble chromic acid as an occupational carcinogen. This adds to the weight of evidence that water-soluble (e.g., sodium chromates, chromic acid) and water-insoluble forms (e.g., lead and zinc chromates) of Cr(VI) are able to cause cancer of the lower respiratory tract.

Royle reported on a cohort mortality study of 1,238 chromium platers employed for a minimum of three consecutive months between February 20, 1969 and May 31, 1972 in 54 plating plants in West Riding, Yorkshire, England (Ex. 7-49). A control population was enumerated from other departments of the larger companies where chromium plating was only a portion of the companies' activities and from the former and current employees of two industrial companies in York where information on past workers was available. Controls were matched for gender, age (within two years) and date last known alive. In addition, 229 current workers were matched for smoking habits.

As of May 1974, there were 142 deaths among the platers (130 males and 12 females) and 104 deaths among the controls (96 males and 8 females). Among the male platers, there were 24 deaths from cancer of the lung and pleura compared to 13 deaths in the control group. The difference was not statistically significant. There were eight deaths from gastrointestinal cancer among male platers versus four deaths in the control group. The finding was not statistically significant.

The Royle cohort was updated by Sorahan and Harrington (Ex. 35-62). Chrome plating was the primary activity at all 54 plants, however 49 of the plants used nickel and 18 used cadmium. Also used, but in smaller quantities according to the authors, were zinc, tin, copper, silver, gold, brass or rhodium. Lead was not used at any of the plants. Four plants, including one of the largest, only used chromium. Thirty-six chrome platers reported asbestos exposure versus 93 comparison workers.

Industrial hygiene surveys were carried out at 42 plants during 1969-1970. Area air samples were done at breathing zone height. With the exception of two plants, the chromic acid air levels were less than 30 μg/m3. The two exceptions were large plants, and in both the chromic acid levels exceeded 100 μg/m3.

The redefined cohort consisted of 1087 platers (920 men and 167 women) from 54 plants employed for a minimum of three months between February 1969 and May 31, 1972 who were alive on May 31, 1972. Mortality data were also available for a comparison group of 1,163 workers (989 men and 174 women) with no chromium exposure. Both groups were followed for vital status through 1997.

The lung cancer SMR for male platers was statistically significant (O=60; E=32.5; SMR=185; 95% CI: 141-238). The lung cancer SMR for the comparison group, while elevated, was not statistically significant (O=47; E=36.9; SMR=127; 95% CI: 94-169). The only statistically significant SMR in the comparison group was for cancer of the pleura (O=7; E=0.57; SMR=1235; 95% CI: 497-2545).

Internal regression analyses were conducted comparing the mortality rates of platers directly with those of the comparison workers. For these analyses, lung cancers mentioned anywhere on the death certificate were considered cases. The redefinition resulted in four additional lung cancer cases in the internal analyses. There was a statistically significant relative risk of 1.44 (p<0.05) for lung cancer mortality among chrome platers that was slightly reduced to 1.39 after adjustment for smoking habits and employment status. There was no clear trend between lung cancer mortality and duration of Cr(VI) exposure. However, any positive trend may have been obscured by the lack of information on worker employment post-1972 and the large variation in chromic acid levels among the different plants.

Sorahan reported the experience of a cohort of 2,689 nickel/chromium platers from the Midlands, U.K. employed for a minimum of six months between 1946 and 1975 and followed through December 1983 (Ex. 7-57). There was a statistically significant lung cancer SMR for males (O=63; E=40; SMR=158; p<0.001). The lung cancer SMR for women, while elevated (O=9; E=8.1; SMR=111), was not statistically significant. Other statistically significant cancer SMRs for males included: stomach (O=21; E=11.3; SMR=186; p<0.05); liver (O=4; E=0.6; SMR=667; p<0.01); and nasal cavities (O=2; E=0.2; SMR=1000; p<0.05). While there were several elevated SMRs for women, none were statistically significant. There were nine lung cancers and one nasal cancer among the women.

Analysis by type of first employment (i.e., chrome bath workers vs. other chrome work) resulted in a statistically significant SMR for lung cancer of 199 (O=46; E=23.1; p<0.001) for chrome bath workers and a SMR of 101 for other chrome work. The SMR for cancer of the stomach for male chrome bath workers was also statistically significantly elevated (O=13; E=6.3; SMR=206; p<0.05); for stomach cancer in males doing other chrome work, the SMR was 160 with 8 observed and 5 expected. Both of the nasal cancers in males and the one nasal cancer in women were chrome bath workers. The nasal cancer SMR for males was statistically significantly elevated (O=2; E=0.1; SMR=2000; p<0.05).

Regression analysis was used to examine evidence of association of several types of cancers and Cr(VI) exposure duration among the cohort. There was a significant positive association between lung cancer mortality and exposure duration as a chrome bath worker controlling for gender as well as year and age at the start of employment. There was no evidence of an association between other cancer types and duration of Cr(VI) exposure. There was no positive association between duration of exposure to nickel bath work and cancer of the lung. The two largest reported SMRs were for chrome bath workers 10-14 years (O=13; E=3.8; SMR=342; p<0.001) and 15-19 years (O=12; E=4.9; SMR=245; p<0.01) after starting employment. The positive associations between lung cancer mortality and duration of chrome bath work suggests Cr(VI) exposure may be responsible for the excess cancer risk.

Sorahan et al. reported the results of a follow-up to the nickel/chromium platers study discussed above (Ex. 271). The cohort was redefined and excluded employees whose personnel records could not be located (650); those who started chrome work prior to 1946 (31) and those having no chrome exposure (236). The vital status experience of 1,762 workers (812 men and 950 women) was followed through 1995. The expected number of deaths was based upon the mortality of the general population of England and Wales.

There were 421 deaths among the men and 269 deaths among the women, including 52 lung cancers among the men and 17 among the women. SMRs were calculated for different categories of chrome work: Period from first chrome work; year of starting chrome work, and cumulative duration of chrome work categories. Poison regression modeling was employed to investigate lung cancer in relation to type of chrome work and cumulative duration of work.

A significantly elevated lung cancer SMR was seen for male workers with Start Printed Page 10132some period of chrome bath work (O=40; E=25.4; SMR=157; 95% CI: 113-214, p<0.01). Lung cancer was not elevated among male workers engaged in other chrome work away from the chromic acid bath (O=9; E=13.7; SMR=66; 95% CI: 30-125). Similar lung cancer mortality results were found for female chrome bath workers (O=15; E=8.6; SMR=175; 95% CI: 98-285; p<0.06). After adjusting for sex, age, calendar year, year starting chrome work, period from first chrome work, and employment status, regression modeling showed a statistically significant positive trend (p<0.05) between duration of chrome bath work and lung cancer mortality risk. The relative lung cancer risk for chrome bath workers with more than five years of Cr(VI) exposure (i.e., relative to the risk of those without any chrome bath work) was 4.25 (95% CI: 1.83-9.37).

Since the Sorahan cohort consists of nickel/chromium workers, the question arises of the potential confounding of nickel. In the earlier study, 144 of the 564 employees with some period of chrome bath work had either separate or simultaneous periods of nickel bath employment. According to the authors, there was no clear association between cancer deaths from stomach, liver, respiratory system, nose and larynx, and lung and bronchus and the duration of nickel bath employment. In the follow-up report, the authors re-iterate this result stating, “findings for lung cancer in a cohort of nickel platers (without any exposure to chrome plating) from the same factory are unexceptional” (Ex. 35-271, p. 241).

Silverstein et al. reported the results of a cohort study of hourly employees and retirees with at least 10 years of credited pension service in a Midwestern plant manufacturing hardware and trim components for use primarily in the automobile industry (Ex. 7-55). Two hundred thirty eight deaths occurred between January 1, 1974 and December 31, 1978. Proportional Mortality Ratio (PMR) analysis adjusted for race, gender, age and year of death was conducted. For white males, the PMR for cancer of the lung and pleura was 1.91 (p<0.001) based upon 28 deaths. For white females, the PMR for cancer of the lung and pleura was 3.70 (p<0.001) based upon 10 deaths.

White males who worked at the plant for less than 15 years had a lung cancer PMR of 1.65. Those with 15 or more years at the plant had a lung cancer PMR of 2.09 (p<0.001). For white males with less than 22.5 years between hire and death (latency) the lung cancer PMR was 1.78 (p<0.05) and for those with 22.5 or more years, the PMR was 2.11 (p<0.01).

A case-control analysis was conducted on the Silverstein cohort to examine the association of lung cancer risk with work experience. Controls were drawn from cardiovascular disease deaths (ICD 390-458, 8th revision). The 38 lung cancer deaths were matched to controls for race and gender. Odds ratios (ORs) were calculated by department depending upon the amount of time spent in the department (ever/never; more vs. less than one year; and more vs. less than five years). Three departments showed increasing odds ratios with duration of work; however, the only statistically significant result was for those who worked more than five years in department 5 (OR=9.17, p=0.04, Fisher's exact test). Department 5 was one of the major die-casting and plating areas of the plant prior to 1971.

Franchini et al. conducted a mortality study of employees and retirees from nine chrome plating plants in Parma, Italy (Ex. 7-56). Three plants produced hard chrome plating. The remaining six plants produced decorative chromium plates. A limited number of airborne chromium measurements were available. Out of a total of 10 measurements at the hard chrome plating plants, the air concentrations of chromium averaged 7 μg/m3 (range of 1-50 μg/m3) as chromic acid near the baths and 3 μg/m3 (range of 0-12 μg/m3) in the middle of the room.

The cohort consisted of 178 males (116 from the hard chromium plating plants and 62 from the bright chromium plating plants) who had worked for at least one year between January 1, 1951 and December 31, 1981. In order to allow for a 10-year latency period, only those employed before January 1972 were included in further analysis. There were three observed lung cancer deaths among workers in the hard chrome plating plants, which was significantly greater than expected (O=3; E=0.6; p<0.05). There were no lung cancer deaths among decorative chrome platers.

Okubo and Tsuchiya conducted a study of plating firms with five or more employees in Tokyo (Exs. 7-51; 7-52). Five hundred and eighty nine firms were sent questionnaires to ascertain information regarding chromium plating experience. The response rate was 70.5%. Five thousand one hundred seventy platers (3,395 males and 1,775 females) met the cohort entrance criteria and were followed from April 1, 1970 to September 30, 1976. There were 186 deaths among the cohort; 230 people were lost to follow-up after retirement. The cohort was divided into two groups: Chromium platers who worked six months or more and a control group with no exposure to chromium (clerical, unskilled workers). There were no deaths from lung cancer among the chromium platers.

The Okubo cohort was updated by Takahashi and Okubo (Ex. 265). The cohort was redefined to consist of 1,193 male platers employed for a minimum of six months between April 1970 and September 1976 in one of 415 Tokyo chrome plating plants and who were alive and over 35 years of age on September 30, 1976. The only statistically significant SMR was for lung cancer for all platers combined (O=16; E=8.9; SMR=179; 95% CI: 102-290). The lung cancer SMR for the chromium plater subcohort was 187 based upon eight deaths and 172 for the nonchromium plater subcohort, also based upon eight deaths. The cohort was followed through 1987. Itoh et al. updated the Okubo metal plating cohort through December 1992 (Ex. 35-163). They reported a lung cancer SMR of 118 (95% CI: 99-304).

4. Evidence From Stainless Steel Welders

Welding is a term used to describe the process for joining any materials by fusion. The fumes and gases associated with the welding process can cause a wide range of respiratory exposures which may lead to an increased risk of lung cancer. The major classes of metals most often welded include mild steel, stainless and high alloy steels and aluminum. The fumes from stainless steel, unlike fumes from mild steel, contain nickel and Cr(VI). There are several cohort and case-control studies as well as two meta analyses of welders potentially exposed to Cr(VI). In general, the studies found an excess number of lung cancer deaths among stainless steel welders. However, few of the studies found clear trends with Cr(VI) exposure duration or cumulative Cr(VI). In most studies, the reported excess lung cancer mortality among stainless steel welders was no greater than mild steel welders, even though Cr(VI) exposure is much greater during stainless steel welding. This weak association between lung cancer and indices of exposure limits the evidence provided by these studies. Other limitations include the co-exposures to other potential lung carcinogens, such as nickel, asbestos, and cigarette smoke, as well as possible healthy worker effects and exposure misclassification in some studies, which may obscure a relationship betweeen Cr(VI) and lung cancer risk. These limitations are discussed further in sections VI.B.5, VI.E.3, and VI.G.4. Start Printed Page 10133Nevertheless, these studies add some further support to the much stronger link between Cr(VI) and lung cancer found in soluble chromate production workers, chromate pigment production workers, and chrome platers. The key studies are summarized in Table V-4.

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Sjogren et al. reported on the mortality experience in two cohorts of welders (Ex. 7-95). The cohort characterized as “high exposure” Start Printed Page 10136consisted of 234 male stainless steel welders with a minimum of 5 years of employment between 1950 and 1965. An additional criterion for inclusion in the study was assurance from the employer that asbestos had not been used or had been used only occasionally and never in a dust-generating way. The cohort characterized as “low exposure” consisted of 208 male railway track welders working at the Swedish State Railways for at least 5 years between 1950 and 1965. In 1975, air pollution in stainless steel welding was surveyed in Sweden. The median time weighted average (TWA) value for Cr(VI) was 110 μg CrO3/m3 (57 μg/m3 measured as CrVI). The highest concentration was 750 μg CrO3/m3 (390 μg/m3 measured as CrVI) found in welding involving coated electrodes. For gas-shielded welding, the median Cr(VI) concentration was 10 μg CrO3/m3 (5.2 μg/m3 measured as CrVI) with the highest concentration measured at 440 μg CrO3/m3 (229 μg/m3 measured as CrVI). Follow-up for both cohorts was through December 1984. The expected number of deaths was based upon Swedish male death rates. Of the 32 deaths in the “high exposure” group, five were cancers of the trachea, bronchus and lung (E=2.0; SMR=249; 95% CI: 0.80-5.81). In the low exposure group, 47 deaths occurred, one from cancer of the trachea, bronchus and lung.

Polednak compiled a cohort of 1,340 white male welders who worked at the Oak Ridge nuclear facilities from 1943 to 1977 (Ex. 277). One thousand fifty-nine cohort members were followed through 1974. The cohort was divided into two groups. The first group included 536 welders at a facility where nickel-alloy pipes were welded; the second group included 523 welders of mild steel, stainless steel and aluminum materials. Smoking data were available for 33.6% of the total cohort. Expectations were calculated based upon U.S. mortality rates for white males. There were 17 lung cancer deaths in the total cohort (E=11.37; SMR=150; 95% CI: 87-240). Seven of the lung cancer deaths occurred in the group which routinely welded nickel-alloy materials (E=5.65; SMR=124; 95% CI: 50-255) versus 10 lung cancer deaths in the “other” welders (E=6.12; SMR=163; 95% CI: 78-300).

Becker et al. compiled a cohort of 1,213 stainless steel welders and 1,688 turners from 25 German metal processing factories who had a minimum of 6 months employment during the period 1950-1970 (Exs. 227; 250; 251). The data collected included the primary type of welding (e.g., arc welding, gas-shielded welding, etc.) used by each person, working conditions, average daily welding time and smoking status. The most recent follow-up of the cohort was through 1995. Expected numbers were developed using German mortality data. There were 268 deaths among the welders and 446 deaths among the turners. An elevated, but non-statistically significant, lung cancer SMR (O=28; E=23; SMR=121.5; 95% CI: 80.7-175.6) was observed among the welders. There were 38 lung cancer deaths among the turners with 38.6 expected, resulting in a SMR slightly below unity. Seven deaths from cancer of the pleura (all mesotheliomas) occurred among the welders with only 0.6 expected (SMR=1,179.9; 95% CI: 473.1-2,430.5), compared to only one death from cancer of the pleura among the turners, suggesting that the welders had exposure to asbestos. Epidemiological studies have shown that asbestos exposure is a primary cause of pleural mesotheliomas.

The International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) cosponsored a study on welders. IARC and WHO compiled a cohort of 11,092 male welders from 135 companies in nine European countries to investigate the relationship between the different types of exposure occurring in stainless steel, mild steel and shipyard welding and various cancer sites, especially lung cancer (Ex. 7-114). Cohort entrance criteria varied by country. The expected number of deaths was compiled using national mortality rates from the WHO mortality data bank.

Results indicated the lung cancer deaths were statistically significant in the total cohort (116 cases; E=86.81; SMR=134; 95% CI: 110-160). Cohort members were assigned to one of four subcohorts based upon type of welding activity. While the lung cancer SMRs were elevated for all of the subcohorts, the only statistically significant SMR was for the mild steel-only welders (O=40; E=22.42; SMR=178; 95% CI: 127-243). Results for the other subgroups were: shipyard welders (O=36; E=28.62; SMR=126; 95% CI: 88-174); ever stainless steel welders (O=39; E=30.52; SMR=128; 95% CI: 91-175); and predominantly stainless steel welders (O=20; E=16.25; SMR=123; 95% CI: 75-190). When analyzed by subcohort and time since first exposure, the SMRs increased over time for every group except shipyard welders. For the predominantly stainless steel welder subcohort, the trend to increase with time was statistically significant (p <.05).

An analysis was conducted of lung cancer mortality in two stainless steel welder subgroups (predominantly and ever) with a minimum of 5 years of employment. Cumulative Cr(VI) was computed from start of exposure until 20 years prior to death. A lung cancer SMR of 170, based upon 14 cases, was observed in the stainless steel ever subgroup for those welders with ≥0.5 mg-years/m3 Cr(VI) exposure; the lung cancer SMR for those in the <0.5 mg-years/m3 Cr(VI) exposure group was 123 (based upon seven cases). Neither SMR was statistically significant. For the predominantly stainless steel welders, which is a subset of the stainless steel ever subgroup, the corresponding SMRs were 167 (≥0.5 mg-years/m3 Cr(VI) exposure) based upon nine cases and 191 (<0.5 mg-years/m3 Cr(VI) exposure) based upon three cases. Neither SMR was statistically significant.

In conjunction with the IARC/WHO welders study, Gerin et al. reported the development of a welding process exposure matrix relating 13 combinations of welding processes and base metals used to average exposure levels for total welding fumes, total chromium, Cr(VI) and nickel (Ex. 7-120). Quantitative estimates were derived from the literature supplemented by limited monitoring data taken in the 1970s from only 8 of the 135 companies in the IARC/WHO mortality study. An exposure history was constructed which included hire and termination dates, the base metal welded (stainless steel or mild steel), the welding process used and changes in exposure over time. When a detailed welding history was not available for an individual, the average company welding practice profile was used. In addition, descriptions of activities, work force, welding processes and parameters, base metals welded, types of electrodes or rods, types of confinement and presence of local exhaust ventilation were obtained from the companies.

Cumulative dose estimates in mg/m3 years were generated for each welder's profile (number of years and proportion of time in each welding situation) by applying a welding process exposure matrix associating average concentrations of welding fumes (mg/m3) to each welding situation. The corresponding exposure level was multiplied by length of employment and summed over the various employment periods involving different welding situations. No dose response relationship was seen for exposure to Cr(VI) for either those who were “ever stainless steel welders” or those who were “predominantly stainless steel Start Printed Page 10137welders”. The authors note that if their exposure estimates are correct, the study had the power to detect a significant result in the high exposure group for Cr(VI). However, OSHA believes that there is likely to be substantial exposure misclassification in this study, as discussed further in section VI.G.4.

The IARC/WHO multicenter study is the sole attempt to undertake even a semi-quantified exposure analysis of stainless steel welders' potential exposure to nickel and Cr(VI) for <5 and ≥0.5 mg-years/m3 Cr(VI) exposures. The IARC/WHO investigators noted that there was more than a twofold increase in SMRs between the long (≥20 years since first exposure) and short (<20 years since first exposure) observation groups for the predominantly stainless steel welders “suggesting a relation of lung cancer mortality with the occupational environment for this group” (Ex. 7-114, p. 152). The authors conclude that the increase in lung cancer mortality does not appear to be related to either duration of exposure or cumulative exposure to total fume, chromium, Cr(VI) or nickel.

Moulin compiled a cohort of 2,721 French male welders and an internal comparison group of 6,683 manual workers employed in 13 factories (including three shipyards) with a minimum of one year of employment from 1975 to 1988 (Ex. 7-92). Three controls were selected at random for each welder. Smoking data were abstracted from medical records for 86.6% of welders and 86.5% of the controls. Smoking data were incorporated in the lung cancer mortality analysis using methods suggested by Axelson. Two hundred and three deaths were observed in the welders and 527 in the comparison group. A non-statistically significant increase was observed in the lung cancer SMR (O=19; E=15.33; SMR=124; 95% CI: 0.75-1.94) for the welders. In the control group, the lung cancer SMR was in deficit (O=44; E=46.72; SMR=94; 95% CI: 0.68-1.26). The resulting relative risk was a non-significant 1.3. There were three deaths from pleural cancer in the comparison group and none in the welders, suggesting asbestos exposure in the comparison group. The welders were divided into four subgroups (shipyard welders, mild steel only welders, ever stainless steel welders and stainless steel predominantly Cr(VI) welders). The highest lung cancer SMR was for the mild steel welders O=9; SMR of 159). The lowest lung cancer SMRs were for ever stainless steel welders (O=3; SMR= 92) and for stainless steel predominantly Cr(VI) welders (O=2; SMR= 103). None of the SMRs are statistically significant.

Hansen conducted a study of cancer incidence among 10,059 male welders, stainless steel grinders and other metal workers from 79 Danish companies (Ex. 9-129). Cohort entrance criteria included: alive on April 1, 1968; born before January 1, 1965; and employed for at least 12 months between April 1, 1964 and December 31, 1984. Vital status follow-up found 9,114 subjects alive, 812 dead and 133 emigrated. A questionnaire was sent to subjects and proxies for decedents/emigrants in an attempt to obtain information about lifetime occupational exposure, smoking and drinking habits. The overall response rate was 83%. The authors stated that no major differences in smoking habits were found between exposure groups with or without a significant excess of lung cancer.

The expected number of cancers was based on age-adjusted national cancer incidence rates from the Danish Cancer Registry. There were statistically significantly elevated Standardized Incidence Ratios (SIRs) for lung cancer in the welding (any kind) group (O=51; E=36.84; SIR=138; 95% CI: 103-181) and in the mild steel only welders (O=28; E=17.42; SIR=161; 95% CI: 107-233). The lung cancer SIR for mild steel ever welders was 132 (O=46; E=34.75; 95% CI: 97-176); for stainless steel ever welders 119 (O=23; E=19.39; 95% CI: 75-179) and for stainless steel only welders 238 (O=5; E=2.10; 95% CI: 77-555).

Laurtitsen reported the results of a nested case-control conducted in conjunction with the Hansen cancer incidence study discussed above (Exs. 35-291; 9-129). Cases were defined as the 94 lung cancer deaths. Controls were defined as anyone who was not a case, but excluded deaths from respiratory diseases other than lung cancer (either as an underlying or a contributing cause of death), deaths from “unknown malignancies” and decedents who were younger than the youngest case. There were 439 decedents eligible for use as controls.

The crude odds ratio (OR) for welding ever (yes/no) was 1.7 (95% CI: 1.0-2.8). The crude OR for mild steel welding only was 1.3 (95% CI: 0.8-2.3) and for stainless steel welding only the crude OR was 1.3 (95% CI: 0.3-4.3). When analyzed by number of years exposed, “ever” stainless steel welding showed no relationship with increasing number of years exposed. The highest odds ratio (2.9) was in the lowest category (1-5 years) based upon seven deaths; the lowest odds ratio was in the highest category (21+ years) based upon three deaths.

Kjuus et al. conducted a hospital-based case-control study of 176 male incident lung cancer cases and 186 controls (matched for age, +/−5 years) admitted to two county hospitals in southeast Norway during 1979-1983 (Ex. 7-72). Subjects were classified according to exposure status of main occupation and number of years in each exposure category and assigned into one of three exposure groups according to potential exposure to respiratory carcinogens and other contaminants. A statistically significantly elevated risk ratio for lung cancer (adjusted for smoking) for the exposure factor “welding, stainless, acid proof” of 3.3 (p<0.05) was observed based upon 16 lung cancer deaths. The unadjusted odds ratio is not statistically significant (OR=2.8). However, the appropriateness of the analysis is questionable since the exposure factors are not discrete (a case or a control may appear in multiple exposure factors and therefore is being compared to himself). In addition, the authors note that several exposure factors were highly correlated and point out specifically that one-half of the cases “exposed to either stainless steel welding fumes or fertilizers also reported moderate to heavy asbestos exposure.” When put into a stepwise logistic regression model, exposure to stainless steel fumes, which was initially statistically significant, loses its significance when smoking and asbestos are first entered into the model.

Hull et al. conducted a case-control study of lung cancer in white male welders aged 20-65 identified through the Los Angeles County tumor registry (Southern California Cancer Surveillance Program) for the period 1972 to 1987 (Ex. 35-243). Controls were welders 40 years of age or older with non-pulmonary malignancies. Interviews were conducted to obtain information about sociodemographic data, smoking history, employment history and occupational exposures to specific welding processes, metals welded, asbestos and confined space welding. Interviews were completed for 90 (70%) of the 128 lung cancer cases and 116 (66%) of the controls. Analysis was conducted using 85 deceased cases and 74 deceased controls after determining that the subject's vital status influenced responses to questions concerning occupational exposures. The crude odds ratio (ever vs. never exposed) for stainless steel welding, based upon 34 cases, was 0.9 (95% CI: 0.3-1.4). For manual metal arc welding on stainless steel, the crude odds ratio Start Printed Page 10138was 1.3 (95% CI: 0.6-2.3) based upon 61 cases.

While the relative risk estimates in both cohort and case-control of stainless steel welders are elevated, none are statistically significant. However, when combined in two meta-analyses, a small but statistically significant increase in lung cancer risk was reported. Two meta-analyses of welders have been published. Moulin carried out a meta-analysis of epidemiologic studies of lung cancer risk among welders, taking into account the role of asbestos and smoking (Ex. 35-285). Studies published between 1954 and 1994 were reviewed. The inclusion criteria were clearly defined: only the most recent updates of cohort studies were used and only the mortality data from mortality/morbidity studies were included. Studies that did not provide the information required by the meta-analysis were excluded.

Five welding categories were defined (shipyard welding, non-shipyard welding, mild steel welding, stainless steel welding and all or unspecified welding). The studies were assigned to a welding category (or categories) based upon the descriptions provided in the paper's study design section. The combined relative risks (odds ratios, standardized mortality ratios, proportionate mortality ratios and standardized incidence ratios) were calculated separately for the population-based studies, case-control studies, and cohort studies, and for all the studies combined.

Three case-control studies (Exs. 35-243; 7-120; 7-72) and two cohort studies (Exs. 7-114; 35-277) were included in the stainless steel welding portion of the meta-analysis. The combined relative risk was 2.00 (O=87; 95% CI: 1.22-3.28) for the case-control studies and 1.23 (O=27; 95% CI: 0.82-1.85) for the cohort studies. When all five studies were combined, the relative risk was 1.50 (O=114; 95% CI: 1.10-2.05).

By contrast, the combined risk ratio for the case-control studies of mild steel welders was 1.56 (O=58; 95% CI: 0.82-2.99) (Exs. 7-120; 35-243). For the cohort studies, the risk ratio was 1.49 (O=79; 95% CI: 1.15-1.93) (Exs. 35-270; 7-114). For the four studies combined, the risk ratio was 1.50 (O=137; 95% CI: 1.18-191). The results for the stainless steel welders and the mild steel welders are basically the same.

The meta-analysis by Sjogren of exposure to stainless steel welding fumes and lung cancer included studies published between 1984 and 1993, which took smoking and potential asbestos exposure into account (Ex. 7-113). Five studies met the author's inclusion criteria and were included in the meta-analysis: two cohort studies, Moulin et al. (Ex. 35-283) and Sjogren et al. (Ex. 7-95); and three case-control studies, Gerin, et al. (Ex. 7-120, Hansen et al. (Ex. 9-129) and Kjuus et al. (Ex. 7-72). The calculated pooled relative risk for welders exposed to stainless steel welding fumes was 1.94 (95% CI: 1.28-2.93).

5. Evidence from Ferrochromium Workers

Ferrochromium is produced by the electrothermal reduction of chromite ore with coke in the presence of iron in electric furnaces. Some of the chromite ore is oxidized into Cr(VI) during the process. However, most of the ore is reduced to chrome metal. The manufacture of ferroalloys results in a complex mixture of particles, fumes and chemicals including nickel, Cr(III) and Cr(VI). Polycyclic aromatic hydrocarbons (PAH) are released during the manufacturing process. The co-exposure to other potential lung carcinogens combined with the lack of a statistically significant elevation in lung cancer mortality among ferrochromium workers were limitations in the key studies. Nevertheless, the observed increase in the relative risks of lung cancer add some further support to the much stronger link between Cr(VI) and lung cancer found in soluble chromate production workers, chromate pigment production workers, and chrome platers. The key studies are summarized in Table V-5.

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Langard et al. conducted a cohort study of male workers producing ferrosilicon and ferrochromium for more than one year between 1928 and 1977 at Start Printed Page 10140a plant located on the west coast of Norway (Exs. 7-34; 7-37). The cohort and study findings are summarized in Table V.5. Excluded from the study were workers who died before January 1, 1953 or had an unknown date of birth. The cohort was defined in the 1980 study as 976 male employees who worked for a minimum of one year prior to January 1, 1960. In the 1990 study, the cohort definition was expanded to include those hired up to 1965.

Production of ferrosilicon at the plant began in 1928 and ferrochromium production began in 1932. Job characterizations were compiled by combining information from company personnel lists and occupational histories contained in medical records and supplemented with information obtained via interview with long-term employees. Ten occupational categories were defined. Workers were assigned to an occupational category based upon the longest time in a given category.

Industrial hygiene studies of the plant from 1975 indicated that both Cr(III) and Cr(VI) were present in the working environment. The ferrochromium furnance operators were exposed to measurements of 0.04-0.29 mg/m3 of total chromium. At the charge floor the mean concentration of total chromium was 0.05 mg/m3, 11-33% of which was water soluble. The water soluble chromium was considered to be in the hexavalent state.

Both observed and expected cases of cancer were obtained via the Norwegian Cancer Registry. The observation period for cancer incidence was January 1, 1953 to December 31, 1985. Seventeen incident lung cancers were reported in the 1990 study (E=19.4; SIR=88). A deficit of lung cancer incidence was observed in the ferrosilicon group (O=2; E=5.8; SIR=35). In the ferrochromium group there were a significant excess of lung cancer; 10 observed lung cancers with 6.5 expected (SIR=154).

Axelsson et al. conducted a study of 1,932 ferrochromium workers to examine whether exposure in the ferrochromium industry could be associated with an increased risk of developing tumors, especially lung cancer (Ex. 7-62). The study cohort and findings are summarized in Table V.5. The study cohort was defined as males employed at a ferrochromium plant in Sweden for at least one year during the period January 1, 1930 to December 31, 1975.

The different working sites within the industry were classified into four groups with respect to exposure to Cr(VI) and Cr(III). Exposure was primarily to metallic and trivalent chromium with estimated levels ranging from 0-2.5 mg/m3. Cr(VI) was also present in certain operations with estimated levels ranging from 0-0.25 mg/m3. The highest exposure to Cr(VI) was in the arc-furnace operations. Cr(VI) exposure also occurred in a chromate reduction process during chromium alum production from 1950-1956. Asbestos-containing materials had been used in the plant. Cohort members were classified according to length and place of work in the plant.

Death certificates were obtained and coded to the revision of the International Classification of Diseases in effect at the time of death. Data on cancer incidence were obtained from the Swedish National Cancer Registry. Causes of death in the cohort for the period 1951-1975 were compared with causes of death for the age-adjusted male population in the county in which the plant was located.

There were seven cases of cancers of the trachea, bronchus and lung and the pleura with 5.9 expected (SIR=119) for the period 1958-1975. Four of the seven cases in the lung cancer group were maintenance workers and two of the four cases were pleural mesotheliomas. In the arc furnace group, which was thought to have the highest potential exposure to both Cr(III) and Cr(VI), there were two cancers of the trachea, bronchus and lung and the pleura. One of the cases was a mesothelioma. Of the 380 deaths that occurred during the period 1951-1975, five were from cancer of the trachea, bronchus and lung and the pleura (E=7.2; SMR=70). For the “highly” exposed furnace workers, there was one death from cancer of the trachea, bronchus and lung and the pleura.

Moulin et al. conducted a cohort mortality study in a French ferrochromium/stainless steel plant to determine if exposure to chromium compounds, nickel compounds and polycyclic aromatic hydrocarbons (PAHs) results in an increased risk of lung cancer (Ex. 282). The cohort was defined as men employed for at least one year between January 1, 1952 and December 31, 1982; 2,269 men met the cohort entrance criteria. No quantitative exposure data were available and no information on the relative amounts of Cr(VI) and Cr(III) was provided. In addition, some workers were also exposed to other carcinogens, such as silica and asbestos. The authors estimated that 75.7% of the cohort had been exposed to combinations of PAH, nickel and chromium compounds. Of the 137 deaths identified, the authors determined 12 were due to cancer of the trachea, bronchus and lung (E=8.56; SMR=140; 95% CI: 0.72-2.45). Eleven of the 12 lung cancers were in workers employed for at least one year in the ferrochromium or stainless steel production workshops (E=5.4; SMR=204; 95% CI: 1.02-3.64).

Pokrovskaya and Shabynina conducted a cohort mortality study of male and female workers employed “some time” between 1955 and 1969 at a chromium ferroalloy production plant in the U.S.S.R (Ex. 7-61). Workers were exposed to both Cr(III) and Cr(VI) as well as to benzo [a] pyrene. Neither the number of workers nor the number of cancer deaths by site were provided. Death certificates were obtained and the deaths were compared with municipal mortality rates by gender and 10 year age groups. The investigators state that they were able to exclude those in the comparison group who had chromium exposures in other industries. The lung cancer SMR for male chromium ferroalloy workers was 440 in the 30-39 year old age group and 660 in the 50-59 year old age group (p=0.001). There were no lung cancer deaths in the 40-49 and the 60-69 year old age groups. The data suggest that these ferrochromium workers may have been had an excess risk of lung cancer.

The association between Cr(VI) exposure in ferrochromium workers and the incidence of respiratory tract cancer these studies is difficult to assess because of co-exposures to other potential carcinogens (e.g., asbestos, PAHs, nickel, etc.), absence of a clear exposure-response relationship and lack of information on smoking. There is suggestive evidence of excess lung cancer mortality among Cr(VI)-exposed ferrochromium workers in the Norwegian (Langard) cohort when compared to a similar unexposed cohort of ferrosilicon workers. However, there is little consistency for this finding in the Swedish (Axelsson) or French (Moulin) cohorts.

6. Evidence From Workers in Other Industry Sectors

There are several other epidemiological studies that do not fit into the five industry sectors previously reviewed. These include worker cohorts in the aerospace industry, paint manufacture, and leather tanning operations, among others. The two cohorts of aircraft manufacturing workers are summarized in Table V-6. All of the cohorts had some Cr(VI) exposure, but certain cohorts may have included a sizable number of workers with little or no exposure to Cr(VI). This creates an additional complexity in assessing whether the study findings Start Printed Page 10141support a Cr(VI) etiology for cancer of the respiratory system.

Alexander et al. conducted a cohort study of 2,429 aerospace workers with a minimum of six months of cumulative employment in jobs involving chromate Start Printed Page 10142exposure during the period 1974 through 1994 (Ex. 31-16-3). Exposure estimates were based on industrial hygiene measurements and work history records. Jobs were classified into categories of “high” (spray painters, decorative painters), “moderate” (sanders/maskers, maintenance painters) and “low” (chrome platers, surface processors, tank tenders, polishers, paint mixers) exposure. Each exposure category was assigned a summary TWA exposure based upon the weighted TWAs and information from industrial hygienists. The use of respiratory protection was accounted for in setting up the job exposure matrix. The index of cumulative total chromium exposure (reported as μg/m3 chromate TWA-years) was computed by multiplying the years in each job by the summary TWAs for each exposure category.

In addition to cumulative chromate exposure, chromate exposure jobs were classified according to the species of chromate. According to the authors, in painting operations the exposure is to chromate pigments with moderate and low solubility such as zinc chromate, strontium chromate and lead chromate; in sanding and polishing operations the same chromate pigments exist as dust; while platers and tank tenders are exposed to chromium trioxide, which is highly soluble.

Approximately 26% of the cohort was lost to follow-up. Follow-up on the cohort was short (average 8.9 years per cohort member). Cases were identified through the Cancer Surveillance System (CSS) at the Fred Hutchinson Cancer Research Center in Seattle, Washington. CSS records primary cancer diagnoses in 13 counties in western Washington. Expected numbers were calculated using race-, gender-, age- and calendar-specific rates from the Puget Sound reference population for 1974 through 1994. Fifteen lung cancer cases were identified with an overall standardized incidence ratio (SIR) of 80 (95% CI: 0.4-1.3). The SIRs for lung cancer by cumulative years of employment in the “high exposure” painting job category were based upon only three deaths in each of the cumulative years categories (<5 and ≥5); years of employment was inversely related to the risk of lung cancer. For those in the “low exposure” category, the SIRs were 130 for those who worked less than five years in that category (95% CI: 0.2-4.8) and 190 for those who worked five years or more (95% CI: 0.2-6.9). However, there were only two deaths in each category. The SIR for those who worked ≥5 years was 270 (95% CI: 0.5-7.8), but based only on three deaths.

Boice et al. conducted a cohort mortality study of 77,965 workers employed for a minimum of one year on or after January 1960 in aircraft manufacturing (Ex. 31-16-4). Routine exposures to Cr(VI) compounds occurred primarily while operating plating and coating process equipment or when using chromate based primers or paints. According to the authors, 3,634 workers, or 8% of the cohort, had the potential for routine exposure to chromate and 3,809 workers, or 8.4%, had the potential for intermittent exposure to chromate. Limited chromate air sampling was conducted between 1978 and 1991. The mean full shift air measurement was 1.5 μg CrO3/m3 (0.78 μg Cr(VI)/m3) indicating fairly low airborne Cr(VI) in the plant (Ex. 47-19-5).

Follow up of the cohort was through 1996. Expectations were calculated based on the general population of California for white workers, while general population rates for the U.S. were used for non-white workers. For the 3,634 cohort members who had potential for routine exposure to chromates, the lung cancer SMR (race and gender combined) was 102 based upon 87 deaths (95% CI: 82-126). There was a slight non-significant positive trend (p value >2.0) for lung cancer with duration of potential exposure. The SMR was 108 (95% CI: 75-157) for workers exposed to chromate for ≥5 years. Among the painters, there were 41 deaths from lung cancer yielding a SMR of 111 (95% CI: 80-151). For those who worked as a process operator or plater the SMR for lung cancer was 103 based upon 38 deaths (95% CI: 73-141).

OSHA believes the Alexander (Ex. 31-16-3) and the Boice et al. (Ex. 31-16-4) studies have several limitations. The Alexander cohort has few lung cancers (due in part to the young age of the population) and lacks smoking data. The authors note that these factors “[limit] the overall power of the study and the stability of the risk estimates, especially in exposure-related subanalyses” (Ex. 31-16-3, p. 1256). Another limitation of the study is the 26.3% of cohort members lost to follow-up. Boice et al. is a large study of workers in the aircraft manufacturing industry, but was limited by a lack of Cr(VI) exposure measurement during the 1960s and most of the 1970s. I was also limited by a substantial healthy worker survivor effect that may have masked evidence of excess lung cancer mortality in Cr(VI) exposed workers (Ex. 31-16-4). These studies are discussed further in section VI, including section VI.B.6 (Alexander cohort) and section VI.G.4.a (Alexander and Boice cohorts).

Dalager et al. conducted a proportionate mortality study of 977 white male spray painters potentially exposed to zinc chromate in the aircraft maintenance industry who worked at least three months and terminated employment within ten years prior to July 31, 1959 (Ex. 7-64). Follow-up was through 1977. The expected numbers of deaths were obtained by applying the cause-specific proportionate mortality of U.S. white males to the total numbers of deaths in the study group by five year age groups and five year time intervals. Two hundred and two deaths were observed. There were 21 deaths from cancer of the respiratory system (PMR=184), which was statistically significant. The Proportionate Cancer Mortality Ratio for cancer of the respiratory system was not statistically significant (PCMR= 146). Duration of employment as a painter with the military as indicated on the service record was used as an estimate of exposure to zinc chromate pigments, which were used as a metal primer. The PMRs increased as duration of employment increased (<5 years, O=9, E=6.4, PMR=141; 5-9 years, O=6, E=3, PMR=200; and 10+ years, O=6, E=2, PMR=300) and were statistically significant for those who worked 10 or more years.

Bertazzi et al. studied the mortality experience of 427 workers employed for a minimum of six months between 1946 and 1977 in a plant manufacturing paint and coatings (Ex. 7-65). According to the author, chromate pigments represented the “major exposure” in the plant. The mortality follow-up period was 1954-1978. There were eight deaths from lung cancer resulting in a SMR of 227 on the local standard (95% CI: 156-633) and a SMR of 334 on the national standard (95% CI: 106-434). The authors were unable to differentiate between exposures to different paints and coatings. In addition, asbestos was used in the plant and may be a potential confounding exposure.

Morgan conducted a cohort study of 16,243 men employed after January 1, 1946 for at least one year in the manufacture of paint or varnish (Ex. 8-4). Analysis was also conducted for seven subcohorts, one of which was for work with pigments. Expectations were calculated based upon the mortality experience of U.S. white males. The SMR for cancer of the trachea, bronchus and lung was below unity based upon 150 deaths. For the pigment subcohort, the SMR for cancer of the trachea, bronchus and lung was 117 based upon 43 deaths. In a follow-up study of the subcohorts, case-control analyses were conducted for several causes of death Start Printed Page 10143including lung cancer (Ex. 286). The details of matching were not provided. The authors state that no significant excesses of lung cancer risk by job were found. No odds ratios were presented.

Pippard et al. conducted a cohort mortality study of 833 British male tannery workers employed in 1939 and followed through December 31, 1982 (Ex. 278). Five hundred and seventy three men worked in tanneries making vegetable tanned leathers and 260 men worked in tanneries that made chrome tanned leathers. The expected number of deaths was calculated using the mortality rates of England and Wales as a whole. The lung cancer SMR for the vegetable tanned leather workers was in deficit (O=31; E=32.6; 95% CI: 65-135), while the lung cancer SMR for the chrome tanned leather workers was slightly elevated but not statistically significant (O=13; E=12; SMR=108; 95% CI: 58-185).

In a different study of two U.S. tanneries, Stern et al. investigated mortality in a cohort of all production workers employed from January 1, 1940 to June 11, 1979 at tannery A (N=2,807) and from January 1, 1940 to May 1, 1980 at tannery B (N=6,558) (Ex. 7-68). Vital status was followed through December 31, 1982. There were 1,582 deaths among workers from the two tanneries. Analyses were conducted employing both U.S. mortality rates and the mortality rates for the state in which the plant is located. There were 18 lung/pleura cancer deaths at tannery A and 42 lung/pleura cancer deaths at tannery B. The lung cancer/pleura SMRs were in deficit on both the national standard and the state standard for both tanneries. The authors noted that since the 1940s most chrome tanneries have switched to the one-bath tanning method in which Cr(VI) is reduced to Cr(III).

Blot et al. reported the results of a cohort study of 51,899 male workers of the Pacific Gas & Electric Company alive in January 1971 and employed for at least six months before the end of 1986 (Ex. 239). A subset of the workers were involved in gas generator plant operations where Cr(VI) compounds were used in open and closed systems from the 1950s to early 1980s. One percent of the workers (513 men) had worked in gas generator jobs, with 372 identified from post-1971 listing at the company's three gas generator plants and 141 from gas generator job codes. Six percent of the cohort members (3,283) had trained at one of the gas generator plants (Kettleman).

SMRs based on national and California rates were computed. Results in the paper are based on the California rates, since the overall results reportedly did not differ substantially from those using the national rates. SMRs were calculated for the entire cohort and for subsets defined by potential for gas generator plant exposure. No significant cancer excesses were observed and all but one cancer SMR was in deficit. There were eight lung cancer deaths in the gas generator workers (SMR=81; 95% CI: 0.35-1.60) and three lung cancer deaths among the Kettleman trainees (SMR=57; 95% CI: 0.12-1.67). There were no deaths from nasal cancer among either the gas generator workers or the Kettleman trainees. The risk of lung cancer did not increase with length of employment or time since hire.

Rafnsson and Johannesdottir conducted a study of 450 licensed masons (cement finishers) in Iceland born between 1905 and 1945, followed from 1951 through 1982 (Ex. 7-73). Stonecutters were excluded. Expectations were based on the male population of Iceland. The SMR for lung cancer was 314 and is statistically significant based upon nine deaths (E=2.87; 95% CI: 1.43-5.95). When a 20 year latency was factored into the analysis, the lung cancer SMR remained statistically significant (O=8; E=2.19; SMR=365; 95% CI: 1.58-7.20).

Svensson et al. conducted a cohort mortality study of 1,164 male grinding stainless steel workers employed for three months or more during the period 1927-1981 (Ex.266). Workers at the facility were reportedly exposed to chromium and nickel in the stainless steel grinding process. Records provided by the company were used to assign each worker to one of three occupational categories: those considered to have high exposure to chromium, nickel as well as total dust, those with intermediate exposure, and those with low exposure. Mortality rates for males in Blekinge County, Sweden were used as the reference population. Vital status follow-up was through December 31, 1983. A total of 194 deaths were observed (SMR=91). No increased risk of lung cancer was observed (SMR=92). The SMR for colon/rectum cancer was 2.47, but was not statistically significant.

Cornell and Landis studied the mortality experience of 851 men who worked in 26 U.S. nickel/chromium alloy foundries between 1968 and 1979 (Ex. 7-66). Standardized Proportionate Mortality Ratio (SPMR) analyses were done using both an internal comparison group (foundry workers not exposed to nickel/chromium) and the mortality experience of U.S. males. The SPMR for lung cancer was 105 (O=60; E=56.9). No nasal cancer deaths were observed.

Brinton et al. conducted a case-control study of 160 patients diagnosed with primary malignancies of the nasal cavity and sinuses at one of four hospitals in North Carolina and Virginia between January 1, 1970 and December 31, 1980 (Ex. 8-8). For each case determined to be alive at the time of interview, two hospital controls were selected matched on vital status, hospital, year of admission (±2 years), age (±5 years), race and state economic area or county or usual residence. Excluded from control selection were malignant neoplasms of the buccal cavity and pharynx, esophagus, nasal cavity, middle ear and accessory sinuses, larynx, and secondary neoplasms. Also excluded were benign neoplasms of the respiratory system, mental disorders, acute sinusitis, chronic pharyngitis and nasopharyngitis, chronic sinusitis, deflected nasal septum or nasal polyps. For those cases who were deceased at the time of interview, two different controls were selected. One control series consisted of hospital controls as described previously. The second series consisted of decedents identified through state vital statistics offices matched for age (±5 years), sex, race, county of usual residence and year of death. A total of 193 cases were identified and 160 case interviews completed. For those exposed to chromates, the relative risk was not significantly elevated (OR=5.1) based upon five cases. According to the authors, chromate exposure was due to the use of chromate products in the building industry and in painting, rather than the manufacture of chromates.

Hernberg et al. reported the results of a case-control study of 167 living cases of nasal or paranasal sinus cancer diagnosed in Denmark, Finland and Sweden between July 1, 1977 and December 31, 1980 (Exs. 8-7; 7-71). Controls were living patients diagnosed with malignant tumors of the colon and rectum matched for country, gender and age at diagnosis (±3 years) with the cases. Both cases and controls were interviewed by telephone to obtain occupational histories. Patients with work-related exposures during the ten years prior to their illness were excluded. Sixteen cases reported exposure to chromium, primarily in the “stainless steel welding” and “nickel” categories, versus six controls (OR=2.7l; 95% CI: 1.1-6.6).

7. Evidence From Experimental Animal Studies

Most of the key animal cancer bioassays for chromium compounds were conducted before 1988. These Start Printed Page 10144studies have been critically reviewed by the IARC in the Monograph Chromium, Nickel, and Welding (Ex. 35-43). OSHA reviewed the key animal cancer bioassays in the NPRM (69 FR at 59341-59347) and requested any additional data in experimental animals that were considered important to evaluating the carcinogenicity of Cr(VI). The discussion below describes these studies along with any new study information received during the public hearing and comment periods.

In the experimental studies, Cr(VI) compounds were administered by various routes including inhalation, intratracheal instillation, intrabronchial implantation, and intrapleural injection, as well as intramuscular and subcutaneous injection. For assessing human health effects from occupational exposure, the most relevant route is inhalation. However, as a whole, there were very few inhalation studies. In addition to inhalation studies, OSHA is also relying on intrabronchial implantation and intratracheal instillation studies for hazard identification because these studies examine effects directly administered to the respiratory tract, the primary target organ of concern, and they give insight into the relative potency of different Cr(VI) compounds. In comparison to studies examining inhalation, intrabronchial implantation, and intratracheal instillation, studies using subcutaneous injection and intramuscular administration of Cr(VI) compounds were of lesser significance but were still considered for hazard identification.

In its evaluation, OSHA took into consideration the exposure regimen and experimental conditions under which the experiments were performed, including the exposure level and duration; route of administration; number, species, strain, gender, and age of the experimental animals; the inclusion of appropriate control groups; and consistency in test results. Some studies were not included if they did not contribute to the weight of evidence, lacked adequate documentation, were of poor quality, or were less relevant to occupational exposure conditions (e.g., some intramuscular injection studies).

The summarized animal studies are organized by Cr(VI) compound in order of water solubility as defined in section IV on Chemical Properties (i.e., Cr(VI) compounds that are highly soluble in water; Cr(VI) compounds that are slightly soluble in water, and Cr(VI) compounds that insoluble in water). Solubility is an important factor in determining the carcinogenicity of Cr(VI) compounds (Ex. 35-47).

a. Highly Water Soluble Cr(VI) Compounds

Multiple animal carcinogenicity studies have been conducted on highly water soluble sodium dichromate and chromic acid. The key studies are summarized in Table V-7.

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Chromic acid (Chromium trioxide). In a study by Adachi et al., ICR/JcI mice were exposed by inhalation to 3.63 mg/m3 for 30 minutes per day, two days per week for up to 12 months (Ex. 35-26-1). The mice were observed for an additional six months. The authors used a miniaturized chromium electroplating system to generate chromic acid for the study. The authors found there were elevations in lung adenomas at 10-14 Start Printed Page 10146months (3/14 vs. 0/10) and lung adenocarcinomas at 15-18 months (2/19 vs. 0/10), but the results were not statistically significant. The small number of animals (e.g. 10-20 per group) used in this study limited its power to detect all but a relatively high tumor incidence (e.g. >20%) with statistical precision. Statistically significant increases in nasal papillomas were observed in another study by Adachi et al., in which C57B1 mice were exposed by inhalation to 1.81 mg/m3 chromic acid for 120 min per day, two days per week for up to 12 months (Ex. 35-26). At 18 months, the tumor incidence was 6/20 in exposed animals vs. 0/20 in the control animals (p<0.05).

In separate but similar studies, Levy et al. and Levy and Venitt, using similar exposure protocol, conducted bronchial implantation experiments in which 100 male and female Porton-Wistar rats were dosed with single intrabronchial implantations of 2 mg chromic acid (1.04 mg Cr(VI)) mixed 50:50 with cholesterol in stainless steel mesh pellets (Exs. 11-2; 11-12). The authors found no statistically significant increases in lung tumors, although Levy et al. found a bronchial carcinoma incidence of 2/100 in exposed rats compared with 0/100 in control rats. Levy and Venitt found a bronchial carcinoma incidence of 1/100 accompanied by a statistically significant increase in squamous metaplasia, a lesion believed capable of progressing to carcinoma. There was no statistically significant increase in the incidence of squamous metaplasia in control rats or rats treated with Cr(III) compounds in the same study. This finding suggests that squamous metaplasia is specific to Cr(VI) and is not evoked by a non-specific stimuli, the implantation procedure itself, or treatment with Cr(III) containing materials.

Similar to Levy et al. and Levy and Venitt studies, Laskin et al. gave a single intrabronchial implantation of 3-5 mg chromic acid mixed 50:50 with cholesterol in stainless steel mesh pellets to 100 male and female Porton-Wistar rats (Ex. 10-1). The rats were observed for 2 years. No tumors were identified in the treated or control animals (0/100 vs. 0/24).

Sodium dichromate. Glaser et al. exposed male Wistar rats to aerosolized sodium dichromate by inhalation for 22-23 hours per day, seven days per week for 18 months (Exs. 10-10; 10-11). The rats were held for an additional 12 months at which point the study was terminated. Lung tumor incidences among groups exposed to 25, 50, and 100 μg Cr(VI)/m3 were 0/18, 0/18, and 3/19, respectively, vs. 0/37 for the control animals. Histopathology revealed one adenocarcinoma and two adenomas in the highest group. The slightly elevated tumor incidence at the highest dose was not statistically significant. A small number of animals (20 per group) were used in this study limiting its power to detect all but a relatively high tumor incidence (e.g. >20%) with statistical precision. In addition, the administered doses used in this study were fairly low, such that the maximum tolerated dose (i.e., the maximum dose level that does not lead to moderate reduction in body weight gain) may not have been achieved. Together, these factors limit the interpretation of the study.

In an analysis prepared by Exponent and submitted by the Chrome Coalition, Exponent stated that “inhalation studies of Glaser et al. support a position that exposures to soluble Cr(VI) at concentrations at least as high as the current PEL (i.e., 52 μg/m3) do not cause lung cancer” (Ex. 31-18-1, page 2). However, it should be noted that the Glaser et al. studies found that 15% (3/19) of the rats exposed to an air concentration just above the current PEL developed lung tumors, and that the elevated tumor incidence was not statistically significant in the highest dose group because the study used a small number of animals. OSHA believes the Glaser study lacks the statistical power to state with sufficient confidence that Cr(VI) exposure does not cause lung cancer at the current PEL, especially when given the elevated incidence of lung tumors at the next highest dose level.

Steinhoff et al. studied the carcinogenicity of sodium dichromate in Sprague-Dawley rats (Ex. 11-7). Forty male and 40 female Sprague-Dawley rats were divided into two sets of treatment groups. In the first set, doses of 0.01, 0.05 or 0.25 mg/kg body weight in 0.9% saline were instilled intratracheally five times per week. In the second set of treatment groups, 0.05, 0.25 or 1.25 mg/kg body weight in 0.9% saline doses were instilled intratracheally once per week. Duration of exposure in both treatment groups was 30 months. The total cumulative dose for the lowest treatment group of animals treated once per week was the same as the lowest treatment group treated five times per week. Similarly, the medium and high dose groups treated once per week had total doses equivalent to the medium and high dose animals treated five times per week, respectively. No increased incidence of lung tumors was observed in the animals dosed five times weekly. However, in the animals dosed once per week, tumor incidences were 0/80 in control animals, 0/80 in the 0.05 mg/kg exposure group, 1/80 in the 0.25 mg/kg exposure group and 14/80 in the 1.25 mg/kg exposure group (p <0.01). The tumors were malignant in 12 of the 14 animals in the 1.25 mg/kg exposure group. Tracheal instillation at the highest dose level (i.e. 1.25 mg/kg) caused emphysematous lesions and pulmonary fibrosis in the lungs of Cr(VI)-treated rats. A similar degree of lung damage did not occur at the lower dose levels. Exponent commented that the Steinhoff and Glaser results are evidence that the risk of lung cancer from occupational exposure does not exist below a threshold Cr(VI) air concentration of approximately 20 μg/m3 (Ex. 38-233-4). This comment is addressed in Section VI.G.2.c.

In separate but similar studies, Levy et al. and Levy and Venitt implanted stainless steel mesh pellets filled with a single dose of 2 mg sodium dichromate (0.80 mg Cr(VI)) mixed 50:50 with cholesterol in the bronchi of male and female Porton-Wistar rats (Exs. 11-2; 11-12). Control groups (males and females) received blank pellets or pellets loaded with cholesterol. The rats were observed for two years. Levy et al. and Levy and Venitt reported a bronchial tumor incidence of 1/100 and 0/89, respectively, for exposed rats. However, the latter study reported a statistically significant increase in squamous metaplasia, a lesion believed capable of progressing to carcinoma, among exposed rats when compared to unexposed rats. There were no bronchial tumors or squamous metaplasia in any of the control animals and no significant increases in lung tumors were observed in the two studies.

b. Slightly Water Soluble Cr(VI) Compounds

Animal carcinogenicity studies have been conducted on slightly water soluble calcium chromate, strontium chromate, and zinc chromates. The key studies are summarized in Table V-8.

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Calcium chromate. Nettesheim et al. conducted the only available inhalation carcinogenicity study with calcium chromate showing borderline statistical significance for increased lung adenomas in C57B1/6 mice exposed to 13 mg/m3 for 5 hours per day, 5 days per week over the life of the mice. The tumor incidences were 6/136 in exposed male mice vs. 3/136 in control male mice and 8/136 in exposed female mice Start Printed Page 10148vs. 2/136 in control female mice (Ex. 10-8).

Steinhoff et al. observed a statistically significant increase in lung tumors in Sprague-Dawley rats exposed by intratracheal instillation to 0.25 mg/kg body weight calcium chromate in 0.9% saline five times weekly for 30 months (Ex. 11-7). Tumors were found in 6/80 exposed animals vs. 0/80 in unexposed controls (p<0.01). Increased incidence of lung tumors was also observed in those rats exposed to 1.25 mg/kg calcium chromate once per week (14/80 vs. 0/80 in controls) for 30 months. At the highest dose, the authors observed 11 adenomas, one adenocarcinoma, and two squamous carcinomas. The total administered doses for both groups of dosed animals (1 × 1.25 mg/kg and 5 × 0.25 mg/kg) were equal, but the tumor incidence in the rats exposed once per week was approximately double the incidence in rats exposed to the same weekly dose divided into five smaller doses. The authors suggested that the dose-rate for calcium chromate compounds may be important in determining carcinogenic potency and that limiting higher single exposures may offer greater protection against carcinogenicity than reducing the average exposure alone.

Snyder et al. administered Cr(VI)-contaminated soil of defined aerodynamic diameter (2.9 to 3.64 micron) intratracheally to male Sprague-Dawley rats (Ex. 31-18-12). For the first six weeks of treatment, the rats were instilled with weekly suspensions of 1.25 mg of material per kg body weight, followed by 2.5 mg/kg every other week, until treatments were terminated after 44 weeks. The investigation included four exposure groups: control animals (50 rats), rats administered Cr(VI)-contaminated soil (50 rats), rats administered Cr(VI)-contaminated soil supplemented with calcium chromate (100 rats), and rats administered calcium chromate alone (100 rats). The total Cr(VI) dose for each group was: control group (0.000002 mg Cr(VI)/kg), soil alone group (0.324 mg Cr(VI)/kg), soil plus calcium chromate group (7.97 mg Cr(VI)/kg), and calcium chromate alone group (8.70 mg Cr(VI)/kg). No primary tumors were observed in the control group or the chromium contaminated soil group. Four primary tumors of the lung were found in the soil plus calcium chromate group and one primary lung tumor was observed in the group treated with calcium chromate alone; however, these incidences did not reach statistical significance.

Statistically significant increases in the incidence of bronchial carcinoma in rats exposed to calcium chromate through intrabronchial instillation were reported by Levy et al. (Ex. 11-2) and Levy and Venitt (Ex. 11-12). These studies, using a similar protocol, implanted a single dose of 2 mg calcium chromate (0.67 mg Cr(VI)) mixed 50:50 with cholesterol in stainless steel pellets into the bronchi of Porton-Wistar rats. Levy et al. and Levy and Venitt found bronchial carcinoma incidences of 25/100 and 8/84, respectively, following a 24-month observation. The increased incidences were statistically significant when compared to the control group. Levy and Venitt also reported statistically significant increases in squamous metaplasia in the calcium chromate-treated rats (Ex. 11-12).

Laskin et al. observed 8/100 tumors in rats exposed to a single dose of 3-5 mg calcium chromate mixed with cholesterol in stainless steel mesh pellets implanted in the bronchi (Ex. 10-1). Animals were observed for a total of 136 weeks. The sex, strain, and species of the rats were not specified in the study. Tumor incidence in control animals was 0/24. Although tumor incidence did not reach statistical significance in this study, OSHA agrees with the IARC evaluation that the incidences are due to calcium chromate itself rather than background variation.

Strontium chromate. Strontium chromate was tested by intrabronchial implantation and intrapleural injection. In a study by Levy et al., two strontium chromate compounds mixed 50:50 with cholesterol in stainless steel mesh pellets were administered by intrabronchial instillation of a 2 mg (0.48 mg Cr(VI)) dose into 100 male and female Porton-Wistar rats (Ex. 11-2). Animals were observed for up to 136 weeks. The strontium chromate compounds induced bronchial carcinomas in 43/99 (Sr, 42.2%; CrO4, 54.1%) and 62/99 rats (Sr, 43.0%; Cr, 24.3%)], respectively, compared to 0/100 in the control group. These results were statistically significant. The strontium chromates produced the strongest carcinogenic response out of the 20 Cr(VI) compounds tested by the intrabronchial implantation protocol. Boeing Corporation commented that the intrabronchial implantation results with strontium chromate should not be relied upon in an evaluation of carcinogenicity and that the data is inconsistent with other Cr(VI) studies (Ex. 38-106-2, p. 26). This comment is discussed in the Carcinogenic Effects Conclusion Section V.B.9 dealing with the carcinogenicity of slightly soluble Cr(VI) compounds.

In the study by Hueper, strontium chromate was administered by intrapleural injection (doses unspecified) lasting 27 months (Ex. 10-4). Local tumors were observed in 17/28 treated rats vs. 0/34 for the untreated rats. Although the authors did not examine the statistical significance of tumors, the results clearly indicate a statistical significance.

Zinc chromate compounds. Animal studies have been conducted to examine several zinc chromates of varying water solubilities and composition. In separate, but similarly conducted studies, Levy et al. and Levy and Venitt studied two zinc chromate powders, zinc potassium chromate, and zinc tetroxychromate (Exs. 11-2; 11-12). Two milligrams of the compounds were administered by intrabronchial implantation to 100 male and female Porton-Wistar rats. Zinc potassium chromate (0.52 mg Cr(VI)) produced a bronchial tumor incidence of 3/61 which was statistically significant (p<0.05) when compared to a control group (Ex. 11-12). There was also an increased incidence of bronchial tumors (5/100, p=0.04; 3/100, p=0.068) in rats receiving the zinc chromate powders (0.44 mg Cr(VI)). Zinc tetroxychromate (0.18 mg Cr(VI)) did not produce a statistically significant increase in tumor incidence (1/100) when compared to a control group. These studies show that most slightly water soluble zinc chromate compounds elevated incidences of tumors in rats.

Basic potassium zinc chromate was administered to mice, guinea pigs and rabbits via intratracheal instillation (Ex. 35-46). Sixty-two Strain A mice were given six injections of 0.03 ml of a 0.2% saline suspension of the zinc chromate at six week intervals and observed until death. A statistically significant increase in tumor incidence was observed in exposed animals when compared to controls (31/62 vs. 7/18). Statistically significant effects were not observed among guinea pigs or rabbits. Twenty-one guinea pigs (sex and strain not given) received six injections of 0.3 ml of a 1% suspension of zinc chromate at three monthly intervals and observed until death. Results showed pulmonary adenomas in only 1/21 exposed animals vs. 0/18 in controls. Seven rabbits (sex and strain not given) showed no increase in lung tumors when given 3-5 injections of 1 ml of a saline suspension of 10 mg zinc chromate at 3-month intervals. However, as noted by IARC, the small numbers of animals used in the guinea pig and rabbit experiments (as few as 13 guinea pigs and 7 rabbits per group) limit the power of the study to detect increases in cancer incidence.

Hueper found that intrapleural injection of slightly water soluble zinc Start Printed Page 10149yellow (doses were unspecified) resulted in statistically significant increases in local tumors in rats (sex, strain, and age of rat unspecified; dose was unspecified). The incidence of tumors in exposed rats was 22/33 vs. 0/34 in controls (Ex. 10-4).

Maltoni et al. observed increases in the incidence of local tumors after subcutaneous injection of slightly water soluble zinc yellow in 20 male and 20 female Sprague-Dawley rats (statistical significance was not evaluated) (Ex. 8-37). Tumor incidences were 6/40 in 20% CrO3 dosed animals at 110 weeks and 17/40 in 40% CrO3 dosed animals at 137 weeks compared to 0/40 in control animals.

c. Water Insoluble Cr(VI) Compounds

There have been a number of animal carcinogenicity studies involving implantation or injection of principally water insoluble zinc, lead, and barium chromates. The key studies are summarized in Table V-9.

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Lead chromate and lead chromate pigments. Levy et al. examined the carcinogenicity of lead chromate and several lead chromate-derived pigments in 100 male and female Porton-Wistar rats after a single intrabronchial implantation followed by a two year observation period (Ex. 11-12). The rats were dosed with two mg of a lead chromate compound and lead chromate pigments, which were mixed 50:50 with Start Printed Page 10151cholesterol in stainless steel mesh pellets and implanted in the bronchi of experimental animals. The lead chromate and lead chromate pigment compositions consisted of the following: lead chromate (35.8% CrO4; 0.32 mg Cr(VI)), primrose chrome yellow (12.6% Cr; 0.25 mg Cr(VI)), molybdate chrome orange (12.9% Cr; 0.26 mg Cr(VI)), light chrome yellow (12.5% Cr; 0.25 mg Cr(VI)), supra LD chrome yellow (26.9% CrO3; 0.28 mg Cr(VI)), medium chrome yellow (16.3% Cr; 0.33 mg Cr(VI)) and silica encapsulated medium chrome yellow (10.5% Cr; 0.21 mg Cr(VI)). No statistically significant tumors were observed in the lead chromate group compared to controls (1/98 vs. 0/100), primrose chrome yellow group (1/100 vs. 0/100), and supra LD chrome yellow group (1/100 vs. 0/100). The authors also noted no tumors in the molybdate chrome orange group, light chrome yellow group, and silica encapsulated medium chrome yellow group.

Maltoni (Ex. 8-25), Maltoni (Ex. 5-2), and Maltoni et al. (Ex. 8-37) examined the carcinogenicity of lead chromate, basic lead chromate (chromium orange) and molybdenum orange in 20 male and 20 female Sprague-Dawley rats by a single subcutaneous administration of the lead chromate compound in water. Animals were observed for 117 to 150 weeks. After injection of 30 mg lead chromate, local injection site sarcomas were observed in 26/40 exposed animals vs. 0/60 and 1/80 in controls. Although the authors did not examine the statistical significance of sarcomas, the results clearly indicate a statistical significance. Animals injected with 30 mg basic lead chromate (chromium orange) were found to have an increased incidence of local injection site sarcomas (27/40 vs. 0/60 and 1/80 in controls). Animals receiving 30 mg molybdenum orange in 1 ml saline were also found to have an increased incidence of local injection site sarcomas (36/40 vs. 0/60 controls).

Carcinogenesis was observed after intramuscular injection in a study by Furst et al. (Ex. 10-2). Fifty male and female Fischer 344 rats were given intramuscular injections of 8 mg lead chromate in trioctanoin every month for nine months and observed up to 24 months. An increase in local tumors at the injection site (fibrosarcomas and rhabdomyosarcomas) was observed (31/47 in treated animals vs. 0/22 in controls). These rats also had an increased incidence of renal carcinomas (3/23 vs. 0/22 in controls), but IARC noted that the renal tumors may be related to the lead content of the compound. In the same study, 3 mg lead chromate was administered to 25 female NISH Swiss weanling mice via intramuscular injection every 4 months for up to 24 months. In the exposed group, the authors observed three lung alveologenic carcinomas after 24 months of observation and two lymphomas after 16 months of observation. Two control groups were used: an untreated control group (22 rats) and a vehicle injected control group (22 rats). The authors noted that one alveologenic carcinoma and one lymphoma were observed in each control group. The Color Pigment Manufacturers Association (CPMA) commented that the lack of elevated tumor incidence in the intrabronchial implantation studies confirmed that lead chromate was not carcinogenic and that the positive injection studies by the subcutaneous, intrapleural, and intramuscular routes were of questionable relevance (Ex. 38-205, p. 93). This comment is further discussed in the Carcinogenic Effects Conclusion Section V.B.9 dealing with the carcinogenicity of lead chromate.

Barium chromate. Barium chromate was tested in rats via intrabronchial, intrapleural and intramuscular administration. No excess lung or local tumors were observed (Ex. 11-2; Ex. 10-4; Ex. 10-6).

d. Summary. Several Cr(VI) compounds produced tumors in laboratory animals under a variety of experimental conditions using different routes of administration. The animals were generally given the test material(s) by routes other than inhalation (e.g., intratracheal administration, intramuscular injection, intrabronchial implantation, and subcutaneous injection). Although the route of administration may have differed from that found in an occupational setting, these studies have value in the identification of potential health hazards associated with Cr(VI) and in assessing the relative potencies of various Cr(VI) compounds.

OSHA believes that the results from Adachi et al. (Ex. 35-26-1), Adachi et al. (Ex. 35-26), Glaser et al. (Ex. 10-4), Glaser et al. (Ex. 10-10), Levy et al. (Ex. 11-2), and Steinhoff et al. (Ex. 11-7) studies provide valuable insight on the carcinogenic potency of Cr(VI) compounds in laboratory animals. Total dose administered, dose rate, amount of dosage, dose per administration, number of times administered, exposure duration and the type of Cr(VI) compound are major influences on the observed tumor incidence in animals. It was found that slightly water soluble calcium, strontium, and zinc chromates showed the highest incidence of lung tumors, as indicated in the results of the Steinhoff and Levy studies, even when compared to similar doses of the more water soluble sodium chromates and chromic acid compounds. The highly insoluble lead chromates did not produce lung tumors by the intrabronchial implantation procedure but did produce tumors by subcutaneous injection and intramuscular injection.

8. Mechanistic Considerations

Mechanistic information can provide insight into the biologically active form(s) of chromium, its interaction with critical molecular targets, and the resulting cellular responses that trigger neoplastic transformation. There has been considerable scientific study in recent years of Cr(VI)-initiated cellular and molecular events believed to impact development of respiratory carcinogenesis. Much of the research has been generated using in vitro techniques, cell culture systems, and animal administrations. The early mechanistic data were reviewed by IARC in 1990 (Ex. 35-43). Recent experimental research has identified several biological steps critical to the mode of action by which Cr(VI) transforms normal lung cells into a neoplastic phenotype. These are: (a) Cellular uptake of Cr(VI) and its extracellular reduction, (b) intracellular Cr(VI) reduction to produce biologically active products, (c) damage to DNA, and (d) activation of signaling pathways in response to cellular stress. Each step will be described in detail below.

a. Cellular Uptake and Extracellular Reduction. The ability of different Cr(VI) particulate forms to be taken up by the bronchoalveolar cells of the lung is an essential early step in the carcinogenic process. Particle size and solubility are key physical factors that influence uptake into these cells. Large particulates (>10 μm) are generally deposited in the upper nasopharygeal region of the respiratory tract and do not reach the bronchoalveolar region of the lungs. Smaller Cr(VI) particulates will increasingly reach these lower regions and come into contact with target cells.

Once deposited in the lower respiratory tract, solubility of Cr(VI) particulates becomes a major influence on disposition. Highly water soluble Cr(VI), such as sodium chromate and chromic acid, rapidly dissolves in the fluids lining the lung epithelia and can be taken up by lung cells via facilitated diffusion mediated by sulfate/phosphate anion transport channels (Ex. 35-148). This is because Cr(VI) exists in a tetrahedral configuration as a chromate oxyanion similar to the physiological anions, sulfate and phosphate (Ex. 35-Start Printed Page 10152231). Using cultured human epithelial cells, Liu et al. showed that soluble Cr(VI) uptake was time- and dose-dependant over a range of 1 to 300 μm in the medium with 30 percent of the Cr(VI) transported into the cells within two hours and 67 percent at 16 hours at the lowest concentration (Ex. 31-22-18).

Water insoluble Cr(VI) particulates do not readily dissolve into epithelial lining fluids of the bronchoalveolar region. This has led to claims that insoluble chromates, such as lead chromate pigments, are not bioavailable and, therefore, are unable to cause carcinogenesis (Ex. 31-15). However, several scientific studies indicate that insoluble Cr(VI) particulates can come in close contact with the bronchoalveolar epithelial cell surface, allowing enhanced uptake into cells. Wise et al. showed that respirable lead chromate particles adhere to the surface of rodent cells in culture causing cell-enhanced dissolution of the chromate ion as well as phagocytosis of lead chromate particles (Exs. 35-68; 35-67). The intracellular accumulation was both time- and dose-dependant. Cellular uptake resulted in damage to DNA, apoptosis (i.e., form of programmed cell death), and neoplastic transformation (Ex. 35-119). Singh et al. showed that treatment of normal human lung epithelial cells with insoluble lead chromate particulates (0.4 to 2.0 μg/cm2) or soluble sodium chromate (10 μM) for 24 hours caused Cr(VI) uptake, Cr-DNA adduct formation, and apoptosis (Ex. 35-66). The proximate genotoxic agent in these cell systems was determined to be the chromate rather than the lead ions (Ex. 35-327). Elias et al. reported that cell-enhanced particle dissolution and uptake was also responsible for the cytotoxicity and neoplastic transformation in Syrian hamster embryo cells caused by Cr(VI) pigments, including several complex industrial chrome yellow and molybdate orange pigments (Ex. 125). These studies are key experimental evidence in the determination that water-insoluble Cr(VI) compounds, as well as water soluble Cr(VI) compounds, are to be regarded as carcinogenic agents. This determination is further discussed in the next section (see V.B.9).

Reduction to the poorly permeable Cr(III) in the epithelial lining fluid limits cellular uptake of Cr(VI). Ascorbic acid and glutathione (GSH) are believed to be the key molecules responsible for the extracellular reduction. Cantin et al. reported high levels of GSH in human alveolar epithelial lining fluid and Susuki et al. reported significant levels of ascorbic acid in rat lung lavage fluids (Exs. 35-147; 35-143). Susuki and Fukuda studied the kinetics of soluble Cr(VI) reduction with ascorbic acid and GSH in vitro and following intratracheal instillation (Ex. 35-90). They reported that the rate of reduction was proportional to Cr(VI) concentration with a half-life of just under one minute to several hours. They found the greatest reduction rates with higher levels of reductants. Ascorbic acid was more active than GSH. Cr(VI) reduction was slower in vivo than predicted from in vitro and principally involved ascorbic acid, not GSH. This research indicates that extracellular Cr(VI) reduction to Cr(III) is variable depending on the concentration and nature of the reductant in the epithelial fluid lining regions of the respiratory tract. De Flora et al. determined the amount of soluble Cr(VI) reduced in vitro by human bronchiolar alveolar fluid and pulmonary alveolar macrophage fractions over a short period and used these specific activities to estimate an “overall reducing capacity” of 0.9-1.8 mg Cr(VI) and 136 mg Cr(VI) per day per individual, respectively (Ex. 35-140).

De Flora, Jones, and others have interpreted the extracellular reduction data to mean that very high levels of Cr(VI) are required to “overwhelm” the reductive defense mechanism before target cell uptake can occur and, as such, impart a “threshold” character to the exposure-response (Exs. 35-139; 31-22-7). However, the threshold capacity concept does not consider that facilitated lung cell uptake and extracellular reduction are dynamic and parallel processes that happen concurrently. If their rates are comparable then some cellular uptake of Cr(VI) would be expected, even at levels that do not “overwhelm” the reductive capacity. Based on the in vitro kinetic data, it would appear that such situations are plausible, especially when concentrations of ascorbic acid are low. Unfortunately, there has been little systematic study of the dose-dependence of Cr(VI) uptake in the presence of physiological levels of ascorbate and GSH using experimental systems that possess active anion transport capability. The implications of extracellular reduction on the shape of Cr(VI) dose—lung cancer response curve is further discussed in Section VI.G.2.c.

Wise et al. did study uptake of a single concentration of insoluble lead chromate particles (0.8 μg/cm2) and soluble sodium chromate (1.3 μM) in Chinese hamster ovary cells co-treated with a physiological concentration (1mM) of ascorbate (Ex. 35-68). They found that the ascorbate substantially reduced, but did not eliminate, chromate ion uptake over a 24 hour period. Interestingly, ascorbate did not affect phagocytic uptake of lead chromate particles, although it eliminated the Cr(VI)-induced clastogenesis (e.g., DNA strand breakage and chromatid exchange) as measured under their experimental conditions.

Singh et al. suggested that cell surface interactions with insoluble lead chromate particulates created a concentrated microenvironment of chromate ions resulting in higher intracellular levels of chromium than would occur from soluble Cr(VI) (Ex. 35-149). Cell membrane-enhanced uptake of Cr(VI) is consistent with the intratracheal and intrabronchial instillation studies in rodents that show greater carcinogenicity with slightly soluble (e.g., calcium chromate and strontium chromate) than with the highly water-soluble chromates (e.g., sodium chromate and chromic acid) (Ex. 11-2).

Finally, Cr(VI) deposited in the tracheobronchial and alveolar regions of the respiratory tract is cleared by the mucocilliary escalator (soluble and particulate Cr(VI)) and macrophage phagocytosis (particulate Cr(VI) only). In most instances, these clearance processes take hours to days to completely clear Cr(VI) from the lung, but it can take considerably longer for particulates deposited at certain sites. For example, Ishikawa et al. showed that some workers had substantial amounts of chromium particulates at the bifurcations of the large bronchii for more than two decades after cessation of exposure (Ex. 35-81). Mancuso reported chromium in the lungs of six chromate production workers who died from lung cancer (as cited in Ex. 35-47). The interval between last exposure to Cr(VI) until autopsy ranged from 15 months to 16 years. Using hollow casts of the human tracheobronchial tree and comparing particle deposition with reported occurrence of bronchogenic tumors, Schlesinger and Lippman were able to show good correlations between sites of greatest deposition and increased incidence of bronchial tumors (Ex. 35-102).

b. Intracellular Reduction of Cr(VI). Once inside the cell, the hexavalent chromate ion is rapidly reduced to intermediate oxidation states, Cr(V) and Cr(IV), and the more chemically stable Cr(III). Unlike Cr(VI), these other chromium forms are able to react with DNA and protein to generate a variety of adducts and complexes. In addition, reactive oxygen species (ROS) are produced during the intracellular reduction of Cr(VI) that are also capable of damaging DNA. These reactive Start Printed Page 10153intermediates, and not Cr(VI) itself, are considered to be the ultimate genotoxic agents that initiate the carcinogenic process.

After crossing the cell membrane, Cr(VI) compounds can be non-enzymatically converted to Cr(III) by several intracellular reducing factors (Ex. 35-184). The most plentiful electron donors in the cell are GSH, and other thiols, such as cysteine, and ascorbate. Connett and Wetterhahn showed that a Cr(VI)-thioester initially forms in the presence of GSH (Ex. 35-206). A two-phase reduction then occurs with rapid conversion to Cr(V) and glutathionyl radical followed by relatively slower reduction to Cr(III) that requires additional molecules of GSH. Depletion of cellular GSH and other thiols is believed to retard complete reduction of Cr(VI) to Cr(III), allowing buildup of intermediates Cr(V) and Cr(IV). The molecular kinetics of the Cr(VI) to Cr(III) reduction with ascorbate is less well understood but can also involve intermediate formation of Cr(V) and free radicals (Ex. 35-184).

Another important class of intracellular Cr(VI) reductions are catalyzed by flavoenzymes, such as GSH reductase, lipoyl dehydrogenase, and ferredoxin-NADP oxidoreductase. The most prominent among these is GSH reductase that uses NADPH as a cofactor in the presence of molecular oxygen (O2) to form Cr(V)-NADPH complexes. During the reaction, O2 undergoes one electron reduction to the superoxide radical (O2-) which produces hydrogen peroxide (H2 O2) through the action of the enzyme superoxide dismutase. The Cr(V)-NADPH can then react with H2 O2 to regenerate Cr(VI) giving off hydroxyl radicals, a highly reactive oxygen species, by a Fenton-like reaction. It is, therefore, possible for a single molecule of Cr(VI) to produce many molecules of potentially DNA damaging ROS through a repeated reduction/oxidation cycling process. Shi and Dalal used electron spin resonance (ESR) to establish formation of Cr(V)-NADPH and hydroxyl radical in an in vitro system (Ex. 35-169; 35-171). Sugiyama et al. reported Cr(V) formation in cultured Chinese hamster cells treated with soluble Cr(VI) (Ex.35-133). Using a low frequency ESR, Liu et al. provided evidence of Cr(V) formation in vivo in mice injected with soluble Cr(VI) (Ex. 35-141-28).

Several studies have documented that Cr(VI) can generate Cr(V) and ROS in cultured human lung epithelial cells and that this reduction/oxidation pathway leads to DNA damage, activation of the p53 tumor suppressor gene and stress-induced transcription factor NF-κB, cell growth arrest, and apptosis (Exs. 35-125; 35-142; 31-22-18; 35-135). Leonard et al. used ESR spin trapping, catalase, metal chelators, free radical scavengers, and O2-free atmospheres to show that hydroxyl radical generation involves a Fenton-like reaction with soluble potassium dichromate (Ex. 31-22-17) and insoluble lead chromate (Ex.35-137) in vitro. Liu et al. showed that the Cr(IV)/Cr(V) compounds are also able to generate ROS with H2 O2 in a Fenton reduction/oxidation cycle in vitro (Ex. 35-183).

Although most intracellular reduction of Cr(VI) is believed to occur in the cytoplasm, Cr(VI) reduction can also occur in mitochondria and the endoplasmic reticulum. Cr(VI) reduction can occur in the mitochondria through the action of the electron transport complex (Ex. 35-230). The microsomal cytochrome P-450 system in the endoplasmic reticulum also enzymatically reduces Cr(VI) to Cr(V), producing ROS through reduction/oxidation cycling as described above (Ex. 35-171).

c. Genotoxicity and Damage to DNA. A large number of studies have examined multiple types of genotoxicity in a wide range of experimental test systems. Many of the specific investigations have been previously reviewed by IARC (Ex. 35-43), Klein (Ex. 35-134), ATSDR (Ex. 35-41), and the K.S. Crump Group (Ex. 35-47) and will only be briefly summarized here. The body of evidence establishes that both soluble and insoluble forms of Cr(VI) cause structural DNA damage that can lead to genotoxic events such as mutagenisis, clastogenisis, inhibition of DNA replication and transcription, and altered gene expression, all of which probably play a role in neoplastic transformation. The reactive intermediates and products that occur from intracellular reduction of Cr(VI) cause a wide variety of DNA lesions. The type(s) of DNA damage that are most critical to the carcinogenic process is an area of active investigation.

Many Cr(VI) compounds are mutagenic in bacterial and mammalian test systems (Ex. 35-118). In the bacterial Salmonella typhimurium strains, soluble Cr(VI) caused base pair substitutions at A-T sites as well as frame shift mutations (Ex. 35-161). Nestmann et al. also reported forward and frame shift mutations in Salmonella typhimurium with pre-solubilized lead chromate (Ex. 35-162). Several Cr(VI) compounds have produced mutagenic responses at various genetic loci in mammalian cells (Ex. 12-7). Clastogenic damage, such as sister chromatid exchange and chromosomal aberrations, have also been reported for insoluble Cr(VI) and soluble Cr(VI) (Exs. 35-132; 35-115). Mammalian cells undergo neoplastic transformation following treatment with soluble Cr(VI) or insoluble Cr(VI), including a number of slightly soluble zinc and insoluble lead chromate pigments (Exs. 12-5; 35-186).

Genotoxicity has been reported from Cr(VI) administration to animals in vivo. Soluble Cr(VI) induced micronucleated erythrocytes in mice following intraperitoneal (IP) administration (Ex. 35-150). It also increased the mutation frequency in liver and bone marrow following IP administration to lacZ transgenic mice (Exs. 35-168; 35-163). Izzotti et al. reported DNA damage in the lungs of rats exposed to soluble Cr(VI) by intratracheal instillation (Ex. 35-170). Intratracheal instillation of soluble Cr(VI) produced a time- and dose-dependant elevation in mutant frequency in the lung of Big Blue transgenic mice (Ex. 35-174). Oral administration of soluble Cr(VI) in animals did not produce genotoxicity in several studies probably due to route-specific differences in absorption. OSHA is not aware of genotoxicity studies from in vivo administration of insoluble Cr(VI). Studies of chromosomal and DNA damage in workers exposed to Cr(VI) vary in their findings. Some studies reported higher levels of chromosomal aberrations, sister chromatid exchanges, or DNA strand breaks in peripheral lymphocytes of stainless steel welders (Exs. 35-265; 35-160) and electroplaters (Ex. 35-164). Other studies were not able to find excess damage in DNA from the blood lymphocytes of workers exposed to Cr(VI) (Exs. 35-185; 35-167). These reports are difficult to interpret since co-exposure to other genotoxic agents (e.g., other metals, cigarette smoke) likely existed and the extent of Cr(VI) exposures were not known.

Because of the consistent positive response across multiple assays in a wide range of experimental systems from prokaryotic organisms (e.g., bacteria) to human cells in vitro and animals in vivo, OSHA regards Cr(VI) as an agent able to induce carcinogenesis through a genotoxic mode of action. Both soluble and insoluble forms of Cr(VI) are reported to cause genotoxicity and neoplastic transformation. On the other hand, Cr(III) compounds do not easily cause genotoxicity in intact cellular systems, presumably due to the inability of Cr(III) to penetrate cell membranes (Exs. 12-7; 35-186).

There has been a great deal of research to identify the types of damage to DNA caused by Cr(VI), the reactive Start Printed Page 10154intermediates that are responsible for the damage, and the specific genetic lesions critical to carcinogenesis. It was shown that Cr(VI) was inactive in DNA binding assays with isolated nuclei or purified DNA (Ex. 35-47). However, Cr(III) was able to produce DNA protein cross-links, sister chromatid exchanges, and chromosomal aberrations in an acellular system. Zhitkovich et al. showed that incubation of Chinese hamster ovary cells with soluble Cr(VI) produced ternary complexes of Cr(III) cross-linked to cysteine, other amino acids, or glutathione and the DNA phosphate backbone (Ex. 312). Utilizing the pSP189 shuttle vector plasmid, they showed these DNA-Cr(III)-amino acid cross-links were mutagenic when introduced in human fibroblasts (Ex. 35-131).

Another research group showed that plasmid DNA treated with Cr(III) produced intrastrand crosslinks and the production of these lesions correlated with DNA polymerase arrest (Ex. 35-126). The same intrastrand crosslinks and DNA polymerase arrest could also be induced by Cr(VI) in the presence of ascorbate as a reducing agent to form Cr(III) (Ex. 35-263). These results were confirmed in a cell system by treating human lung fibroblasts with soluble Cr(VI), isolating genomic DNA, and demonstrating dose-dependent guanine-specific arrest in a DNA polymerase assay (Ex. 35-188). Cr(V) may also form intrastrand crosslinks since Cr(V) interacts with DNA in vitro (Ex. 35-178). The Cr(V)-DNA crosslinks are probably readily reduced to Cr(III) in cell systems. Intrastrand crosslinks have also been implicated in inhibition of RNA polymerase and DNA topoisomerase, leading to cell cycle arrest, apoptosis and possibly other disturbances in cell growth that contribute to the carcinogenic pathway (Ex. 35-149).

DNA strand breaks and oxidative damage result from the one electron reduction/oxidation cycling of Cr(VI), Cr(V), and Cr(IV). Shi et al. showed that soluble Cr(VI) in the presence of ascorbate and H2 O2 caused DNA double strand breaks and 8-hydroxy deoxyguanine (8-OHdG, a marker for oxidative DNA damage) in vitro (Ex. 35-129). Leonard et al. showed that the DNA strand breaks were reduced by several experimental conditions including an O2-free atmosphere, catabolism of H2 O2 by catalase, ROS depletion by free radical scavengers, and chelation of Cr(V). They concluded that the strand breaks and 8-OHdG resulted from DNA damage caused by hydroxyl radicals from Cr(VI) reduction/oxidation cycling (Ex. 31-22-17). Generation of ROS-dependant DNA damage could also be shown with insoluble Cr(VI) (Ex. 35-137). DNA strand breaks and related damage caused by soluble Cr(VI) have been reported in Chinese hamster cells (Ex. 35-128), human fibroblasts (Ex. 311), and human prostate cells (Ex. 35-255). Pretreatment of Chinese hamster cells with a metal chelator suppressed Cr(V) formation from Cr(VI) and decreased DNA strand breaks (Ex. 35-197). Chinese hamster cells that developed resistance to H2 O2 damage also had reduced DNA strand breaks from Cr(VI) treatment compared to the normal phenotype (Ex. 35-176).

Several researchers have been able to modulate Cr(VI)-induced DNA damage using cellular reductants such as ascorbate, GSH and the free radical scavenger tocopherol (vitamin E). This has provided insight into the relationships between DNA damage, reduced chromium forms and ROS. Sugiyama et al. showed that Chinese hamster cells pretreated with ascorbate decreased soluble Cr(VI)-induced DNA strand damage (e.g., alkali-labile sites), but enhanced DNA-amino acid crosslinks (Ex. 35-133). Standeven and Wetterhahn reported that elimination of ascorbate from rat lung cytosol prior to in vitro incubation with soluble Cr(VI) completely inhibited Cr-DNA binding (Ex. 35-180). However, not all types of Cr-DNA binding are enhanced by ascorbate. Bridgewater et al. found that high ratios of ascorbate to Cr(VI) actually decreased intrastrand crosslinks in vitro while low ratios induced their formation (Ex. 35-263). This finding is consistent with research by Stearns and Watterhahn who showed that excessive ascorbate relative to Cr(VI) leads to two-electron reduction of Cr(III) and formation of Cr(III)-DNA monoadducts and DNA-Cr(III)-amino acid crosslinks (Ex. 35-166). Low amounts of ascorbate primarily cause one-electron reduction to intermediates Cr(V) and Cr(IV) that form crosslinks with DNA and ROS responsible for DNA strand breaks, alkali-labile sites, and clastogenic damage. This explains the apparent paradox that extracellular Cr(VI) reduction by ascorbate to Cr(III) reduces Cr(VI)-induced DNA binding but intracellular Cr(VI) reduction by ascorbate to Cr(III) enhances Cr-DNA binding. The aforementioned studies used soluble forms of Cr(VI), but Blankenship et al. showed that ascorbate pretreatment inhibited chromosomal aberrations in Chinese hamster ovary cells caused by both insoluble lead chromate particles as well as soluble Cr(VI) (Ex. 35-115). Pretreatment with the free radical scavenger tocopherol also inhibits chromosomal aberrations and alkali-labile sites in Cr(VI)-treated cells (Exs. 35-115; 35-128).

Studies of the different types of DNA damage caused by Cr(VI) and the modulation of that damage inside the cell demonstrate that Cr(VI) itself is not biologically active. Cr(VI) must undergo intracellular reduction to Cr(V), Cr(IV), and Cr(III) before the damage to DNA can occur. The evidence suggests that Cr(III) can cause DNA-Cr-amino acid, DNA-Cr-DNA crosslinks and Cr-DNA monoadducts. Cr(V) and possibly Cr(IV) contribute to intrastrand crosslinks and perhaps other Cr-DNA binding. ROS generated during intracellular reduction of Cr(VI) lead to lesions such as chromosomal aberrations, DNA strand breaks, and oxidative DNA damage. The specific DNA lesions responsible for neoplastic transformation have yet to be firmly established so all forms of DNA damage should, at this time, be regarded as potential contributors to carcinogenicity.

d. Cr(VI)-induced Disturbances in the Regulation of Cell Replication. Recent research has begun to elucidate how Cr(VI)-induced oxidative stress and DNA lesions trigger cell signaling pathways that regulate the cell growth cycle. The complex regulation of the cell growth cycle by Cr(VI) involves activation of the p53 protein and other transcription factors that respond to oxidative stress and DNA damage. The cellular response ranges from a temporary pause in the cell cycle to terminal growth arrest (i.e., viable cells that have lost the ability to replicate) and a programmed form of cell death, known as apoptosis. Apoptosis involves alterations in mitochondrial permeability, release of cytochrome c and the action of several kinases and caspases. Less is known about the molecular basis of terminal growth arrest. Terminal growth arrest and apoptosis serve to eliminate further growth of cells with unrepaired Cr(VI)-induced genetic damage. However, it is believed that cells which escape these protective mechanisms and regain replicative competence eventually become resistant to normal growth regulation and can transform to a neoplastic phenotype (Exs. 35-121; 35-122; 35-120).

Blankenship et al. first described apoptosis as the primary mode of cell death following a two hour treatment of Chinese hamster ovary cells with high concentrations (>150 μM) of soluble Cr(VI) (Ex. 35-144). Apoptosis also occurs in human lung cells following short-term treatment with soluble Cr(VI) Start Printed Page 10155(Ex. 35-125) as well as longer term treatment (e.g., 24 hours) with lower concentrations of soluble Cr(VI) (e.g., 10 μM) and insoluble Cr(VI) in the form of lead chromate (Ex. 35-166). Ye et al. found that the Cr(VI) treatment that caused apoptosis also activated expression of p53 protein (Ex. 35-125). This apoptotic response was substantially reduced in a p53-deficient cell line treated with Cr(VI), suggesting that the p53 activation was required for apoptosis. Other studies using p53 null cells from mice and humans confirmed that Cr(VI)-induced apoptosis is p53-dependent (Ex. 35-225).

The p53 protein is a transcription factor known to be activated by DNA damage, lead to cell cycle arrest, and regulate genes responsible for either DNA repair or apoptosis. Therefore, it is likely that the p53 activation is a response to the Cr(VI)-induced DNA damage. Apoptosis (i.e., programmed cell death) is triggered once the Cr(VI)-induced DNA damage becomes too extensive to successfully repair. In this manner, apoptosis serves to prevent replication of genetically damaged cells.

Several researchers have gone on to further elucidate the molecular pathways involved in Cr(VI)-induced apoptosis. ROS produced by intracellular Cr(VI) reduction/oxidation cycling have been implicated in the activation of p53 and apoptosis (Exs. 35-255; 35-122). Using specific inhibitors, Pritchard et al. showed that mitochondrial release of cytochrome c is critical to apoptotic death from Cr(VI) (Ex. 35-159). Cytochrome c release from mitochondria could potentially result from either direct membrane damage caused by Cr(VI)-induced ROS or indirectly by enhanced expression of the p53-dependent apoptotic proteins, Bax and Nova, known to increase mitochondrial membrane permeability.

Cr(VI) causes cell cycle arrest and reduces clonogenic potential (i.e., normal cell growth) at very low concentrations (e.g., 1 μM) where significant apoptosis is not evident. Xu et al. showed that human lung fibroblasts treated with low doses of Cr(VI) caused guanine-guanine intrastrand crosslinks, guanine-specific polymerase arrest, and inhibited cell growth at the G1/S phase of the cell cycle (Ex. 35-188). Zhang et al. described a dose-dependent increase in growth arrest at the G2/M phase of the cell cycle in a human lung epithelial cell line following 24 hour Cr(VI) treatment over a concentration range of 1 to 10 μM (Ex. 35-135). The cell cycle arrest could be partially eliminated by reducing production of Cr(VI)-induced ROS. Apoptosis was not detected in these cells until a concentration of 25 μM Cr(VI) had been reached. These data suggest that low cellular levels of Cr(VI) are able to cause DNA damage and disrupt the normal cell growth cycle.

Pritchard et al. studied the clonogenicity over two weeks of human fibroblasts treated 24 hours with soluble Cr(VI) concentrations from 1 to 10 μM (Ex. 35-120). They reported a progressive decline in cell growth with increasing Cr(VI) concentration. Terminal growth arrest (i.e., viable cells that have lost the ability to replicate) was primarily responsible for the decrease in clonogenic survival below 4 μM Cr(VI). At higher Cr(VI) concentrations, apoptosis was increasingly responsible for the loss in clonogenicity. Pritchard et al. and other research groups have suggested that a subset of cells that continue to replicate following Cr(VI) exposure could contain unrepaired genetic damage or could have become intrinsically resistant to processes (e.g., apoptosis, terminal growth arrest) that normally control their growth (Exs. 35-121; 35-122; 35-120). These surviving cells would then be more prone to neoplastic progression and have greater carcinogenic potential.

e. Summary. Respirable chromate particulates are taken up by target cells in the bronchoalveolar region of the lung, become intracellularly reduced to several reactive genotoxic species able to damage DNA, disrupt normal regulation of cell division and cause neoplastic transformation. Scientific studies indicate that both water soluble and insoluble Cr(VI) can be transported into the cell. In fact, cell surface interactions with slightly soluble and insoluble chromates may create a concentrated microenvironment of chromate ion, especially in the case of the slightly soluble Cr(VI) compounds that more readily dissociate. The higher concentration of chromate ion in close proximity to the lung cells will likely result in higher intracellular Cr(VI) than would occur from the highly water-soluble chromates. This is consistent with the studies of respiratory tract carcinogenesis in animals that indicate the most tumorigenic chromates had low to moderate water solubility. Once inside the cell, Cr(VI) is converted to several lower oxidation forms able to bind to and crosslink DNA. ROS are produced during intracellular reduction/oxidation of Cr(VI) that further damage DNA. These structural lesions are functionally translated into a impaired DNA replication, mutagenesis, and altered gene expression that ultimately lead to neoplastic transformation.

9. Conclusion

In the NRPM, OSHA preliminarily concluded that the weight of evidence supports the determination that all Cr(VI) compounds should be regarded as carcinogenic to workers (69 FR at 59351). This conclusion included the highly water soluble chromates, such as sodium chromate, sodium dichromate, and chromic acid; chromates of slight and intermediate water solubility such as calcium chromate, strontium chromates, and many zinc chromates (e.g. zinc yellow); and chromates that have very low water solubility and are generally considered to be water insoluble such as barium chromate and lead chromates. The strongest evidence supporting this conclusion comes from the many cohort studies reporting excess lung cancer mortality among workers engaged in the production of soluble chromates (Exs. 7-14; 31-22-11; 23; 31-18-4), chromate pigments (Exs. 7-36; 7-42; 7-46), and chrome plating (Exs. 35-62; 35-271). Chromate production workers were principally exposed to the highly soluble sodium chromate and dichromate (Ex. 35-61) although lesser exposure to other chromates, such as highly soluble chromic acid and slightly soluble calcium chromate probably occurred. Pigment production workers were principally exposed Cr(VI) in the form of lead and zinc chromates. Significantly elevated lung cancer mortality was found in two British chromium electroplating cohorts (Exs. 35-62; 35-271). These workers were exposed to Cr(VI) in the form of chromic acid mist. Therefore, significantly elevated lung cancer rates have been observed in working populations exposed to a broad range of Cr(VI) compounds.

Cellular research has shown that both highly water soluble (e.g. sodium chromate) Cr(VI) and water insoluble (e.g. lead chromate) Cr(VI) enter lung cells (see Section V.8.a) and undergo intracellular reduction to several lower oxidation forms able to bind to and crosslink DNA as well as generate reactive oxygen species that can further damage DNA (see Section V.8.b). Soluble and insoluble Cr(VI) compounds are reported to cause mutagenesis, clastogenesis, and neoplastic transformation across multiple assays in a wide range of experimental systems from prokaryotic organisms to human cells in vitro and animals in vivo (see Section V.8.c).

The carcinogenicity of various Cr(VI) compounds was examined after instillation in the respiratory tract of rodents. Slightly water soluble Cr(VI) Start Printed Page 10156compounds, strontium chromate, calcium chromate, and some zinc chromates produced a greater incidence of respiratory tract tumors than highly water soluble (e.g. sodium dichromate and chromic acid) and water insoluble (e.g. barium chromate and lead chromates) Cr(VI) compounds under similar experimental protocol and conditions (see Section V.7). This likely reflects the greater tendency for chromates of intermediate water solubility to provide a persistent high local concentration of solubilized Cr(VI) in close proximity to the target cell. Highly soluble chromates rapidly dissolve and diffuse in the aqueous fluid lining the epithelia of the lung. Thus, these chromates are less able to achieve the higher local concentrations within close proximity of the lung cell surface than the slightly water soluble chromates. However, it has been shown that water-soluble Cr(VI) can still enter lung cells, damage DNA, and cause cellular effects consistent with carcinogenesis (Ex. 31-22-18; 35-125; 35-135; 35-142). Like the slightly water soluble chromates, water insoluble Cr(VI) particulates are able to come in close contact with the lung cell surface and slowly dissolve into readily absorbed chromate ion. For example, water insoluble lead chromate has been shown to enter human airway cells both through extracellular solubilization as chromate ion (Exs. 35-66; 35-327; 47-12-3) as well as internalization as unsolubilized particulate (Exs. 35-66; 47-19-7). However, the rate of solubilization and uptake of water insoluble Cr(VI) is expected to be more limited than chromates with moderate solubility. Once chromate ion is inside lung cells, studies have shown that similar cellular events believed critical to initiating neoplastic transformation occur regardless of whether the source is a highly soluble or insoluble Cr(VI) compound (Ex. 35-327).

a. Public Comment on the Carcinogenicity of Cr(VI) Compounds

In the NRPM, OSHA requested comment on whether currently available epidemiologic and experimental studies supported the determination that all Cr(VI) compounds possess carcinogenic potential and solicited additional information that should be considered in evaluating relative carcinogenic potency of the different Cr(VI) compounds (69 FR 59307). Several comments supported the view that sufficient scientific evidence exists to regard all Cr(VI) compounds as potential occupational carcinogens (Exs. 38-106-2; 38-222; 39-73-2; 40-10-2; 42-2). The AFL-CIO stated that “ * * * the agency has fully demonstrated that Cr(VI) is a human carcinogen and that exposed workers are at risk of developing lung cancer” (Ex. 38-222). NIOSH stated that “the epidemiologic and experimental studies cited by OSHA support the carcinogenic potential of all Cr(VI) compounds (i.e. water soluble, insoluble, and slightly soluble)” (Ex. 40-10-2, p. 4). Peter Lurie of Public Citizen testified:

As we heard repeatedly in the course of this hearing, scientific experts, in fact, agree. They agree that the most reasonable approach to the regulation is to consider them all [Cr(VI) compounds] to be carcinogenic (Tr. 710).

Several commenters agreed that the evidence supported the qualitative determination that Cr(VI) compounds were carcinogenic but wished to make clear that the information was inadequate to support quantitative statements about relative potency of the individual chromates (Exs. 38-106-2; 40-10-2; 42-2). For example, the Boeing Company in their technical comments stated:

The available data does support the conclusion that the low solubility hexavalent chromium compounds [e.g. strontium chromate] can cause cancer but evidence to support a quantitative comparison of carcinogenic potency based on differences in solubility is lacking (Ex. 38-106-2, p. 18).

Pigment Manufacturers' Comments on Carcinogenicity of Lead Chromate—One group that did not regard all Cr(VI) compounds as occupational carcinogens was the color pigment manufacturers who manufacture and market lead chromate pigments which are primarily used in industrial coatings and colored plastic articles. The color pigment manufacturers maintain that their lead chromate products are unreactive in biological systems, are not absorbed into the systemic circulation by any route, and can not enter lung cells (Ex. 38-205, p. 14). Their principal rationale is that lead chromate is virtually insoluble in water, is unable to release chromate ion into aqueous media, and therefore, is incapable of interacting with biological systems (Exs. 38-205, p. 95; 38-201-1, p. 9). The color pigment manufacturers assert that their lead chromate pigment products are double encapsulated in a resin/plastic matrix surrounded by a silica coating and that the encapsulated pigment becomes even less “bioavailable” than unencapsulated “less stabilized” lead chromates. They believe the extreme stability and non-bioavailable nature of their products makes them a non-carcinogenic form of Cr(VI) (Ex. 38-205, p. 106).

According to the Color Pigment Manufacturers Association (CPMA), several pieces of scientific evidence support their position, namely, the lack of a significant excess of lung cancer mortality in three cohorts of pigment workers engaged in the production of water-insoluble lead chromate (Ex. 38-205, pp. 88-91) and the lack of statistically significant elevated tumor incidence following a single instillation of lead chromate in the respiratory tract of rats (Ex. 38-205, pp. 88-92). They dismiss as irrelevant other animal studies that produced statistically significant increases in tumors when lead chromate was repeatedly injected by other routes. In addition, CPMA claims that the lead chromate used in cellular studies that report genotoxicity was reagent grade, was contaminated with soluble chromate, and was inappropriately solubilized using strong acids and bases prior to treatment (Exs. 38-205, pp. 93-94; 47-31, pp. 9-13). They are especially critical of studies conducted by the Environmental and Genetic Toxicology group at the University of Southern Maine that report lead chromate particulates to be clastogenic in human lung cells (Exs. 34-6-1; 38-205, pp. 98-102 & appendix D; 47-22). Instead, they rely on two in vitro studies of lead chromate pigments that report a lack of genotoxicity in cultured bacterial and hamster ovary cells, respectively (Exs. 47-3 Appendix C; 38-205, p. 94).

OSHA addresses many of the CPMA claims in other sections of the preamble. The bioavailability issue of encapsulated lead chromate is addressed in Section V.A.2. The CPMA request to consider the lack of excess lung cancer mortality among pigment workers exposed exclusively to lead chromate is discussed in Section V.B.2. The CPMA assertions that animal studies are evidence that lead chromates are not carcinogenic to workers are addressed in Section V.B.7. The studies documenting uptake of lead chromate into lung cells are described in Section V.B.8.a. Section V.B.8.c describes evidence that lead chromate is genotoxic. As requested by CPMA, OSHA will pull these responses together and expand on their concerns below.

Lung Cancer Mortality in Pigments Workers Exposed to Lead Chromate—Comments and testimony from NIOSH and others cite evidence of excess lung cancer among pigment workers and support the results of OSHA's preliminary risk assessment for color pigments in general and for lead chromate in particular (Tr. 135-146, 316, 337, Ex. 40-18-1, p. 2). However, comments submitted by the CPMA and Start Printed Page 10157the Dominion Colour Corporation (DCC) attributed the excess lung cancer risk observed in pigment worker studies to zinc chromate (Tr. 1707, 1747, Exs. 38-201-1, p. 13; 38-205, p. 90; 40-7, p. 92). For example, the CPMA stated that:

When lead chromate and zinc chromate exposures occur simultaneously, there appears to be a significant cancer hazard. However, when lead chromate pigments alone are the source of chromium exposure, a significant carcinogenic response has never been found (Ex. 40-7, p. 92).

The latter statement refers to the Davies et al. (1984) study of British pigment workers, the Cooper et al. (1983) study of U.S. pigment workers, and the Kano et al. (1993) study of pigment workers in Japan, all of which calculated separate observed and expected lung cancer deaths for workers exposed exclusively to lead chromate (Ex. 38-205, p. 89). DCC and the Small Business Administration's Office of Advocacy similarly stated that the excess lung cancer risk observed among workers exposed to both zinc chromate and lead chromate cannot necessarily be attributed to lead chromate (Exs. 38-201-1, p. 13; 38-7, p. 4).

OSHA agrees with CPMA and DCC that the excess lung cancer observed in most pigment worker studies taken alone cannot be considered conclusive evidence that lead chromate is carcinogenic. Given that the workers were exposed to both zinc chromate and lead chromate, it is not possible to draw strong conclusions about the effects of either individual compound using only these studies. However, based on the overall weight of available evidence, OSHA believes that the excess lung cancer found in these studies is most likely attributable to lead chromate as well as zinc chromate exposure. Lead chromate was the primary source of Cr(VI) for several worker cohorts with excess lung cancer (e.g., Davies et al. (1984), Factory A; Hayes et al. (1989); and Deschamps et al. (1995)) (Exs. 7-42; 7-46; 35-234), and as previously discussed, there is evidence from animal and mechanistic studies supporting the carcinogenicity of both zinc chromate and lead chromate. Considered in this context, the elevated risk of lung cancer observed in most chromate pigment workers is consistent with the Agency's determination that all Cr(VI) compounds—including lead chromate—should be regarded as carcinogenic.

Moreover, OSHA disagrees with the CPMA and DCC interpretation of the data on workers exposed exclusively to lead chromate. In the Preamble to the Proposed Rule, OSHA stated that “[t]he number of lung cancer deaths [in the Davies, Cooper, and Kano studies] is too small to be meaningful” with respect to the Agency's determination regarding the carcinogenicity of lead chromate (FR 69 at 59332). The CPMA subsequently argued that:

[b]y this rationale, OSHA could never conclude that a compound such as lead chromate pigment exhibits no carcinogenic potential because there can never be enough lung cancer deaths to produce a “meaningful” result. This is an arbitrary and obviously biased assessment which creates an insurmountable barrier. Since the lead chromate pigments did not create an excess of lung cancer, there cannot be a significant enough mortality from lung cancer to be meaningful (Ex. 38-205, p. 90).

OSHA believes that these comments reflect a misunderstanding of the sense in which the Davies, Cooper, and Kano studies are too small to be meaningful, and also a misunderstanding of the Agency's position.

Contrary to CPMA's argument, a study with no excess in lung cancer mortality can provide evidence of a lack of carcinogenic effect if the confidence limits for the measurement of effect are close to the null value. In other words, the measured effect must be close to the null and the study must have a high level of precision. In the case of the Davies, Cooper, and Kano studies, the standardized mortality ratio (SMR) is the measurement of interest and the null value is an SMR of 1. Table V.10 below shows that the SMRs for these study populations are near or below 1; however, the 95% confidence intervals for the SMRs are quite wide, indicating that the estimated SMRs are imprecise. The Kano data, for example, are statistically consistent with a “true” SMR as low as 0.01 or as high as 2.62. The results of these studies are too imprecise to provide evidence for or against the hypothesis that lead chromate is carcinogenic.

This lack of precision may be partly explained by the small size of the studies, as reflected in the low numbers of expected lung cancers. However, it is the issue of precision, and not the number of lung cancer deaths per se, that led OSHA to state in the preamble to the proposed rule that the Davies, Cooper, and Kano studies cannot serve as the basis of a meaningful analysis of lead chromate carcinogenicity (Exs. 7-42; 2-D-1; 7-118). In contrast, a study population that has confidence limits close to or below 1 would provide evidence to support the DCC claim that “ * * * if lead chromate pigments possess any carcinogenic potential at all, it must be extremely small” (Ex. 38-201-1, p. 14) at the exposure levels experienced by that population. While this standard of evidence has not been met in the epidemiological literature for pigment workers exposed exclusively to lead chromate (i.e., the Davies, Cooper, and Kano studies), it is hardly an “insurmountable barrier” that sets up an impossible standard of proof for those who contend that lead chromate is not carcinogenic.

Some comments suggested that the Davies, Cooper, and Kano studies should be combined to derive a summary risk measure for exposure to lead chromate (see e.g. Ex. 38-201-1, pp. 13-14). However, OSHA believes that these studies do not provide a Start Printed Page 10158suitable basis of meta-analysis. There is little information with which to assess factors recognized by epidemiologists as key to meta-analysis, for example sources of bias or confounding in the individual studies and comparability of exposures and worker characteristics across studies, and to verify certain conditions required for comparability of SMRs across these studies (see e.g. Modern Epidemiology, Rothman and Greenland, p. 655). In addition, the inclusion criteria and length of follow-up differ across the three studies. Finally, each of the studies is extremely small. Even if it were appropriate to calculate a ‘summary’ SMR based on them, the precision of this SMR would not be much improved compared to those of the original studies.

In their written testimony, DCC suggested that OSHA should aggregate the data from the Davies, Cooper, and Kano studies in order to determine whether there is a discrepancy between the results of these three studies, taken together, and OSHA's preliminary risk assessment (Ex. 38-201-1, pp. 13-14). DCC performed a calculation to compare OSHA's risk model with the observed lung cancer in the three cohorts. DCC stated that:

OSHA estimates a chromate worker's risk of dying from lung cancer due to occupational exposure as about one chance in four * * * [Assuming that there were about] 200 workers in the Kano study, the total in the three studies would be 600. A calculation of one quarter would be 150 deaths. To compensate for a working life of less than OSHA's 45 years [an assumption of 20 years] provides * * * a refined estimate of about 70 deaths. An observed number less than this could be due either to exposures already in practice averaging much less than the current PEL of 52, or to lead chromate having much less potential (if any) for carcinogenicity than other chromates. In any event the actual incidence of death from lung cancer would appear to be no more than one tenth of OSHA's best estimate (Ex. 38-201-1, pp. 15-16).

The method suggested by DCC is not an appropriate way to assess the carcinogenicity of lead chromate, to identify a discrepancy between the pigment cohort results and OSHA's risk estimates, or to determine an exposure limit for lead chromate. Among other problems, DCC's calculation does not make a valid comparison between OSHA's risk estimates and the results of the Davies, Cooper, and Kano studies. OSHA's ‘best estimate’ of lung cancer risk for any given Cr(VI)-exposed population depends strongly on factors including exposure levels, exposure duration, population age, and length of follow-up. The ‘one in four’ prediction cited by DCC applies to one specific risk scenario (lifetime risk from 45 years of occupational exposure at the previous PEL of 52 μg/m3). OSHA's best estimate of risk would be lower for a population with lower exposures (as noted by DCC), shorter duration of exposure, or less than a lifetime of follow-up. Without adequate information to adjust for each of these factors, a valid comparison cannot be drawn between OSHA's risk predictions and the results of the lead chromate cohort studies.

The importance of accounting for cohort age and follow-up time may be illustrated using information provided in the Cooper et al. study. As shown in Table V-11 below, approximately three-fourths of the Cooper et al. Plant 1 cohort members were less than 60 years old at the end of follow-up.

For a population of 600 with approximately the same distribution of follow-up time as described in the Cooper et al. publication (e.g., 0.4% of workers are followed to age 84, 2% to age 79, etc.), OSHA's risk model predicts about 3-15 excess lung cancers (making the DCC assumption that workers are exposed for 20 years at 52 μg/m3), rather than the 70 deaths calculated by the DCC. If the workers were typically exposed for less than 20 years or at levels lower than 52 μg/m3, OSHA s model would predict still lower risk. A precise comparison between OSHA's risk model and the observed lung cancer risk in the Davies, Cooper and Kano cohorts is not possible without demographic, work history and exposure information on the lead chromate workers. (In particular, note that year 2000 background lung cancer rates were used in the calculation above, as it was not feasible to reconstruct appropriate reference rates without work history information on the cohorts.) However, this exercise illustrates that DCC's assertion of a large discrepancy between OSHA's risk model and the available data on workers exposed exclusively to lead chromate is not well-founded. To make a valid comparison between the OSHA risk Start Printed Page 10159model and the lung cancer observed in the lead chromate cohorts would require more information on exposure and follow-up than is available for these cohorts.

OSHA received comments and testimony from NIOSH and others supporting of the Agency's interpretation of the epidemiological literature on Cr(VI) color pigments, including lead chromate (Tr. 135-146, 316, 337, Ex. 40-18-1, p. 2). At the hearing, Mr. Robert Park of NIOSH stated that the available studies of workers exposed to chromate pigments show “ * * * a general pattern of excess [lung cancer] * * * ” and pointed out that “[i]n several of the studies, lead [chromate] was by far the major component of production, like 90 percent * * * So I don't think there is any epidemiological evidence at this point that gets lead off the hook” (Tr. 337). Regarding the lack of statistically significant excess lung cancer in several pigment worker cohorts, Mr. Park identified study attributes that may have obscured an excess in lung cancer, such as the high percentage of workers lost to follow-up among immigrant workers in the Davies et al. study (Tr. 337) or a healthy worker effect in the Hayes et al. study (Tr. 316). Dr. Paul Schulte of NIOSH explained that

* * * a lot of these studies that appear to be negative were either of low power or had [some] other kind of conflicting situation [so] that we can't really consider them truly negative studies (Tr. 338).

Dr. Herman Gibb testified that the epidemiological studies relied on by CPMA and DCC to question the carcinogenicity of lead chromate have very low expected numbers of lung cancer deaths, so they “ * * * really don't have a lot of ability to be able to detect a risk” (Tr. 135-136). Public Citizen agreed with OSHA's preliminary conclusion that lead chromate is carcinogenic. Based on the major pigment worker cohorts identified by OSHA in the Preamble to the Proposed Rule, Public Citizen's Health Research Group concluded that

* * * inadequately-powered studies, the standardized mortality ratios for exposed workers are significantly elevated (range 1.5-4.4) and a relationship between extent of exposure (whether measured by duration of exposure or factory) generally emerges; [moreover,] [t]hese studies must be placed in the context * * * of the animal carcinogenicity studies * * * and the mechanistic studies reviewed by OSHA (Ex. 40-18-1, p. 2).

Tumor Incidence in Experimental Animals Administered Lead Chromate—CPMA also claims that the absence of evidence for carcinogenicity found among the three cited cohorts of lead chromate pigment workers “ * * * is further confirmed by the rat implantation studies of Levy” (Ex. 38-205, p. 98). They argue that these studies which involved implantation into rat lungs “ * * * indicated no increased incidence of tumors for lead chromate pigment, although more soluble chromates exhibited varying degrees of carcinogenicity” (Ex. 38-205, p. 93). They dismissed other animal studies involving intramuscular and subcutaneous injection of lead chromate which did report increased incidence of tumors because they believe these techniques

* * * are of questionable relevance in relation to human workplace exposure conditions in industry, whereas tests involving implantation in rat lung * * * are relevant to inhalation in industrial exposures (Ex. 38-205, p. 93).

In a more recent submission, CPMA remarked that the intramuscular and subcutaneous injection studies with lead chromate were contradictory and “ * * * problematic in that false positive results frequently occur during the study procedure (Ex. 47-31, p. 13).

The rat implantation studies of Levy involved the surgical placement of a Cr(VI)-containing pellet in the left bronchus of an anesthetized rat (Exs. 10-1; 11-12; 11-2). This pellet procedure was an attempt to deliver Cr(VI) compounds directly to the bronchial epithelium and mimic continuous chronic in vivo dosing at the tissue target site in order to assess the relative ability of different Cr(VI) compounds to induce bronchogenic carcinoma. Histopathological evaluation of the rat lung was conducted after a two year exposure time. In most cases, approximately 100 rats were implanted with a single pellet for each Cr(VI) test compound. The total lifetime dose of Cr(VI) received by the animal was generally between 0.2 and 1.0 mg depending on the compound. The amount of Cr(VI) that actually leached from the cholesterol pellet and remained near the lung tissue was never determined. At least 20 different commercially relevant Cr(VI) compounds ranging from water insoluble to highly water soluble were tested using this intrabronchial implantation protocol.

The results of these studies are described in preamble section V.B.7 and tables V-7, V-8, and V-9. Reagent grade lead chromate and six different lead chromate pigments were tested. The lead chromate pigments were a variety of different chrome yellows, including a silica encapsulated chrome yellow, and molybdenum orange. The incidence of bronchogenic cancer in the rats under this set of experimental conditions was one percent or less for all the lead chromates tested. This incidence was not statistically different from the negative controls (i.e. rats implanted with a cholesterol pellet containing no test compound) or rats administered either the water-insoluble barium chromate or the highly soluble chromic acid and sodium dichromate. The percent incidence of bronchogenic cancer in lead chromate-treated rats was substantially less than that of rats treated with slightly soluble strontium chromates (about 52 percent) and calcium chromate (24 percent). The type of bronchogenic cancer induced in these experiments was almost entirely squamous cell carcinomas.

OSHA does not agree with the CPMA position that absence of a significant tumor incidence in the intrabronchial implantation studies confirms that lead chromates lack carcinogenic activity and, therefore, should not be subject to the OSHA Cr(VI) standard. The bioassay protocol used approximately 100 test animals per experimental group. This small number of animals limits the power of the bioassay to detect tumor incidence below three to four percent with an acceptable degree of statistical confidence. Three of the lead chromates, in fact, produced a tumor incidence of about one percent (e.g. 1 tumor in 100 rats examined) which was not statistically significant. The researchers only applied a single 2 mg [approximately 0.3 mg Cr(VI)] dose of lead chromate to the bronchus of the rats. Since it was not experimentally confirmed that the lead chromate pigments were able to freely leach from the cholesterol pellet, the amount of Cr(VI) actually available to the lung tissue is not entirely clear. Therefore, OSHA believes a more appropriate interpretation of the study findings is that lead chromates delivered to the respiratory tract at a dose of about 0.3 mg Cr(VI) (maybe lower) lead to a less than three percent tumor incidence.

However, OSHA agrees that the intrabronchial implantation protocol does provide useful information regarding the relative carcinogenicity of different Cr(VI) compounds once they are delivered and deposited in the respiratory tract. No other study examines the carcinogenicity of such a broad range of commercial Cr(VI) compounds under the same experimental conditions in the relevant target organ to humans (i.e. respiratory tract) following in vivo administration. OSHA agrees with CPMA that the results of this study provide credible Start Printed Page 10160evidence that water insoluble lead chromates are less carcinogenic than some of the more moderately soluble chromates. Specifically, this includes the slightly soluble zinc chromates (e.g. zinc yellow, zinc potassium chromates, basic zinc chromates) as well as strontium chromate and calcium chromate. Intrabronchial implantation of chromic acid and other highly soluble Cr(VI) salts, such as sodium chromates, did not induce a significant number of tumors. Therefore, these experiments do not indicate lead chromate are less carcinogenic than the highly water soluble Cr(VI) compounds.

If the histopathology data from the intrabronchial implantation is examined more closely, all lead chromates increased the incidence of squamous metaplasia relative to controls, and, for some lead chromates, squamous dysplasia of the bronchial epithelium occurred (Table 2, Ex. 11-2). Squamous metaplasia and dysplasia are generally considered to be transformed cellular states from which a neoplasm (e.g. carcinomas) can arise (Ex. 11-12). Increased squamous metaplasia was common among all tested Cr(VI) compounds but not among Cr(III)-containing materials or the negative controls (Ex. 11-12). The increased metaplasia induced by lead chromates is unlikely to be due to bronchial inflammation since the degree of inflammation was no greater than that observed in the cholesterol-implanted controls (Table 2, Ex. 11-2).

The squamous metaplasia and dysplasia in the rat lung model following low dose lead chromate administration is consistent with a low carcinogenic response (e.g. incidence of one percent or less) not able to be detected under the conditions of the animal bioassay. This explanation is supported by studies (discussed later in the section) that show lead chromate can enter lung cells, damage DNA, and cause genotoxic events leading to neoplastic transformation.

Lead chromate carcinogenicity is also supported by the animal studies that CPMA dismisses as problematic and of questionable relevance. These studies administered lead chromates to rodents by either the subcutaneous (Exs. 8-25, 5-2, 8-37) or intramuscular routes (Ex. 10-2). While OSHA agrees that these routes may be less relevant to occupational inhalation than implantation in the respiratory tract, the studies exposed rats to a larger dose of lead chromate. The higher amounts of Cr(VI) produced a significant incidence of tumors at the injection site (see section V.B.7.c).

The lead chromate pigments, chrome yellow and chrome orange, induced injection site rhabdomyosarcomas and fibrosarcomas in 65 percent of animals following a single 30 mg injection in a saline suspension (Ex. 8-37). The rats received a roughly ten fold higher dose of Cr(VI) than in the intrabronchial bioassay. Rats injected with saline alone did not develop injection site tumors. Only two percent or less of rats receiving equal quantities of the inorganic pigments iron yellow and iron red developed these tumors. The iron oxides are not considered to be carcinogenic and do not give a significant neoplastic response in this bioassay. OSHA has no reason to believe the experimental procedure was problematic or given to frequent false positives.

A similarly high incidence (i.e. 70 percent) of the same injection site sarcomas were found in an independent study in which rats were injected intramuscularly with reagent grade lead chromate once a month for nine months (Ex. 10-2). Each injection contained approximately 1.3 mg of Cr(VI) and the total dose administered was over 30 times higher than the intrabronchial implantation. The lead chromate was administered in a glycerin vehicle. The vehicle produced less than a two percent incidence of injection site sarcomas when administered alone.

Contrary to statements by Eurocolour (Ex. 44-3D), lead chromate did produce a low incidence of site-of-contact tumors in rats in an earlier study when administered by either intramuscular or intrapleural implantation (Ex. 10-4). There was no tumor incidence in the control animals. The dose of lead chromate in this early publication was not stated.

Based on the increase in pre-neoplastic changes from the single low dose intrabronchial implantation and the high incidence of malignant tumors resulting from larger doses administered by subcutaneous and intramuscular injection, it is scientifically reasonable to expect that larger doses of lead chromate may have produced a higher incidence of tumors in the more relevant intrabronchial implantation procedure. The highly soluble sodium dichromate produced a small (statistically insignificant) incidence of squamous cell carcinoma (i.e. one percent) upon single low dose intrabronchial implantation similar to the lead chromates (Ex. 11-2). In another study, sodium dichromate caused a significant 17 percent increase in the incidence of respiratory tract tumors when instilled once a week for 30 months in the trachea of rats (Ex. 11-7). The weekly-administered dose for this repeated instillation was about 1/5th the dose of that used in the intrabronchial implantation assay but the total administered dose after 30 months was about 25 times higher. Rats that received a lower total dose of sodium dichromate or the same total dose in more numerous instillations (i.e. lower dose rate) developed substantially fewer tumors that were statistically indistinguishable from the saline controls. A third study found a 15 percent increase (not statistically significant) in lung tumor incidence when rats repeatedly inhaled aerosolized sodium dichromate for 18 months at the highest air concentrations tested (Ex. 10-11). These sodium dichromate studies are further described in section V.B.7.a. The findings suggest that the lack of significant carcinogenic activity in the intrabronchial implantation study reflects, in part, the low administered dose employed in the bioassay.

In his written testimony to OSHA, Dr. Harvey Clewell directly addressed the issue of interpreting the absence of carcinogenicity in an animal study as it relates to significant risk.

First, the ability to detect an effect depends on the power of the study design. A statistically-based No Observed Adverse Effect Level (NOAEL) in a toxicity study does not necessarily mean that there is no risk of adverse effect. For example, it has been estimated that a NOAEL in a typical animal study can actually be associated with the presence of an effect in as many as 10% to 30% of the animals. Thus the failure to observe a statistically significant increase in tumor incidence at a particular exposure does not rule out the presence of a substantial carcinogenic effect at that exposure * * *. Similarly the failure of Levy et al. (1986) to detect an increase in tumors following intrabronchial instillation of lead chromate does not in itself demonstrate a lack of carcinogenic activity for that compound. It only demonstrates a lower activity than for other compounds that showed activity in the same experimental design. Presumably this lower activity is primarily due to its low solubility; evidence of solubilization, cellular uptake, and carcinogenic activity of this compound [i.e. lead chromate] is provided in other studies (Maltoni et al. 1974, Furst et al., 1976, Blankenship et al., 1997; Singh et al., 1999; Wise et al., 2004) (Ex. 44.5, p. 13-14).

OSHA agrees with Dr. Clewell that the inability to detect a statistically significant incidence of tumors in one study that administers a single low dose of lead chromate to a limited number of animals is not evidence that this Cr(VI) compound lacks carcinogenic activity. This is especially true when there exists an elevation in pre-neoplastic lesions and other studies document significant Start Printed Page 10161tumor incidence in animals administered higher doses of lead chromate.

Cellular Uptake and Genotoxicity of Lead Chromate—CPMA disputes the many studies that report lead chromate to be genotoxic or clastogenic in cellular test systems (Exs. 35-162; 12-5; 35-119; 35-188; 35-132; 35-68; 35-67; 35-115; 35-66; 47-22-1; 47-12-3; 35-327; 35-436). They claim that the studies inappropriately solubilized the lead chromate “ * * * in non-biological conditions such as strong alkali or strong acid that causes the chemical breakdown of the lead chromate crystal” (Ex. 38-205, p. 94) and the “lead chromate had been dissolved * * * using aggressive substances” (Ex. 38-205, p. 99). In a later submission, CPMA states state that some of the cellular studies used reagent grade lead chromate that is only ≥98 percent pure and may contain up to 2 percent soluble chromate (Ex. 47-31, p. 11). They speculate that the interactions (e.g. chromate ion uptake, chromosomal aberrations, DNA adducts, etc.) described in studies using cell cultures treated with lead chromate are either due to the presumed contamination of soluble chromate or some other undefined “reactive nature” of lead chromate. CPMA adds that “ * * * the studies referenced by OSHA [that use reagent grade lead chromate] have no relevance to occupational exposures to commercial lead chromate pigments” (Ex. 38-205, p. 11-12).

OSHA agrees that studies involving lead chromate pre-solubilized in solutions of hydrochloric acid, sodium hydroxide or other strong acids and bases prior to treatment with cells are not particularly relevant to the inhalation of commercial lead chromate particulates. However, several relevant cellular studies have demonstrated that lead chromate particulates suspended in biological media and not can enter lung cells, damage DNA, and cause altered gene expression as described below.

Beginning in the late 1980s, there has been a consistent research effort to characterize the genotoxic potential of lead chromate particulate in mammalian cells. The lead chromate was not pre-solubilized prior to cell treatment in any of these investigations. In most of the studies, lead chromate particles were rinsed with water and then acetone. The rinses cleansed the particles of water- and acetone-soluble contaminants before cell treatment. This served to remove any potential water-soluble Cr(VI) present that might confound the study results. In most instances, the lead chromate particles were filtered, stirred or sonicated in suspension to break up the aggregated particles into monomeric lead chromate particulates. These lead chromate particulates were primarily less than 5 μm in diameter. This is consistent with the inhaled particle size expected to deposit in the bronchial and alveolar regions of the lung where lung cancer occurs. Air-dried lead chromate particulates were introduced to the cell cultures in a suspension of either saline-based media or acetone. Lead chromate particulate is considered to be insoluble in both solvents so significant solubilization is not expected during the process of creating a homogenous suspension.

The initial research showed that lead chromate particulate morphologically transformed mouse and hamster embryo cells (Exs. 35-119; 12-5). One study tested a variety of lead chromate pigments of different types (e.g. chrome yellows, chrome oranges, molybdate oranges) as well as reagent grade lead chromate (Ex. 12-5). The transformed cells displayed neoplastic properties (e.g. growth in soft agar) and were tumorigenic when injected into animals (Ex. 35-119; 12-5). While lead chromate particulate transformed mouse embryo cells, it is important to note that lead chromate particulate was not found to be mutagenic in these cells suggesting that other types of genetic lesions (e.g. clastogenicity) may be involved (Ex. 35-119).

Follow-on research established that lead chromate particulate caused DNA-protein crosslinks, DNA strand breaks, and chromosomal aberrations (i.e. chromatid deletions and achromatic lesions combined) in mammalian cells rather than DNA nucleotide binding often associated with base substitution and frameshift mutations captured in a standard Ames assay (Exs. 35-132; 35-188). This distinguishes lead chromate particulate from high concentrations of soluble Cr(VI) compounds or pre-solubilized lead chromate which can cause these mutations.

Lead chromate particulate enters mammalian embryo cells by two distinct pathways (Ex. 35-68). It partially dissolves in the culture medium (i.e. biological saline solution) to form chromate ion, which is then transported into the cell. The rate of particle dissolution was shown to be time- and concentration-dependent. The measured chromate ion concentration was consistent with that predicted from the lead chromate solubility constant in water. Lead chromate particulates were shown to adhere to the embryo cell surface enhancing chromate ion solubilization leading to sustained intracellular chromium levels and measurable chromosomal damage (Ex. 35-67).

Lead chromate particulates are also internalized into embryo cells, without dissolution, by a phagocytic process (Ex. 35-68). The lead chromate particles appeared to remain undissolved in tight vacuoles (i.e. phagosomes) within the cell over a 24 hour period. Treatment of embryo cells with lead chromate particulates in the presence of a reducing agent (i.e. ascorbate) substantially reduced cellular uptake of dissolved chromate ions and the chromosomal damage, but did not impact the internalization of lead chromate particulates (Ex. 35-68). This suggests that chromosomal damage by lead chromate was the result of extracellular particle dissolution and not internalization under the particular experimental conditions. Embryo cell treatment with large amounts of lead glutamate that produced high intracellular lead in the absence of Cr(VI) did not cause chromosomal damage further implicating intracellular chromium as the putative clastogenic agent (Ex. 35-67).

As the ability to maintain human tissue cells in culture improved in the 1990s, dissolution and internalization of lead chromate particulates, uptake of chromate ion, and the resulting chromosomal damage were verified in human lung cells (Exs. 35-66; 47-22-1; 47-12-3; 35-327; 35-436). Lead chromate particulates are internalized, form chromium adducts with DNA, and trigger dose-dependent apoptosis in human small airway epithelial cells (Ex. 35-66). They also cause dose-dependent increases in intracellular chromium, internalized lead chromate particulates and chromosomal damage in human lung fibroblasts (Exs. 47-22-1; 47-12-3). The chromosomal damage from lead chromate in these human lung cells is dependent on the extracellular dissolution and cell uptake of the chromate, rather than lead, in a manner similar to dilute concentrations of the highly soluble sodium chromate (Ex. 47-12-3; 35-327). Another water insoluble Cr(VI) compound, barium chromate particulate, produces very similar responses in human lung fibroblasts (Ex. 35-328). Human lung macrophages can phagocytize lead chromate particulates and trigger oxidation-reduction of Cr(VI) to produce reactive oxygen species capable of damaging DNA and altering gene expression (Ex. 35-436).

OSHA finds these recent studies to be carefully conceived and executed by reputable academic laboratories. The scientific findings have been published in well-respected peer reviewed Start Printed Page 10162molecular cancer and toxicology journals, such as Carcinogenesis (Exs. 12-5, 35-68), Cancer Research (Ex. 35-119), Toxicology and Applied Pharmacology (Exs. 35-66; 25-115), and Mutation Research (Exs. 35-132; 47-22-1; 35-327). Contrary to statements by CPMA, the results indicate that lead chromate particulates are able to dissociate in the presence of biological media without the aid of aggressive substances. The resulting chromate ion is bioavailable to enter lung cells, damage genetic material and initiate events critical to carcinogenesis. These effects can not be attributed to small amounts of soluble chromate contaminants since these substances are usually removed as part of the test compound preparation prior to cell treatment.

As one of the study authors, Dr. John Wise of the University of Southern Maine, stated in his post-hearing comments:

At no time did we dissolve lead chromate particles prior to administration. At the initial onset of the administration of lead chromate particles in our studies, the cells encountered intact lead chromate particles. Any dissolution that occurred was the natural result of the fate of lead chromate particles in a biological environment (Ex. 47-12, p. 3).

Other scientists concurred that the methods and findings of the cellular research with lead chromate were reasonable. Dr. Kathleen MacMahon, a biologist from NIOSH stated:

NIOSH believes that the methods that were used in the [lead chromate] studies were credible and we support the results and conclusions from those studies (Tr. 342).

Dr. Clewell said:

As I recall, it [lead chromate particles] was suspended in acetone and ultrasonically shaken to reduce it to submicron particles, which seems like a reasonably good thing to do. There are actually a couple of studies besides the Wise studies that have looked at the question of the uptake of lead chromate. I have looked at those studies and I don't really see any basic flaws in what they did. It is obviously a challenge to reproduce inhalation exposure in vitro (Tr. 180-181).

Chromosal Aberrations and Lead Chromate—Several submissions contained testimony from another researcher, Dr. Earle Nestmann of CANTOX Health Sciences International, that criticized the methodology and findings of a study published by the research group at the University of Southern Maine (Exs. 34-6-1; 38-205D; 47-12-1; 47-22). Dr. Nestmann viewed as inappropriate the practice of combining the chromatid deletions and achromatic lesions together as chromosomal aberrations. He indicated the standard practice was to score these two types of lesions separately and that only the deletions had biological relevance. According to Dr. Nestmann, achromatic lesions are chromatid gaps (i.e. lesion smaller than the width of one chromatid) that have no clastogenic significance and serve to inflate the percentage of cells with chromosomal aberrations (i.e. chromatid deletions or breaks). Dr. Nestmann criticized the studies for not including a positive control group that shows the experimental system responds to a ‘true’ clastogenic effect (i.e. a compound that clearly increases chromosomal deletions without contribution from chromatid gaps).

Dr. John Wise, the Director of the research laboratory at the University of Southern Maine, responded that distinguishing chromatid gaps from breaks is a subjective distinction (e.g. requiring judgment as to the width of a lesion relative to the width of a chromatid) and pooling these lesions simply reduces this potential bias (Ex. 47-12; 47-12-1). He stated that there is no consensus on whether gaps should or should not be scored as a chromosomal aberration and that gaps have been included as chromosomal aberrations in other publications. Dr. Wise also points out that achromatic lesions have not been shown to lack biological significance and that the most recent research indicates that they may be related to DNA strand breaks, a scientifically accepted genotoxic endpoint. Dr. Wise further believed that a positive control was unnecessary in his experiments since the purpose was not to determine whether lead chromate was a clastogenic agent, which had already been established by other research. Rather, the purpose of his studies was to assess Cr(VI) uptake and chromosomal damage caused by water-insoluble lead chromate compared to that of highly water soluble sodium chromate using a relevant in vitro cell model (i.e. human lung cells).

OSHA is not in a position to judge whether achromatic lesions should be scored as a chromosomal aberration. However, OSHA agrees with Dr. Nestmann that combining gaps and breaks together serves to increase the experimental response rate in the studies. Given the lack of consensus on the issue, it would have been of value to record these endpoints separately. OSHA is not aware of data that show achromatic gaps to be of no biological significance. The experimental data cited above indicate that soluble and insoluble Cr(VI) compounds clearly increase achromatic gaps in a concentration-dependent manner. The chromatid lesions (gaps and breaks) may be chromosomal biomarkers indicative of genetic damage that is critical to neoplastic transformation. Furthermore, OSHA agrees with Dr. Wise that other evidence establishes lead chromate as an agent able to cause DNA damage and transform cells. The Agency considers the use of sodium chromate-treated cells in the above set of experiments to be the appropriate comparison group and does not find the absence of an additional positive control group to be a technical deficiency of the studies. OSHA considers the research conducted at the University of Southern Maine documenting chromosomal damage in human lung cells following treatment with lead chromate particulates to be consistent with results from other studies (see Section V.B.8) and, thus, contributes to the evidence that water insoluble lead chromate, like other chromates, is able to enter lung cells and damage DNA.

In post-hearing comments, CPMA provided a Canadian research laboratory report that tested the lead chromate Pigment Yellow 34 for chromosomal aberrations in a hamster embryo cell system (Ex. 47-3, appendix C). The research was sponsored by DCC and its representative Dr. Nestmann. Lead chromate particles over the concentration range of 0.1 μ/cm2 to 10 μ/cm2 were reported to not induce chromosomal aberrations under the experimental test conditions. Chromatid structural and terminal gaps were not scored as aberrations in this study, even though the percentage of cells with these lesions increased in a dose-dependent manner from two percent in the absence of lead chromate to over thirteen percent in cells treated with 1 μ/cm2 lead chromate pigment particles.

This result is consistent with other experimental data that show lead chromate particulates cause chromosomal lesions when administered to mammalian embryo cells (Exs. 35-188; 35-132; 35-68; 35-67). The key difference is how the various researchers interpreted the data. The George Washington University group (i.e. Pateirno, Wise, Blankenship et al.) considered the dose-dependent achromatic lesions (i.e. chromatid gaps) as a clastogenic event and included them as chromosomal damage. The Canadian test laboratory (i.e. Nucrotechnics) reported achromatic lesions but did not score them as chromosomal aberrations. Reporting achromatic lesions but not scoring them as chromosomal aberrations is consistent with regulatory test guidelines as currently recommended by EPA and OECD. The Nucrotechnics Start Printed Page 10163data suggest that the tested lead chromate pigment caused a similar degree of chromosomal damage (i.e. dose-dependent achromatic lesions and chromosomal aberrations combined) in mammalian cells. This result was similar to results produced by reagent grade lead chromate in previous studies.

Mutagenicity and Lead Chromate—CPMA also relied on a study that reported a lack of mutagenicity for lead chromate pigments in a bacterial assay using Salmonella Typhimurium TA 100 (Ex. 11-6). As previously mentioned, this assay specifically measures point and frameshift mutations usually caused by DNA adduct formation. The assay is not sensitive to chromosomal damage, DNA strand breaks, or DNA crosslinks most commonly found with low concentrations of Cr(VI) compounds. Large amounts (50 to 500 μg/plate) of highly soluble sodium dichromate and slightly soluble calcium, strontium, and zinc chromates, were found to be mutagenic in the study, but not the water insoluble barium chromate and lead chromate pigments. However, mutagenicity was observed when the acidic chelating agent, nitrilotriacetic acid (NTA), was added to the assay to help solubilize the water insoluble Cr(VI) compounds. The chelating agent was unable to solubilize sufficient amounts of lead chromate pigments to cause bacterial mutagenicity, if these pigments were more than five percent encapsulated (weight to weight) with amorphous silica.

OSHA finds the results of this study to be consistent with the published literature that shows Cr(VI) mutagenicity requires high concentrations of solubilized chromate ion (Exs. 35-118; 35-161). Large amounts of water-soluble and slightly soluble Cr(VI) compounds produce a mutagenic response in most studies since these Cr(VI) compounds can dissociate to achieve a high concentration of chromate ion. Insoluble lead chromate usually needs to be pre-solubilized under acidic or alkaline conditions to achieve sufficient chromate ion to cause mutagenicity (Ex. 35-162). The above study found highly and slightly soluble chromates to be mutagenic as well as water insoluble lead chromate pigments pre-solubilized with NTA. The lack of mutagenicity for silica encapsulated lead chromate pigments under these experimental conditions is likely the result of their greater resistance to acidic digestion than unencapsulated lead chromate pigment.

Failure to elicit a mutagenic response in a bacterial assay, with or without NTA, is not a convincing demonstration that chromate ion can not partially dissociate from encapsulated lead chromate in biological media, enter mammalian cells, and elicit other types of genotoxicity. As described above, chromosomal damage, believed to result from DNA strand breaks and crosslinks, appears to be the critical genotoxic endpoint for low concentrations of Cr(VI) compounds. Research has shown that lead chromate and lead chromate pigment particulates in biological media can cause chromosomal lesions and cell transformation without the aid of strongly acidic or basic substances (Exs. 12-5; 35-119; 35-188; 35-132; 35-68; 35-67; 47-12-3; 35-327). While silica-encapsulated lead chromate pigments have not been as thoroughly investigated as the unencapsulated pigments or reagent grade lead chromate, one study reported that lead silicochromate particles did have low solubility in biological culture media and transformed hamster embryo cells (Ex. 12-5).

Information is not available in the record to adequately demonstrate the efficiency and stability of the encapsulation process, despite OSHA statements that such information would be of value in its health effects evaluation and its request for such information (69 FR 59315-59316, 10/4/2004; Ex. 2A). In the absence of data to the contrary, OSHA believes it prudent and plausible that encapsulated lead chromate pigments are able to partially dissociate into chromate ion available for lung cell uptake and/or be internalized in a manner similar to other lead chromate particulates. The resulting intracellular Cr(VI) leads to genotoxic damage and cellular events critical to carcinogenesis.

Public Comments on Carcinogenicity of Slightly Water Soluble Cr(VI) Compounds—In its written comments to the NPRM, Boeing Corporation stated that “there is no persuasive scientific evidence for OSHA's repeated assertion that low solubility hexavalent chromium compounds [e.g. strontium and zinc chromates] are more potent carcinogens than [highly] soluble [Cr(VI)] compounds” (Ex. 38-106, p. 2). Boeing and others in the aerospace industry are users of certain slightly soluble Cr(VI) compounds, particularly strontium chromate, found in the protective coatings applied to commercial and military aircraft.

Boeing argues that OSHA, along with IARC, ACGIH and others, have exclusively relied on intrabronchial implantation studies in animals that are both not representative of inhalation exposures in the workplace and are not consistent with the available animal inhalation data (Ex. 38-106-2, p. 26). Boeing asserts that there is no evidence that slightly soluble chromates behave differently in terms of their absorption kinetics than highly soluble chromates when instilled in the lungs of rats (Ex. 38-106-2, p. 19). Boeing believes the OSHA position that slightly soluble Cr(VI) compounds are retained in the lung, associate with cells, and cause high uptake or high local concentrations to be inconsistent with other data showing these Cr(VI) compounds quickly disperse in water (Ex. 38-106-2, p. 26). Boeing concludes:

There is no basis for the conclusion that low solubility [i.e. slightly soluble] chromates could be more potent than [highly] soluble, and some evidence the opposite may be the case. As a worst case OSHA should conclude that there is inadequate evidence to conclude that [highly] soluble and low-solubility compounds differ in carcinogenic potency. It is critical that OSHA maintain a distinction between low-solubility chromates and highly insoluble chromates based on this data. (Ex. 38-106-2, p. 26)

As noted earlier, OSHA as well as other commenters agree with Boeing that the animal intrabronchial and intratracheal instillation studies are not appropriate for quantitatively predicting lung cancer risk to a worker breathing Cr(VI) dust and aerosols. However, many stakeholders disagreed with the Boeing view and believed these animal studies can be relied upon as qualitative evidence of relative carcinogenic potency. CPMA, which relies on the rat intrabronchial implantation results as evidence that lead chromate is non-carcinogenic, states “tests involving implantation in rat lung, as carried out by Levy et al. in 1986, are relevant to inhalation in industrial exposures” (Ex. 38-205, p. 93). In their opening statement NIOSH agreed with the preliminary OSHA determination that “the less water soluble [Cr(VI)] compounds may be more potent than the more water soluble [Cr(VI)] compounds” (Tr. 299). NIOSH identified the rat intrabronchial implantation findings as the basis for their position that the slightly soluble Cr(VI) compounds appear to be more carcinogenic than the more soluble and insoluble Cr(VI) compounds (Tr. 334). Dr. Clewell testified that:

Some animal studies suggest the solubility of hexavalent chromium compounds influences their carcinogenic potency with slightly soluble compounds having the higher potencies than highly soluble or insoluble compounds. However, the evidence is inadequate to conclude that specific hexavalent chromium compounds are not carcinogenic. Moreover the designs of the studies were not sufficient to quantitatively Start Printed Page 10164estimate comparative potencies (Ex. 44-5, p. 15).

Respiratory Tract Instillation of Slightly Soluble Cr(VI) Compounds in Rats—OSHA agrees that animal intrabronchial and intratracheal implantation studies provide persuasive evidence that slightly soluble Cr(VI) are more carcinogenic than the highly soluble Cr(VI) compounds. As mentioned previously, these studies provide useful information regarding the relative carcinogenicity of different Cr(VI) compounds once they are delivered and deposited in the respiratory tract. For example, one study examined the carcinogenicity of over twenty different Cr(VI) compounds in rats, spanning a broad range of solubilities, under the same experimental conditions in the relevant target organ to humans (i.e. respiratory tract) following in vivo administration (Ex. 11-2). A single administration of each Cr(VI) test compound was instilled in the lower left bronchus of approximately 100 rats. The results were dramatic. Roughly 50 and 25 percent of the rats receiving the slightly soluble strontium and calcium chromates, respectively, developed bronchogenic carcinoma. No other Cr(VI) compounds produced more than five percent tumor incidence. The highly soluble sodium dichromate under the same experimental conditions caused bronchogenic carcinoma in only a single rat.

The higher relative potency of the slightly soluble calcium chromate compared to the highly soluble sodium dichromate was confirmed in another study in which each test compound was instilled at a low dose level (i.e., 0.25 mg/kg) in the trachea of 80 rats five times weekly for 30 months (Ex. 11-7). Using this experimental protocol, 7.5 percent of the slightly soluble calcium chromate-treated animals developed brochioalveolar adenomas while none of the highly soluble sodium dichromate-treated rats developed tumors. The tumor incidence at this lower dose level occurred in the absence of serious lung pathology and is believed to reflect the tumorigenic potential of the two Cr(VI) compounds at workplace exposures of interest to OSHA. On the other hand, a five-fold higher dose level that caused severe damage and chronic inflammation to the rat lungs produced a similar fifteen percent lung tumor incidence in both calcium and sodium chromate treated rats. OSHA, as well as the study authors, believe the later tumor response with the higher dose level did not result from direct Cr(VI) interaction with cellular genes, but, instead, was primarily driven by the cellular hyperplasia secondary to the considerable damage to the lung tissue. Boeing also seems to attribute this result to tissue damage stating “most of the tumors were found in areas of chronic inflammation and scarring, suggesting an effect that is secondary to tissue damage” (Ex. 38-106-2, p. 21).

OSHA does not agree with some study interpretations advanced by Boeing in support of their position that slightly soluble Cr(VI) compounds are no more carcinogenic than highly soluble Cr(VI). For example, Boeing claims that the intrabronchial implantation experiments cannot be relied upon because the results do not correspond to findings from animal inhalation studies (Ex. 38-106-2, p. 24-25). The primary basis for the Boeing comparison were two rodent bioassays that reported tumor incidence from the inhalation of different Cr(VI) compounds (Exs. 10-8; 10-11). In one study over 200 mice inhaled slightly soluble calcium chromate powder for five hours per day, five days per week for roughly two years (Ex. 10-8). In the other study, 19 rats inhaled an aqueous sodium dichromate liquid aerosol virtually around the clock for 22 hours a day, seven days a week for eighteen months (Ex. 10-11). The two studies reported a similar tumor incidence despite the lower total weekly Cr(VI) dose of sodium dichromate in the second study. OSHA believes the vastly different experimental protocols employed in these studies do not allow for a legitimate comparison of carcinogenic potency between Cr(VI) compounds. First, mouse and rat strains can differ in their susceptibility to chemical-induced lung tumors. Second, the proportion of respirable Cr(VI) may differ between a liquid aerosol of aqueous sodium dichromate mist and an aerosol solid calcium chromate particles suspended in air. Third, the opportunity for Cr(VI) clearance will undoubtedly differ between a Cr(VI) dose inhaled nearly continuously (e.g., 22 hours per day, seven days a week) and inhaled intermittently (e.g., five hours a day, five days a week) over the course of a week. These experimental variables can be expected to have a major influence on tumor response and, thus, will obscure a true comparison of carcinogenic potency. Boeing acknowledges that “these [inhalation] studies used very different protocols and are not directly comparable” (Ex. 38-106-2, p.24). On the other hand, slightly soluble Cr(VI) compounds were found to cause a greater incidence of lung tumors than highly soluble Cr(VI) compounds in two independent studies in which the test compounds were instilled under the same dosing regime in the same rodent models in research specifically designed to assess relative Cr(VI) carcinogenic potency (Exs. 11-2; 11-7). Therefore, OSHA believes any apparent lack of correspondence between animal inhalation and instillation studies is due to an inability to compare inhalation data from vastly different experimental protocols and should not diminish the relevance of the instillation findings.

Epidemiological Studies of Slightly Soluble Cr(VI) Compounds—Boeing further argues that the greater carcinogenic potency experienced by rats intrabronchially instilled with slightly soluble chromates compared to rats instilled with highly soluble and water-insoluble Cr(VI) compounds “do not correspond qualitatively to observed lung cancer in occupational exposure” (Ex. 38-106-2, p. 21). Several other industry stakeholders disagree. In explaining the excess lung cancer mortality among pigment production workers, CPMA commented:

[water-insoluble] Lead chromate pigments must be differentiated from [slightly soluble] zinc chromate corrosion inhibitor additives, which are consistently shown to be carcinogenic in various studies. When [water insoluble] lead chromate and [slightly soluble] zinc chromate exposures occur simultaneously, there appears to be a significant cancer hazard. However, when lead chromate pigments alone are the source of chromium exposure, a significant cancer response has never been found (Ex. 38-205, p. 91).

In explaining the excess lung cancer mortality among chromate production workers in the Gibb and Luippold cohorts, the Electric Power Research Institute states that:

One important distinction is that workers of the historical chromate production industry were exposed to sparingly soluble forms of calcium chromate in the roast mix, which are recognized to have greater carcinogenic potential as compared to soluble forms of Cr(VI) based on animal implantation studies (Ex. 38-8, p. 12).

Deborah Proctor of Exponent also testified:

Several studies of chromate production worker cohorts have demonstrated that the excess cancer risk is reduced when less lime is added to the roast mixture, reducing worker exposure to the sparingly soluble calcium chromate compounds” (Ex. 40-12-5).

OSHA believes there is merit to the above comments that workplace exposure to slightly soluble Cr(VI) compounds may have contributed to the higher lung cancer mortality in both pigments workers producing mixed zinc and lead chromate pigments as well as Start Printed Page 10165chromate production workers exposed to calcium chromate from high lime production processes in the 1930s and 1940s. Other factors, such as greater Cr(VI) exposure, probably also contributed to the higher lung cancer mortality observed in these cohorts. In any case, these epidemiological findings support the Boeing contention that the epidemiological findings are inconsistent with the results from animal intrabronchial implantation studies (Ex. 38-106-2, p. 26).

Clearance, Retention, and Dissolution of Slightly Soluble Cr(VI) Compounds in the Lung—Boeing argues that animal experiments that examined the absorption, distribution and excretion of Cr(VI) compounds after intratracheal instillation of Cr(VI) compounds in rats do not show that highly soluble Cr(VI) is cleared more rapidly or retained in the lung for shorter periods than slightly soluble Cr(VI) compounds (Ex. 38-106-2, p. 18-19). The results of one study found that larger amounts of water-insoluble lead chromate were retained in the lungs of rats at both 30 minutes and at 50 days after instillation than for highly soluble sodium chromate or slightly soluble zinc chromate (Ex. 35-56). Although the authors concluded that slightly soluble zinc chromate was more slowly absorbed from the lung than the highly soluble sodium chromate, the excretion and distribution of the absorbed chromium from the zinc and sodium chromate instillations was similar. Furthermore, there was little difference in the amounts of zinc and sodium chromate retained by the lung at the two extreme time points (e.g., 30 minutes and 50 days) measured in the study. OSHA agrees with Boeing that these findings indicate slower clearance and longer retention in the lung of the water insoluble lead chromate relative to highly soluble sodium chromate, but not in the case of the slightly soluble zinc chromate. Slower clearance and longer residence time in the lung will generally enhance carcinogenic potential assuming other dosimetric variables such as lung deposition, Cr(VI) concentration at the lung cell surface, and dissociation into chromate ion are unchanged.

Boeing asserts that a study of strontium chromate dissociation from paint primer contradicts the notion that slightly soluble are more likely than highly soluble Cr(VI) compounds to concentrate and dissociate at the lung cell surface (Ex. 38-106-2, p. 25). This experimental research found that roughly 75 and 85 percent of strontium chromate contained in metal surface primer coating particles was solubilized in water after one and 24 hours, respectively (Ex. 31-2-1). The primer particles were generated using a high volume, low pressure spray gun according to manufacturer specifications, and collected in water impingers. The authors concluded that their study demonstrated that chromate dissociation from primer particles into the aqueous fluid lining lung cells would be modestly hindered relative to highly water soluble Cr(VI) aerosols.

The slower dissociation of the slightly soluble Cr(VI) compound, strontium chromate, plausibly explains its higher carcinogenicity in animal implantation studies. The ‘modest hindrance’ allows the undissociated chromate to achieve higher concentrations at the surface of the lung cells facilitating chromate transport into the cell. The unhindered, instantaneous dispersion of highly water soluble chromates in aqueous fluid lining of the respiratory tract is less likely to achieve a high chromate concentration at the lung cell membrane. OSHA believes the results of the above study support, not contradict, that slightly soluble Cr(VI) may lead to higher chromium uptake into lung cells than highly soluble Cr(VI) compounds.

In summary, slightly soluble Cr(VI) compounds have consistently caused higher lung tumor incidence in animal instillation studies specifically designed to examine comparative carcinogenic potency in the respiratory tract. The higher carcinogenic activity of slightly soluble Cr(VI) is consistent with cellular studies that indicate that chromate dissociation in close proximity to the lung cell surface may be a critical feature to efficient chromate ion uptake. This is probably best achieved by Cr(VI) compounds that have intermediate water solubility rather than by highly water-soluble Cr(VI) that rapidly dissolves and diffuses in the aqueous fluid layers lining the respiratory tract. The higher carcinogenicity of slightly soluble Cr(VI) may contribute, along with elevated Cr(VI) workplace exposures, to the greater lung cancer mortality in certain occupational cohorts exposed to both slightly soluble and other forms of Cr(VI). The vastly different study protocols employed in the few animal inhalation bioassays do not allow a valid comparison of lung tumor incidence between slightly soluble and highly soluble Cr(VI) compounds.

b. Summary of Cr(VI) Carcinogenicity

After carefully considering all the epidemiological, animal and mechanistic evidence presented in the rulemaking record, OSHA regards all Cr(VI) compounds as agents able to induce carcinogenesis through a genotoxic mode of action. This position is consistent with findings of IARC, EPA, and ACGIH that classified Cr(VI) compounds as known or confirmed human carcinogens. Based on the above animal and experimental evidence, OSHA believes that slightly soluble Cr(VI) compounds are likely to exhibit a greater degree of carcinogenicity than highly water soluble or water insoluble Cr(VI) when the same dose is delivered to critical target cells in the respiratory tract of the exposed worker. In its evaluation of different Cr(VI) compounds, ACGIH recommended lower occupational exposure limits for the slightly soluble strontium chromate (TLV of 0.5 μg/m3) and calcium chromate (TLV of 1 μg/m3) than either water insoluble (TLV of 10 μg/m3) or water soluble (TLV of 50 μg/m3) forms of Cr(VI) based on the animal instillation studies cited above. While these animal instillation studies are useful for hazard identification and qualitative determinations of relative potency, they cannot be used to determine a reliable quantitative estimate of risk for human workers breathing these chromates during occupational exposure. This was due to use of inadequate number of dose levels (e.g., single dose level) or a less appropriate route of administration (e.g., tracheal instillation).

It is not clear from the animal or cellular studies whether the carcinogenic potency of water insoluble Cr(VI) compounds would be expected to be more or less than highly water soluble Cr(VI). However, it was found that a greater percentage of water insoluble lead chromate remains in the lungs of rats for longer periods than the highly water soluble sodium chromate when instilled intratracheally at similar doses (Ex. 35-56). Since water insoluble lead chromate can persist for long periods in the lung and increase intracellular levels of Cr and damage DNA in human lung cells at low doses (e.g., 0.1 μg/cm2), OSHA believes that based on the scientific evidence discussed above it is reasonable to regard the water insoluble Cr(VI) to be of similar carcinogenic potency to highly soluble Cr(VI) compounds. No convincing scientific evidence was introduced into the record that shows lead chromate to be less carcinogenic than highly soluble chromate compounds.

C. Non-cancer Respiratory Effects

The following sections describe the evidence from the literature on nasal irritation, nasal ulcerations, nasal perforations, asthma, and bronchitis following inhalation exposure to water Start Printed Page 10166soluble Cr(VI) compounds. The evidence clearly demonstrates that workers can develop impairment to the respiratory system (nasal irritation, nasal ulceration, nasal perforation, and asthma) after workplace exposure to Cr(VI) compounds below the previous PEL.

It is very clear from the evidence that workers may develop nasal irritation, nasal tissue ulcerations, and nasal septum perforations at occupational exposures level at or below the current PEL of 52 μg/m3. However, it is not clear what occupational exposure levels lead to the development of occupational asthma or bronchitis.

1. Nasal Irritation, Nasal Tissue Ulcerations and Nasal Septum Perforations

Occupational exposure to Cr(VI) can lead to nasal tissue ulcerations and nasal septum perforations. The nasal septum separates the nostrils and is composed of a thin strip of cartilage. The nostril tissue consists of an overlying mucous membrane known as the mucosa. The initial lesion after Cr(VI) exposure is characterized by localized inflammation or a reddening of the affected mucosa, which can later lead to atrophy. This may progress to an ulceration of the mucosa layer upon continued exposure (Ex. 35-1; Ex. 7-3). If exposure is discontinued, the ulcer progression will stop and a scar may form. If the tissue damage is sufficiently severe, it can result in a perforation of the nasal septum, sometimes referred to chrome hole. Individuals with nasal perforations may experience a range of signs and symptoms, such as a whistling sound, bleeding, nasal discharge, and infection. Some individuals may experience no noticeable effects.

Several cohort and cross-sectional studies have described nasal lesions from airborne exposure to Cr(VI) at various electroplating and chrome production facilities. Most of these studies have been reviewed by the Center for Disease Control's Agency for Toxic Substances and Disease Registry (ATSDR) toxicological profile for chromium (Ex. 35-41). OSHA reviewed the studies summarized in the profile, conducted its own literature search, and evaluated studies and comments submitted to the rulemaking record. In its evaluation, OSHA took into consideration the exposure regimen and experimental conditions under which the studies were performed, including exposure levels, duration of exposure, number of animals, and the inclusion of appropriate control groups. Studies were not included if they did not contribute to the weight of evidence either because of inadequate documentation or because of poor quality. This section only covers some of the key studies and reviews. OSHA has also identified two case reports demonstrating the development of nasal irritation and nasal septum perforations, and these case reports are summarized as well. One case report shows how a worker can develop the nasal perforations from direct contact (i.e., touching the inner surface of the nose with contaminated fingers).

Lindberg and Hedenstierna examined the respiratory symptoms and effects of 104 Swedish electroplaters (Ex. 9-126). Of the 104 electroplaters, 43 were exposed to chromic acid by inhalation. The remaining 61 were exposed to a mixture of chromic acid and nitric acid, hydrochloric acid, boric acid, nickel, and copper salts. The workers were evaluated for respiratory symptoms, alterations in the condition of the nasal tissue, and lung function. All workers were asked to fill out a detailed questionnaire on their history of respiratory symptoms and function. Physicians performed inspections of the nasal passages of each worker. Workers were given a pulmonary function test to assess lung function. For those 43 workers exposed exclusively to chromic acid, the median exposure time was 2.5 years, ranging from 0.2 to 23.6 years. The workers were divided into two groups, a low exposure group (19 workers exposed to eight-hour time weighted average levels below 2 μg/m3) and a high exposure group (24 workers exposed to eight-hour time weighted average levels above 2 μg/m3). Personal air sampling was conducted on 11 workers for an entire week at stations close to the chrome baths to evaluate peak exposures and variations in exposure on different days over the week. Nineteen office employees who were not exposed to Cr(VI) were used as controls for nose and throat symptoms, and 119 auto mechanics (no car painters or welders) whose lung function had been evaluated using similar techniques to those used on Cr(VI) exposed workers were used as controls for lung function.

The investigators reported nasal tissue ulcerations and septum perforations in a group of workers exposed to chromic acid as Cr(VI) at peak exposure ranging from 20 μg/m3 to 46 μg/m3. The prevalence of ulceration/perforation was statistically higher than the control group. Of the 14 individuals in the 20-46 μg/m3 exposure group, 7 developed nasal ulcerations. In addition to nasal ulcerations, 2 of the 7 also had nasal perforations. Three additional individuals in this group developed nasal perforations in the absence of ulcerations. None of the 14 workers in the 20-46 μg/m3 exposure group were reported to have nasal tissue atrophy in the absence of the more serious ulceration or perforation.

At average exposure levels from 2 μg/m3 to 20 μg/m3, half of the workers complained of “constantly running nose,” “stuffy nose,” or “there was a lot to blow out.” (Authors do not provide details of each complaint). Nasal tissue atrophy, in the absence of ulcerations or perforations, was observed in 66 percent of occupationally exposed workers (8 of 12 subjects) at relatively low peak levels ranging from 2.5 μg/m3 to 11 μg/m3. No one exposed to levels below 1 μg/m3 (time-weighted average, TWA) complained of respiratory symptoms or developed lesions.

The authors also reported that in the exposed workers, both forced vital capacity and forced expiratory volume in one second were reduced by 0.2 L, when compared to controls. The forced mid-expiratory flow diminished by 0.4 L/second from Monday morning to Thursday afternoon in workers exposed to chromic acid as Cr(VI) at daily TWA average levels of 2 μg/m3 or higher. The effects were small, not outside the normal range and transient. Workers recovered from the effects after two days. There was no difference between the control and exposed group after the weekend. The workers exposed to lower levels (2 μg/m3 or lower, TWA) showed no significant changes.

Kuo et al. evaluated nasal septum ulcerations and perforations in 189 electroplaters in 11 electroplating factories (three factories used chromic acid, six factories used nickel-chromium, and two factories used zinc) in Taiwan (Ex. 35-10). Of the 189 workers, 26 used Cr(VI), 129 used nickel-chromium, and 34 used zinc. The control group consisted of electroplaters who used nickel and zinc. All workers were asked to fill out a questionnaire and were given a nasal examination including a lung function test by a certified otolaryngologist. The authors determined that 30% of the workers (8/26) that used chromic acid developed nasal septum perforations and ulcerations and 38% (10/26) developed nasal septum ulcers. Using the Mantel Extension Test for Trends, the authors also found that chromium electroplaters had an increased likelihood of developing nasal ulcers and perforations compared to electroplating workers using nickel-chromium and zinc. Personal sampling of airborne Cr(VI) results indicated the highest levels (32 μg/m3 ± 35 μg/m3, ranging from 0.1 μg/m3-119 μg/m3) near the electroplating tanks of the Cr(VI) electroplating Start Printed Page 10167factories (Ex. 35-11). Much lower personal sampling levels were reported in the “other areas in the manufacturing area” and in the “administrative area” (TWA 0.16 ± 0.10 μg/m3) of the Cr(VI) electroplating plant. The duration of sampling was not indicated. The lung function tests showed that Cr(VI) electroplaters had significantly lower forced vital capacity and forced expiratory volume when compared to other exposure groups.

Cohen et al. examined respiratory symptoms of 37 electroplaters following inhalation exposure to chromic acid (Ex. 9-18). The mean length of employment for the 37 electroplaters was 26.9 months (range from 0.3 to 132 months). Fifteen workers employed in other parts of the plant were randomly chosen for the control group (mean length of employment was 26.1 months; range from 0.1 to 96). All workers were asked to fill out a questionnaire on their respiratory history and to provide details about their symptoms. An otolaryngologist then examined each individual's nasal passages and identified ulcerations and perforations. Air samples to measure Cr(VI) were collected for electroplaters. The air sampling results of chromic acid as Cr(VI) concentrations for electroplaters was a mean of 2.9 μg/m3 (range from non-detectable to 9.1 μg/m3). The authors found that 95% of the electroplaters developed pathologic changes in nasal mucosa. Thirty-five of the 37 workers who were employed for more than 1 year had nasal tissue damage. None of these workers reported any previous job experience involving Cr(VI) exposure. Four workers developed nasal perforations, 12 workers developed ulcerations and crusting of the septal mucosa, 11 workers developed discoloration of the septal mucosa, and eight workers developed shallow erosion of septal mucosa. The control group consisted of 15 workers who were not exposed to Cr(VI) at the plant. All but one had normal nasal mucosa. The one individual with an abnormal finding was discovered to have had a previous Cr(VI) exposure while working in a garment manufacturing operation as a fabric dyer for three years. In addition to airborne exposure, the authors observed employees frequently wiping their faces and picking their noses with contaminated hands and fingers. Many did not wear any protective gear, such as gloves, glasses, or coveralls.

Lucas and Kramkowsi conducted a Health Hazard Evaluation (HHE) on 11 chrome platers in an industrial electroplating facility (Ex. 3-84). The electroplaters worked for about 7.5 years on average. Physicians evaluated each worker for chrome hole scars, nasal septum ulceration, mucosa infection, nasal redness, perforated nasal septum, and wheezing. Seventeen air samples for Cr(VI) exposure were collected in the chrome area. Cr(VI) air concentrations ranged from 1 to 20 μg/m3, with an average of 4 μg/m3. In addition to airborne exposure, the authors observed workers being exposed to Cr(VI) by direct “hand to nose” contact, such as touching the nose with contaminated hands. Five workers had nasal mucosa that became infected, two workers had nasal septum ulcerations, two workers had atrophic scarring (author did not provide explanation), possibly indicative of presence of past ulcerations, and four workers had nasal septum perforations.

Gomes evaluated 303 employees from 81 electroplating operations in Sao Paulo, Brazil (Ex. 9-31). Results showed that more than two-thirds of the workers had nasal septum ulcerations and perforations following exposure to chromic acid at levels greater than 100 μg/m3, but less than 600 μg/m3 (precise duration of exposure was not stated). These effects were observed within one year of employment.

Lin et al. examined nasal septum perforations and ulcerations in 79 electroplating workers from seven different chromium electroplating factories in Taipei, Taiwan (Ex.35-13). Results showed six cases of nasal septum perforations, four having scar formations, and 38 cases of nasal septum ulcerations following inhalation exposure to chromic acid. Air sampling near the electroplating tanks had the highest range of chromic acid as Cr(VI) (mean of 28 μg/m3; range from 0.7 to 168.3 μg/m3). In addition to airborne exposures, the authors also observed direct “hand to nose” contact where workers placed contaminated fingers in their nose. The authors attributed the high number of cases to poor industrial hygiene practices in the facilities. Five of the seven factories did not have adequate ventilation systems in place. Workers did not wear any PPE, including respirators.

Bloomfield and Blum evaluated nasal tissue damage and nasal septum perforations in 23 workers employed at six chromium electroplating plants (Ex. 9-13). They found that daily exposure to chromic acid as Cr(VI) at levels of 52 μg/m3 or higher can lead to nasal tissue damage. Three workers developed nasal ulcerations, two workers had nasal perforations, nine workers had nose bleeds, and nine workers had inflamed mucosa.

Kleinfeld and Rosso found that seven out of nine of chrome electroplaters had nasal septum ulcerations (Ex. 9-41). The nine workers were exposed to chromic acid as Cr(VI) by inhalation at levels ranging from 93 μg/m3 to 728 μg/m3. Duration of exposure varied from two weeks to one year. Nasal septum ulcerations were noted in some workers who had been employed for only one month.

Royle, using questionnaire responses from 997 British electroplaters exposed to chromic acid, reported a significant increase in the prevalence of nasal ulcerations. The prevalence increased the longer the worker was exposed to chromic acid (e.g., from 14 cases with exposure less than one year to 62 cases with exposure over five years) (Ex. 7-50). In all but 2 cases, air samples revealed chromic acid concentrations of 0.03 mg/m3 (i.e., 30 μg/m3).

Gibb et al. reported nasal irritations, nasal septum bleeding, nasal septum ulcerations and perforations among a cohort of 2,350 chrome production workers in a Baltimore plant (Ex. 31-22-12). A description of the cohort is provided in detail in the cancer health effects section V.B. of this preamble. The authors found that more than 60% of the cohort had experienced nasal ulcerations and irritations, and that the workers developed these effects for the first time within the first three months of being hired (median). Gibb et al. found that the median annual exposure to Cr(VI) during first diagnosis of irritated and/or ulcerated nasal septum was 10 μg/m3. About 17% of the cohort reported nasal perforations. Based on historical data, the authors believe that the nasal findings are attributable to Cr(VI) exposure.

Gibb et al. also used a Proportional Hazard Model to evaluate the relationship between Cr(VI) exposure and the first occurrence of each of the clinical findings. Cr(VI) data was entered into the model as a time dependent variable. Other explanatory variables were calendar year of hire and age of hire. Results of the model indicated that airborne Cr(VI) exposure was associated with the occurrence of nasal septum ulceration (p = 0.0001). The lack of an association between airborne Cr(VI) exposure and nasal perforation and bleeding nasal septum may reflect the fact that Cr(VI) concentrations used in the model represent annual averages for the job, in which the worker was involved in at the time of the findings, rather than a short-term average. Annual averages do not factor in day-to-day fluctuations or extreme episodic occurrences. Also, the author believed that poor housekeeping Start Printed Page 10168and hygiene practices may have contributed to these health effects as well as Cr(VI) air borne concentrations.

Based on their hazard model, Gibb et al. estimated the relative risks for nasal septum ulcerations would increase 1.2 for each 52 μg of Cr(VI)/m3 increase in Cr(VI) air levels. They found a reduction in the incidence of nasal findings in the later years. They found workers from the earlier years who did not wear any PPE had a greater risk of developing respiratory problems. They believe that the reduction in ulcerations was possibly due to an increased use of respirators and protective clothing and improved industrial hygiene practices at the facility.

The U.S. Public Health Service conducted a study of 897 chrome production workers in seven chromate producing plants in the early 1950s (Ex. 7-3). The findings of this study were used in part as justification for the current OSHA PEL. Workers were exposed by inhalation to various water soluble chromates and bichromate compounds. The total mean exposure to the workers was a TWA of 68 μg/m3. Of the 897 workers, 57% (or 509 workers) were found to have nasal septum perforations. Nasal septum perforations were even observed in workers during their first year on the job.

Case reports provide further evidence that airborne exposure and direct “hand to nose” contact of Cr(VI) compounds lead to the development of nasal irritation and nasal septum perforations.

For example, a 70-year-old man developed nasal irritation, incrustation, and perforation after continuous daily exposure by inhalation to chromium trioxide (doses were not specified, but most likely quite high given the nature of his duties). This individual inhaled chromium trioxide daily by placing his face directly over an electroplating vessel. He worked in this capacity from 1934 to 1982. His symptoms continued to worsen after he stopped working. By 1991, he developed large perforations of the nasal septum and stenosis (or constriction) of both nostrils by incrustation (Ex. 35-8).

Similarly, a 30-year-old female jigger (a worker who prepares the items prior to electroplating by attaching the items to be plated onto jigs or frames) developed nasal perforation in her septum following continuous exposure (doses in this case were not provided) to chromic acid mists. She worked adjacent to the automated Cr(VI) electroplating shop. She was also exposed to chromic acid from direct contact when she placed her contaminated fingers in her nose. Her hands became contaminated by handling wet components in the jigging and de-jigging processes (Ex. 35-24).

Evidence of nasal septum perforations has also been demonstrated in experimental animals. Adachi exposed 23 C57BL mice to chromic acid by inhalation at concentrations of 1.81 mg Cr(VI)/m3 for 120 min per day, twice a week and 3.63 mg Cr(VI)/m3 for 30 minutes per day, two days per week for up to 12 months (Ex. 35-26). Three of the 23 mice developed nasal septum perforations in the 12 month exposure group.

Adachi et al. also exposed 50 ICR female mice to chromic acid by inhalation at concentrations of 3.18 mg Cr(VI)/m3 for 30 minutes per day, two days per week for 18 months (Ex. 35-26-1). The authors used a miniaturized chromium electroplating system to mimic electroplating processes and exposures similar to working experience. Nasal septum perforations were found in six mice that were sacrificed after 10 months of exposure. Of those mice that were sacrificed after 18 months of exposure, nasal septum perforations were found in three mice.

2. Occupational Asthma

Occupational asthma is considered “a disease characterized by variable airflow limitation and/or airway hyperresponsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace” (Ex. 35-15). Asthma is a serious illness that can damage the lungs and in some cases be life threatening. The common symptoms associated with asthma include heavy coughing while exercising or when resting after exercising, shortness of breath, wheezing sound, and tightness of chest (Exs. 35-3; 35-6).

Cr(VI) is considered to be an airway sensitizer. Airway sensitizers cause asthma through an immune response. The sensitizing agent initially causes production of specific antibodies that attach to cells in the airways. Subsequent exposure to the sensitizing agent, such as Cr(VI), can trigger an immune-mediated narrowing of the airways and onset of bronchial inflammation. All exposed workers do not become sensitized to Cr(VI) and the asthma only occurs in sensitized individuals. It is not clear what occupational exposure levels of Cr(VI) compounds lead to airway sensitization or the development of occupational asthma.

The strongest evidence of occupational asthma has been demonstrated in four case reports. OSHA chose to focus on these four case reports because the data from other occupational studies do not exclusively implicate Cr(VI). The four case reports have the following in common: (1) The worker has a history of occupational exposure exclusively to Cr(VI); (2) a physician has confirmed a diagnosis that the worker has symptoms consistent with occupational asthma; and (3) the worker exhibits functional signs of air restriction (e.g., low forced expiratory volume in one second or low peak expiratory flow rate) upon bronchial challenge with Cr(VI) compounds. These case reports demonstrate, through challenge tests, that exposure to Cr(VI) compounds can cause asthmatic responses. The other general case reports below did not use challenge tests to confirm that Cr(VI) was responsible for the asthma; however, these reports came from workers similarly exposed to Cr(VI) such that Cr(VI) is likely to have been a contributing factor in the development of their asthmatic symptoms.

DaReave reported the case of a 48-year-old cement floorer who developed asthma from inhaling airborne Cr(VI) (Ex. 35-7). This worker had been exposed to Cr(VI) as a result of performing cement flooring activities for more than 20 years. The worker complained of dyspnea, shortness of breath, and wheezing after work, especially after working in enclosed spaces. The Cr(VI) content in the cement was about 12 ppm. A bronchial challenge test with potassium dichromate produced a 50% decrease in forced expiratory volume in one second. The occupational physician concluded that the worker's asthmatic condition, triggered by exposure to Cr(VI) caused the worker to develop bronchial constriction.

LeRoyer reported a case of a 28-year-old roofer who developed asthma from breathing dust while sawing material made of corrugated fiber cement containing Cr(VI) for nine years (Ex. 35-12). This worker demonstrated symptoms such as wheezing, shortness of breath, coughing, rhinitis, and headaches while working. Skin prick tests were all negative. Several inhalation challenges were performed by physicians and immediate asthmatic reactions were observed after nebulization of potassium dichromate. A reduction (by 20%) in the forced expiratory volume in one second after exposure to fiber cement dust was noted.

Novey et al. reported a case of a 32-year-old electroplating worker who developed asthma from working with chromium sulfate and nickel salts (Ex. 35-16). He began experiencing coughs, Start Printed Page 10169wheezing, and dyspnea within the first week of exposure. Separate inhalation challenge tests given by physicians using chromium sulfate and nickel salts resulted in positive reactions. The worker immediately had difficulty breathing and started wheezing. The challenges caused the forced expiratory volume in 1 second to decrease by 22% and the forced expiratory volume in 1 second/forced vital capacity ratio to decrease from 74.5% to 60.4%. The author believes the worker's bronchial asthma was induced from inhaling chromium sulfate and nickel salts. Similar findings were reported in a different individual by Sastre (Ex.35-20).

Shirakawa and Morimoto reported a case of a 50-year-old worker who developed asthma while working at a metal-electroplating plant (Ex. 35-21). Bronchial challenge by physicians produced positive results when using potassium bichromate, followed by a rapid recovery within 5 minutes, when given no exposures. The worker's forced expiratory volume in one second dropped by 37% after inhalation of potassium bichromate. The individual immediately began wheezing, coughing with dyspnea, and recovered without treatment within five minutes. The author believes that the worker developed his asthma from inhaling potassium bichromate.

In addition to the case reports confirming that Cr(VI) is responsible for the development of asthma using inhalation challenge tests, there are several other case reports of Cr(VI) exposed workers having symptoms consistent with asthma where the symptoms were never confirmed by using inhalation challenge tests.

Lockman reported a case of a 41-year-old woman who was occupationally exposed to potassium dichromate during leather tanning (Ex. 35-14). The worker developed an occupational allergy to potassium dichromate. This allergy involved both contact dermatitis and asthma. The physicians considered other challenge tests using potassium dichromate as the test agent (i.e., peak expiratory flow rate, forced expiratory volume in 1 second and methacholine or bronchodilator challenge), but the subject changed jobs before the physicians could administer these tests. Once the subject changed jobs, all her symptoms disappeared. It was not confirmed whether the occupational exposure to Cr(VI) was the cause of the asthma.

Williams reported a 23-year-old textile worker who was occupationally exposed to chromic acid. He worked near two tanks of chromic acid solutions (Ex. 35-23) and inhaled fumes while frequently walking through the room with the tanks. He developed both contact dermatitis and asthma. He believes the tank was poorly ventilated and was the source of the fumes. He stopped working at the textile firm on the advice of his physician. After leaving, his symptoms improved greatly. No inhalation bronchial challenge testing was conducted to confirm that chromic acid was causing his asthmatic attacks. However, as noted above, chromic acid exposure has been shown to lead to occupational asthma, and thus, chromic acid was likely to be a causative agent in the development of asthma.

Park et al. reported a case of four workers who worked in various occupations involving exposure to either chromium sulfate or potassium dichromate (Ex. 35-18). Two worked in a metal electroplating factory, one worked at a cement manufacturer, and the other worked in construction. All four developed asthma. One individual had a positive response to a bronchial provocation test (with chromium sulfate as the test agent). This individual developed an immediate reaction, consisting of wheezing, coughing and dyspnea, upon being given chromium sulfate as the test agent. Peak expiratory flow rate decreased by about 20%. His physician determined that exposure to chromium sulfate was contributing to his asthma condition. Two other individuals had positive reactions to prick skin tests with chromium sulfate as the test agent. Two had positive responses to patch tests using potassium dichromate as the testing challenge agent. Only one out of four underwent inhalation bronchial challenge testing (with a positive result to chromium sulfate) in this report.

3. Bronchitis

In addition to nasal ulcerations, nasal septum perforations, and asthma, there is also limited evidence from reports in the literature of bronchitis associated with Cr(VI) exposure. It is not clear what occupational exposure levels of Cr(VI) compounds would lead to the development of bronchitis.

Royle found that 28% (104/288) of British electroplaters developed bronchitis upon inhalation exposure to chromic acid, as compared to 23% (90/299) controls (Ex. 7-50). The workers were considered to have bronchitis if they had symptoms of persistent coughing and phlegm production. In all but two cases of bronchitis, air samples revealed chromic acid at levels of 0.03 mg/m3. Workers were asked to fill out questionnaires to assess respiratory problems. Self-reporting poses a problem in that the symptoms and respiratory health problems identified were not medically confirmed by physicians. Workers in this study believe they were developing bronchitis, but it is not clear from this study whether the development of bronchitis was confirmed by physicians. It is also difficult to assess the bronchitis health effects of chromic acid from this study because the study results for the exposed (28%) and control groups (23%) were similar.

Alderson et al. reported 39 deaths of chromate production workers related to chronic bronchitis from three chromate producing factories (Bolton, Eaglescliffe, and Rutherglen) from 1947 to 1977 (Ex. 35-2). Neither the specific Cr(VI) compound nor the extent or frequency with which the workers were exposed were specified. However, workers at all three factories were exposed to sodium chromate, chromic acid, and calcium chromate at one time or another. The authors did not find an excess number of bronchitis related deaths at the Bolton and Eaglescliffe factories. At Rutherglen, there was an excess number of deaths (31) from chronic bronchitis with a ratio of observed/expected of 1.8 (p<0.001). It is difficult to assess the respiratory health effects of Cr(VI) compounds from this study because there are no exposure data, there are no data on smoking habits, nor is it clear the extent, duration, and amount of specific Cr(VI) compound to which the workers were exposed during the study.

While the evidence supports an association between bronchitis and Cr(VI) exposure is limited, studies in experimental animals demonstrate that Cr(VI) compounds can cause lung irritation, inflammation in the lungs, and possibly lung fibrosis at various exposure levels. Glaser et al. examined the effects of inhalation exposure of chromium (VI) on lung inflammation and alveolar macrophage function in rats (Ex. 31-18-9). Twenty, 5-week-old male TNO-W-74 Wistar rats were exposed via inhalation to 25-200 μg Cr(VI)/m3 as sodium dichromate for 28 days or 90 days for 22 hours per day, 7 days per week in inhalation chambers. Twenty, 5-week-old male TNO-W-74 Wistar rats also served as controls. All rats were killed at the end of the inhalation exposure period. The authors found increased lung weight in the 50-200 μg/m3 groups after the 90-day exposure period. They also found that 28-day exposure to levels of 25 and 50 μg/m3 resulted in “activated” alveolar macrophages with stimulated phagocytic activities. A more pronounced effect on the activation of Start Printed Page 10170alveolar macrophages was seen during the 90-day exposure period of 25 and 50 μg/m3.

Glaser et al. exposed 150 male, 8-week-old Wistar rats (10 rats per group) continuously by inhalation to aerosols of sodium dichromate at concentrations of 50, 100, 200, and 400 μg Cr(VI)/m3 for 22 hours per day, 7 days a week, for continuous exposure for 30 days or 90 days in inhalation chambers (Ex. 31-18-11). Increased lung weight changes were noticeable even at levels as low as 50 and 100 μg Cr(VI)/m3 following both 30 day and 90 day exposures. Significant accumulation of alveolar macrophages in the lungs was noted in all of the exposure groups. Lung fibrosis occurred in eight rats exposed to 100 μg Cr(VI)/m3 or above for 30 days. Most lung fibrosis disappeared after the exposure period had ceased. At 50 μg Cr(VI)/m3 or higher for 30 days, a high incidence of hyperplasia was noted in the lung and respiratory tract. The total protein in bronchoalveolar lavage (BAL) fluid, albumin in BAL fluid, and lactate dehydrogenase in BAL fluid were significant at elevated levels of 200 and 400 μg Cr(VI)/m3 in both the 30 day and 90 day exposure groups (as compared to the control group). These responses are indicative of severe injury in the lungs of animals exposed to Cr(VI) dose levels of 200 μg Cr(VI)/m3 and above. At levels of 50 and 100 μg Cr(VI)/m3, the responses are indicative of mild inflammation in the lungs. The authors concluded that these results suggest that the severe inflammatory reaction may lead to more chronic and obstructive lesions in the lung.

4. Summary

Overall, there is convincing evidence to indicate that Cr(VI) exposed workers can develop nasal irritation, nasal ulcerations, nasal perforations, and asthma. There is also some limited evidence that bronchitis may occur when workers are exposed to Cr(VI) compounds at high levels. Most of the studies involved exposure to water-soluble Cr(VI) compounds. It is very clear that workers may develop nasal irritations, nasal ulcerations, and nasal perforations at levels below the current PEL of 52 μg/m3. However, it is not clear what occupational exposure levels lead to disorders like asthma and bronchitis.

There are numerous studies in the literature showing nasal irritations, nasal perforations, and nasal ulcerations resulting from Cr(VI) inhalation exposure. It also appears that direct hand-to-nose contact (i.e., by touching inner nasal surfaces with contaminated fingers) can contribute to the incidence of nasal damage. Additionally, some studies show that workers developed these nasal health problems because they did not wear any PPE, including respiratory protection. Inadequate area ventilation and sanitation conditions (lack of cleaning, dusty environment) probably contributed to the adverse nasal effects.

There are several well documented case reports in the literature describing occupational asthma specifically triggered by Cr(VI) in sensitized workers. All involved workers who frequently suffered symptoms typical of asthma (e.g. dyspnea, wheezing, coughing, etc.) while working in jobs involving airborne exposure to Cr(VI). In some of the reports, a physician diagnosed bronchial asthma triggered by Cr(VI) after specific bronchial challenge with a Cr(VI) aerosol produced characteristic symptoms and asthmatic airway responses. Several national and international bodies, such as the National Institute for Occupational Safety and Health, the World Health Organization's International Programme on Chemical Safety, and the United Kingdom Health and Safety Executive have recognized Cr(VI) as an airway sensitizer that can cause occupational asthma. Despite the widespread recognition of Cr(VI) as an airway sensitizer, OSHA is not aware of any well controlled occupational survey or epidemiological study that has found a significantly elevated prevalence of asthma among Cr(VI)-exposed workers. The level of Cr(VI) in the workplace that triggers the asthmatic condition and the number of workers at risk are not known.

The evidence that workers breathing Cr(VI) can develop respiratory disease that involve inflammation, such as asthma and bronchitis is supported by experimental animal studies. The 1985 and 1990 Glaser et al. studies show that animals experience irritation and inflammation of the lungs following repeated exposure by inhalation to water-soluble Cr(VI) at air concentrations near the previous PEL of 52 μg/m3.

D. Dermal Effects

Occupational exposure to Cr(VI) is a well-established cause of adverse health effects of the skin. The effects are the result of two distinct processes: (1) Irritant reactions, such as skin ulcers and irritant contact dermatitis, and (2) delayed hypersensitivity (allergic) reactions. Some evidence also indicates that exposure to Cr(VI) compounds may cause conjunctivitis.

The mildest skin reactions consist of erythema (redness), edema (swelling), papules (raised spots), vesicles (liquid spots), and scaling (Ex. 35-313, p. 295). The lesions are typically found on exposed areas of the skin, usually the hands and forearms (Exs. 9-9; 9-25). These features are common to both irritant and allergic contact dermatitis, and it is generally not possible to determine the etiology of the condition based on histopathologic findings (Ex. 35-314). Allergic contact dermatitis can be diagnosed by other methods, such as patch testing (Ex. 35-321, p. 226). Patch testing involves the application of a suspected allergen to the skin, diluted in petrolatum or some other vehicle. The patch is removed after 48 hours and the skin examined at the site of application to determine if a reaction has occurred.

Cr(VI) compounds can also have a corrosive, necrotizing effect on living tissue, forming ulcers, or “chrome holes” (Ex. 35-315). This effect is apparently due to the oxidizing properties of Cr(VI) compounds (Ex. 35-318, p. 623). Like dermatitis, chrome ulcers generally occur on exposed areas of the body, chiefly on the hands and forearms (Ex. 35-316). The lesions are initially painless, and are often ignored until the surface ulcerates with a crust which, if removed, leaves a crater two to five millimeters in diameter with a thickened, hardened border. The ulcers can penetrate deeply into tissue and become painful. Chrome ulcers may penetrate joints and cartilage (Ex. 35-317, p. 138). The lesions usually heal in several weeks if exposure to Cr(VI) ceases, leaving a flat, atrophic scar (Ex. 35-318, p.623). If exposure continues, chrome ulcers may persist for months (Ex. 7-3).

It is generally believed that chrome ulcers do not occur on intact skin (Exs. 35-317, p. 138; 35-315; 35-25). Rather, they develop readily at the site of small cuts, abrasions, insect bites, or other injuries (Exs. 35-315; 35-318, p. 138). In experimental work on guinea pigs, Samitz and Epstein found that lesions were never produced on undamaged skin (Ex. 35-315). The degree of trauma, as well as the frequency and concentration of Cr(VI) application, was found to influence the severity of chrome ulcers.

The development of chrome ulcers does not appear to be related to the sensitizing properties of Cr(VI). Edmundson provided patch tests to determine sensitivity to Cr(VI) in 56 workers who exhibited either chrome ulcers or scars (Ex. 9-23). A positive response to the patch test was found in only two of the workers examined.

Parkhurst first identified Cr(VI) as a cause of allergic contact dermatitis in 1925 (Ex. 9-55). Cr(VI) has since been Start Printed Page 10171confirmed as a potent allergen. Kligman (1966) used a maximization test (a skin test for screening possible contact allergens) to assess the skin sensitizing potential of Cr(VI) compounds (Ex. 35-327). Each of the 23 subjects was sensitized to potassium dichromate. On a scale of one to five, with five being the most potent allergen, Cr(VI) was graded as five (i.e., an extreme sensitizer). This finding was supported by a guinea pig maximization test, which assigned a grade of four to potassium chromate using the same scale (Ex. 35-328).

1. Prevalence of Dermal Effects

Adverse skin effects from Cr(VI) exposure have been known since at least 1827, when Cumin described ulcers in two dyers and a chromate production worker (Ex. 35-317, p. 138). Since then, skin conditions resulting from Cr(VI) exposure have been noted in a wide range of occupations. Work with cement is regarded as the most common cause of Cr(VI)-induced dermatitis (Exs. 35-313, p. 295; 35-319; 35-320). Other types of work where Cr(VI)-related skin effects have been reported include chromate production, chrome plating, leather tanning, welding, motor vehicle assembly, manufacture of televisions and appliances, servicing of railroad locomotives, aircraft production, and printing (Exs. 31-22-12; 7-50; 9-31; 9-100; 9-63; 9-28; 9-95; 9-54; 35-329; 9-97; 9-78; 9-9; 35-330). Some of the important studies on Cr(VI)-related dermal effects in workers are described below.

a. Cement Dermatitis

Many workers develop cement dermatitis, including masons, tile setters, and cement workers (Ex. 35-318, p. 624). Cement, the basic ingredient of concrete, may contain several possible sources of chromium (Exs. 35-317, p.148; 9-17). Clay, gypsum, and chalk that serve as ingredients may contain traces of chromium. Ingredients may be crushed using chrome steel grinders that, with wear, contribute to the chromium content of the concrete. Refractory bricks in the kiln and ash residues from the burning of coal or oil to heat the kiln serve as additional sources. Trivalent chromium from these sources can be converted to Cr(VI) in the kiln (Ex. 35-317. p. 148).

The prevalence of cement dermatitis in groups of workers with regular contact with wet cement has been reported to be from 8 to 45 percent depending on the countries of origin, type of construction industry, and criteria used to diagnose dermatitis (Exs. 46-74, 9-131; 35-317, 9-57, 40-10-10). Cement dermatitis can be caused by direct irritation of the skin, by sensitization to Cr(VI), or both (Ex. 35-317, p. 147). The reported proportion of allergic and irritant contact dermatitis varies considerably depending on the information source. In a review of 16 different data sets, Burrows (1983) found that, on average, 80% of cement dermatitis cases were sensitized to Cr(VI) (Ex. 35-317, p. 148). The studies were mostly conducted prior to 1970 on European construction workers. More recent occupational studies suggest that Cr(VI) allergy may make up a smaller proportion of all dermatitis in construction workers, depending on the Cr(VI) content of the cement. For example, examination of 1238 German and Austrian construction workers in dermatitis units found about half those with occupational dermatitis were skin sensitized to Cr(VI) (Ex. 40-10-10). Several other epidemiological investigations conducted in the 1980s and 1990s also reported that allergic contact dermatitis made up 50 percent or less of all dermatitis cases in various groups of construction workers exposed to wet cement (Ex. 46-74).

Cement is alkaline, abrasive, and hydroscopic (water-absorbing), and it is likely that the irritant effect resulting from these properties interferes with the skin's defenses, permitting penetration and sensitization to take place more readily (Ex. 35-318, p. 624). Dry cement is considered relatively innocuous because it is not as alkaline as wet cement (Exs. 35-317, p. 147; 9-17). When water is mixed with cement the water liberates calcium hydroxide, causing a rise in pH (Ex. 35-317, p. 147).

Flyvholm et al. (1996) noted a correlation between the Cr(VI) concentration in the local cement and the frequency of allergic contact dermatitis (Ex. 35-326, p. 278). Because the Cr(VI) content depends partially upon the chromium concentration in raw materials, there is a great variability in the Cr(VI) content in cement from different geographical regions. In locations with low Cr(VI) content, the prevalence of Cr(VI)-induced allergic contact dermatitis was reported to be approximately one percent, while in regions with higher chromate concentrations the prevalence was reported to rise to between 9 to 11% of those exposed (Ex. 35-326, p. 278). For example, only one of 35 U.S. construction workers with confirmed cement dermatitis was reported to have a positive Cr(VI) patch test in a 1970 NIOSH study (Ex. 9-57). However, the same study revealed a low Cr(VI) content in 42 representative cement samples from U.S. companies (e.g 80 percent of the samples with C(VI) < 2 μg/g).

The relationship between Cr(VI) content in cement and the prevalence of Cr(VI)-induced allergic contact dermatitis is supported by the findings of Avnstorp (1989) in a study of Danish workers who had daily contact with wet cement during the manufacture of pre-fabricated concrete products (Ex. 9-131). Beginning in September of 1981, low concentrations of ferrous sulfate were added to all cement sold in Denmark to reduce Cr(VI) to trivalent chromium. Two hundred and twenty seven workers were examined in 1987 for Cr(VI)-related skin effects. The findings from these examinations were compared to the results from 190 workers in the same plants who were examined in 1981. The prevalence of hand eczema had declined from 11.7% to 4.4%, and the prevalence of Cr(VI) sensitization had declined from 10.5% to 2.6%. While the two-to four-fold drop in prevalence was statistically significant, the magnitude of the reduction may be overstated because the amount of exposure time was less in the 1987 than the 1981 group. There is also the possibility that other factors, in addition to ferrous sulfate, may have led to less dermal contact to Cr(VI), such as greater automation or less construction work. However, the study found no significant change in the frequency of irritant dermatitis.

Another study also found lower prevalence of allergic contact dermatitis among Finish construction workers following the 1987 decision to reduce Cr(VI) content of cement used in Finland to less than 2 ppm (Ex. 48-8). Ferrous sulfate was typically added to the cement to meet this requirement. There was a significantly decreased risk of allergic Cr(VI) contact dermatitis reported to the Finnish Occupational Disease Registry post-1987 as compared to pre-1987 (OR=0.4, 95% CI: 0.2-0.7) indicating the occurrence of disease dropped one-third after use of the low Cr(VI) content cement. On the other hand, the occurrence of irritant dermatitis remained stable throughout the study period. Time of exposure was not a significant explanatory variable in the analysis. However, the findings may have been somewhat confounded by changes in diagnostic procedure over time. The Finnish study retested patients previously diagnosed with prior patch test protocols and found several false positives (i.e. false diagnosis of Cr(VI) allergy).

In 2003, the Norwegian National Institute of Occupational Health sponsored an expert peer review of 24 Start Printed Page 10172key epidemiological investigations addressing; (1) whether exposure to wet cement containing water soluble Cr(VI) caused allergic contact dermatitis, and (2) whether there was a causal association between reduction of Cr(VI) in cement and reduction in the prevalence of the disease (Ex. 46-74). The panel of four experts concluded that, despite the documented limitations of each individual study, the collective evidence was consistent in supporting “fairly strong associations between Cr(VI) content in cement and the occurrence of allergic dermatitis * * * it seems unlikely that all these associations reported in the reviewed papers are due to systematic errors only” (Ex. 46-74, p. 42).

Even though the Norwegian panel felt that the available evidence indicated a relationship between reduced Cr(VI) content of wet cement and lower occurrence of allergic dermatitis, they stated that the epidemiological literature was “not sufficient to conclude that there is a causal association” (Ex. 46-74, p. 42). This is somewhat different than the view expressed in a written June 2002 opinion by the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) to the European Commission, Directorate for General Health and Consumer Protection (Ex. 40-10-7). In responding to the question of whether it is scientifically justified to conclude that cement containing less than 2 ppm Cr(VI) content could substantially reduce the risk of skin sensitization, the CSTEE stated that “the available information clearly demonstrates that reduction of chromium VI in cement to less than 2 ppm * * * will reduce the prevalence of allergic contact eczema in workers” (Ex. 40-10-7, p. 5)

b. Dermatitis Associated With Cr(VI) From Sources Other Than Cement

In 1953 the U.S. Public Health Service reported on hazards associated with the chromium-producing industry in the United States (Ex. 7-3). Workers were examined for skin effects from Cr(VI) exposure. Workers' eyes were also examined for possible effects from splashes of Cr(VI)-containing compounds that had been observed in the plants. Of the 897 workers examined, 451 had skin ulcers or scars of ulcers. Seventeen workers were reported to have skin lesions suggestive of chrome dermatitis. The authors noted that most plants provided adequate washing facilities, and had facilities for providing clean work clothes. A statistically significant increase in congestion of the conjunctiva was also reported in Cr(VI)-exposed workers when compared with non-exposed workers (38.7% vs. 25.8%).

In the Baltimore, Maryland chromate production plant examined by Gibb et al. (2000), a substantial number of workers were reported to have experienced adverse skin effects (Ex. 31-22-12). The authors identified a cohort of 2,357 workers first employed at the plant between 1950 and 1974. Clinic and first aid records were examined to identify findings of skin conditions. These clinical findings were identified by a physician as a result of routine examinations or visits to the medical clinic by members of the cohort. Percentages of the cohort with various clinical findings were as follows:

Irritated skin: 15.1%

Dermatitis: 18.5%

Ulcerated skin: 31.6%

Conjunctivitis: 20.0%

A number of factors make these results difficult to interpret. The reported findings are not specifically related to Cr(VI) exposure. They may have been the result of other workplace exposures, or non-workplace factors. The report also indicates the percentage of workers who were diagnosed with a condition during their tenure at the plant; however, no information is presented to indicate the expected incidence of these conditions in a population that is not exposed to Cr(VI).

Measurements of Cr(VI) air concentrations by job title were used to estimate worker exposures. Based on these estimates, the authors used a proportional hazards model to find a statistically significant correlation (p=0.004) between ulcerated skin and airborne Cr(VI) exposure. Statistically significant correlations between year of hire and findings of ulcerated skin and dermatitis were also reported. Exposures to Cr(VI) in the plant had generally dropped over time. Median exposure to Cr(VI) at the time of occurrence for most of the findings was said to be about 10 μg/m3 Cr(VI) (reported as 20 μg/m3 CrO3). It is unclear, however, what contribution airborne Cr(VI) exposures may have had to dermal effects. Direct dermal contact with Cr(VI) compounds in the plant may have been a contributing factor in the development of these conditions.

Mean and median times on the job prior to initial diagnosis were also reported. The mean time prior to diagnosis of skin or eye effects ranged from 373 days for ulcerated skin to 719 days for irritated skin. Median times ranged from 110 days for ulcerated skin to 221 days for conjunctivitis. These times are notable because many workers in the plant stayed for only a short time. Over 40% worked for less than 90 days. Because these short-term workers did not remain in the workplace for the length of time that was typically necessary for these effects to occur, the results of this study may underestimate the incidence that would occur with a more stable worker population.

Lee and Goh (1988) examined the skin condition of 37 workers who maintained chrome plating baths and compared these workers with a group of 37 control subjects who worked in the same factories but were not exposed to Cr(VI) (Ex. 35-316). Mean duration of employment as a chrome plater was 8.1 (SD±7.9) years. Fourteen (38%) of the chrome platers had some occupational skin condition; seven had chrome ulcers, six had contact dermatitis and one had both. A further 16 (43%) of the platers had scars suggestive of previous chrome ulcers. Among the control group, no members had ulcers or scars of ulcers, and three had dermatitis.

Where ulcers or dermatitis were noted, patch tests were administered to determine sensitization to Cr(VI) and nickel. Of the seven workers with chrome ulcers, one was allergic to Cr(VI). Of the six workers with dermatitis, two were allergic to Cr(VI) and one to nickel. The worker with ulceration and dermatitis was not sensitized to either Cr(VI) or nickel. Although limited by a relatively small study population, this report clearly indicates that Cr(VI)-exposed workers face an increased risk of adverse skin effects. The fact that the majority of workers with dermatitis were not sensitized to Cr(VI) indicates that irritant factors play an important role in the development of dermatitis in chrome plating operations.

Royle (1975) also investigated the occurrence of skin conditions among workers involved in chrome plating (Ex. 7-50). A questionnaire survey completed by 997 chrome platers revealed that 21.8% had experienced skin ulcers, and 24.6% had suffered from dermatitis. No information was presented to indicate the expected incidence in a comparable population that was not exposed to Cr(VI). Of the 54 plants involved in the study, 49 used nickel, another recognized cause of allergic contact dermatitis.

The author examined the relationship between the incidence of these conditions and length of exposure. The plater population was divided into three groups: those with less than one year of Cr(VI) exposure, those with one to five years of Cr(VI) exposure, and those with over five years of Cr(VI) exposure. A statistically significant trend was found Start Printed Page 10173between length of Cr(VI) exposure and incidence of skin ulcers. The incidence of dermatitis, on the other hand, bore no relationship to length of exposure.

In 1973, researchers from NIOSH reported on the results of a health hazard investigation of a chrome plating establishment (Ex. 3-5). In the plating area, airborne Cr(VI) concentrations ranged from less than 0.71 to 9.12 μg/m3 (mean 3.24 μg/m3; SD=2.48 μg/m3). Of the 37 exposed workers who received medical examinations, five were reported to have chrome-induced lesions on their hands. Hygiene and housekeeping practices in this facility were reportedly deficient, with the majority of workers not wearing gloves, not washing their hands before eating or leaving the plant, and consuming food and beverages in work areas.

Gomes (1972) examined Cr(VI)-induced skin lesions among electroplaters in Sao Paulo, Brazil (Ex. 9-31). A clinical examination of 303 workers revealed 88 (28.8%) had skin lesions, while 175 (58.0%) had skin and mucus membrane lesions. A substantial number of employers (26.6%) also did not provide personal protective equipment to workers. The author attributed the high incidence of skin ulcers on the hands and arms to inadequate personal protective equipment, and lack of training for employees regarding hygiene practices.

Fleeger and Deng (1990) reported on an outbreak of skin ulcerations among workers in a facility where enamel paints containing chromium were applied to kitchen range parts (Ex. 9-97). A ground coat of paint was applied to the parts, which were then placed on hooks and transported through a curing oven. In some cases, small parts were places on hooks before paint application. Tiny holes in the oven coils apparently resulted in improper curing of the paint, leaving sharp edges and a Cr(VI)-containing residue on the hooks. Most of the workers who handled the hooks reportedly did not wear gloves, because the gloves were said to reduce dexterity and decrease productivity. As a result, cuts from the sharp edges allowed the Cr(VI) to penetrate the skin, leading to ulcerations (Ex. 9-97).

2. Prognosis of Dermal Effects

Cr(VI)-related dermatitis tends to become more severe and persistent with continuing exposure. Once established, the condition may persist even if occupational exposure ceases. Fregert followed up on cases of occupational contact dermatitis diagnosed over a 10-year period by a dermatology service in Sweden. Based on responses to questionnaires completed two to three years after treatment, only 7% of women and 10% of men with Cr(VI)-related allergic contact dermatitis were reported to be healed (Ex. 35-322). Burrows reviewed the condition of patients diagnosed with work-related dermatitis 10-13 years earlier. Only two of the 25 cases (8%) caused by exposure to cement had cleared (Ex. 35-323).

Hogan et al. reviewed the literature regarding the prognosis of contact dermatitis, and reported that the majority of patients had persistent dermatitis (Ex. 35-324). It was reported that job changes did not usually lead to a significant improvement for most patients. The authors surveyed contact dermatitis experts around the world to explore their experience with the prognosis of patients suffering from occupational contact dermatitis of the hands. Seventy-eight percent of the 51 experts who responded to the survey indicated that chromate was one of the allergens associated with the worst possible prognosis.

Halbert et al. reviewed the experience of 120 patients diagnosed with occupational chromate dermatitis over a 10-year period (Ex. 35-320). The time between initial diagnosis and the review ranged from a minimum of six months to a maximum of nine years. Eighty-four (70%) of patients were reviewed two or more years after initial diagnosis, and 40 (33%) after five years or more. In the majority of cases (78, or 65%), the dermatitis was attributed to work with cement. For the study population as a whole, 76% had ongoing dermatitis at the time of the review.

When the review was conducted, 62 (58%) patients were employed in the same occupation as when initially diagnosed. Fifty-five (89%) of these workers continued to suffer from dermatitis. Fifty-eight patients (48%) changed occupations after their initial diagnosis. Each of these individuals indicated that they had changed occupations because of their dermatitis. In spite of the change, dermatitis persisted in 40 members of this group (69%).

Lips et al. found a somewhat more favorable outcome among 88 construction workers with occupational chromate dermatitis who were removed from Cr(VI) exposure (Ex. 35-325). Follow-up one to five years after removal indicated that 72% of the patients no longer had dermatitis. The authors speculated that this result might be due to strict avoidance of Cr(VI) contact. Nonetheless, the condition persisted in a substantial portion of the affected population.

3. Thresholds for Dermal Effects

In a response to OSHA's RFI submitted on behalf of the Chrome Coalition, Exponent indicated that the findings of Fowler et al. (1999) and others provide evidence of a threshold for elicitation of allergic contact dermatitis (Ex. 31-18-1, p. 27). Exponent also stated that because chrome ulcers did not develop in the Fowler et al. study, “more aggressive” exposures appear to be necessary for the development of chrome ulcers.

The Fowler et al. study involved the dermal exposure of 26 individuals previously sensitized to Cr(VI) who were exposed to water containing 25 to 29 mg/L Cr(VI) as potassium dichromate (pH 9.4) (Ex. 31-18-5). Subjects immersed one arm in the Cr(VI) solution, while the other arm was immersed in an alkaline buffer solution as a control. Exposure lasted for 30 minutes and was repeated on three consecutive days. Based on examination of the skin, the authors concluded that the skin response experienced by subjects was not consistent with either irritant or allergic contact dermatitis.

The exposure scenario in the Fowler et al. study, however, does not take into account certain skin conditions often encountered in the workplace. While active dermatitis, scratches, and skin lesions served as criteria for excluding both initial and continuing participation in the study, it is reasonable to expect that individuals with these conditions will often continue to work. Cr(VI)-containing mixtures and compounds used in the workplace may also pose a greater challenge to the integrity of the skin than the solution used by Fowler et al. Wet cement, for example, may have a pH higher than 9.4, and may be capable of abrading or otherwise damaging the skin. As damaged skin is liable to make exposed workers more susceptible to Cr(VI)-induced skin effects, the suggested threshold is likely to be invalid. The absence of chrome ulcers in the Fowler et al. study is not unexpected, because subjects with “fissures or lesions” on the skin were excluded from the study (Ex. 31-18-5). As discussed earlier, chrome ulcers are not believed to occur on intact skin.

4. Conclusions

OSHA believes that adverse dermal effects from exposure to Cr(VI), including irritant contact dermatitis, allergic contact dermatitis, and skin ulceration, have been firmly established. The available evidence is not sufficient to relate these effects to any given Cr(VI) air concentration. Rather, it appears that direct dermal contact with Cr(VI) is the Start Printed Page 10174most relevant factor in the development of dermatitis and ulcers. Based on the findings of Gibb et al. (Ex. 32-22-12) and U.S. Public Health Service (Ex. 7-3), OSHA believes that conjunctivitis may result from direct eye contact with Cr(VI).

OSHA does not believe that the available evidence is sufficient to establish a threshold concentration of Cr(VI) below which dermal effects will not occur in the occupational environment. This finding is supported not only by the belief that the exposure scenario of Fowler et al. is not consistent with occupational exposures, but by experience in the workplace as well. As summarized by Flyvholm et al. (1996), numerous reports have indicated that allergic contact dermatitis occurs in cement workers exposed to Cr(VI) concentrations below the threshold suggested by Fowler et al. (1999). OSHA considers the evidence of Cr(VI)-induced allergic contact dermatitis in these workers to indicate that the threshold for elicitation of response suggested by Fowler et al. (1999) is not applicable to the occupational environment.

E. Other Health Effects

OSHA has examined the possibility of health effect outcomes associated with Cr(VI) exposure in addition to such effects as lung cancer, nasal ulcerations and perforations, occupational asthma, and irritant and allergic contact dermatitis. Unlike the Cr(VI)-induced toxicities cited above, the data on other health effects do not definitively establish Cr(VI)-related impairments of health from occupational exposure at or below the previous OSHA PEL.

There is some positive evidence that workplace inhalation of Cr(VI) results in gastritis and gastrointestinal ulcers, especially at high exposures (generally over OSHA's previous PEL) (Ex. 7-12). This is supported by ulcerations in the gastrointestinal tract of mice breathing high Cr(VI) concentration for long periods (Ex. 10-8). Other studies reported positive effects but significant information was not reported or the confounders made it difficult to draw positive conclusions (Ex. 3-84; Sassi 1956 as cited in Ex. 35-41). Other studies reported negative results (Exs. 7-14; 9-135).

Likewise, several studies reported increases in renal proteins in the urine of chromate production workers and chrome platers (Exs. 35-107; 5-45; 35-105; 5-57). The Cr(VI) air levels recorded in these workers were usually below the previous OSHA PEL (Exs. 35-107; 5-45). Workers with the highest urinary chromium levels tended to also have the largest elevations in renal markers (Ex. 35-107). One study reported no relationship between chromium in urine and renal function parameters, no relationship with age or with duration of exposure, and no relationship between the presence of chromium skin ulcers and chromium levels in urine or renal function parameters (Ex. 5-57). In most studies, the elevated renal protein levels were restricted to only one or two proteins out of several examined per study, generally exhibited small increases (Ex. 35-105) and the effects appeared to be reversible (Ex. 5-45). In addition, it has been stated that low molecular weight proteinuria can occur from other reasons and cannot by itself be considered evidence of chronic renal disease (Ex. 35-195). Other human inhalation studies reported no changes in renal markers (Exs. 7-27; 35-104). Animal inhalation studies did not report kidney damage (Exs. 9-135; 31-18-11; 10-11; 31-18-10; 10-10). Some studies with Cr(VI) administered by drinking water or gavage were positive for increases in renal markers as well as some cell and tissue damage (Exs. 9-143; 11-10). However, it is not clear how to extrapolate such findings to workers exposed to Cr(VI) via inhalation. Well-designed studies of effects in humans via ingestion were not found.

OSHA did not find information to clearly and sufficiently demonstrate that exposures to Cr(VI) result in significant impairment to the hepatic system. Two European studies, positive for an excess of deaths from cirrhosis of the liver and hepatobiliarity disorders, were not able to separate chromium exposures from exposures to the many other substances present in the workplace. The authors also could not rule out the role of alcohol use as a possible contributor to the disorder (Ex. 7-92; Sassi as cited in Ex. 35-41). Other studies did not report any hepatic abnormalities (Exs. 7-27; 10-11).

The reproductive studies showed mixed results. Some positive reproductive effects occurred in some welding studies. However, it is not clear that Cr(VI) is the causative agent in these studies (Exs. 35-109; 35-110; 35-108; 35-202; 35-203). Other positive studies were seriously lacking in information. Information was not given on exposures, the nature of the reproductive complications, or the women's tasks (Shmitova 1980, 1978 as cited in Ex. 35-41, p. 52). ATSDR states that because these studies were generally of poor quality and the results were poorly reported, no conclusions can be made on the potential for chromium to produce adverse reproductive effects in humans (Ex. 35-41, p. 52). In animal studies, where Cr(VI) was administered through drinking water or diet, positive developmental effects occurred in offspring (Exs. 9-142; 35-33; 35-34; 35-38). However, the doses administered in drinking water or given in the diet were high (i.e., 250, 500, and 750 ppm). Furthermore, strong studies showing reproductive or developmental effects in other situations where employees were working exclusively with Cr(VI) were not found. In fact, the National Toxicology Program (NTP) (Exs. 35-40; 35-42; 35-44) conducted an extensive multigenerational reproductive assessment by continuous breeding where the chromate was administered in the diet. The assessment yielded negative results (Exs. 35-40; 35-42; 35-44). Animal inhalation studies were also negative (Exs. 35-199; 9-135; 10-10; Glaser 1984 as cited in Ex. 31-22-33;). Thus, it cannot be concluded that Cr(VI) is a reproductive toxin for normal working situations.

VI. Quantitative Risk Assessment

A. Introduction

The Occupational Safety and Health (OSH) Act and some landmark court cases have led OSHA to rely on quantitative risk assessment, where possible, to support the risk determinations required to set a permissible exposure limit (PEL) for a toxic substance in standards under the OSH Act. Section 6(b)(5) of the Act states that “The Secretary [of Labor], in promulgating standards dealing with toxic materials or harmful agents under this subsection, shall set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life.” (29 U.S.C. 651 et seq.)

In a further interpretation of the risk requirements for OSHA standard setting, the United States Supreme Court, in the 1980 “benzene” decision, (Industrial Union Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607 (1980)) ruled that the OSH Act requires that, prior to the issuance of a new standard, a determination must be made that there is a significant risk of material impairment of health at the existing PEL and that issuance of a new standard will significantly reduce or eliminate that risk. The Court stated that “before he can promulgate any Start Printed Page 10175permanent health or safety standard, the Secretary is required to make a threshold finding that a place of employment is unsafe in the sense that significant risks are present and can be eliminated or lessened by a change in practices” [448 U.S. 642]. The Court also stated “that the Act does not limit the Secretary's power to require the elimination of significant risks” [488 U.S. 644]. While the Court indicated that the use of quantitative risk analysis was an appropriate means to establish significant risk, they made clear that “OSHA is not required to support its finding that a significant risk exists with anything approaching scientific certainty.”

The Court in the Cotton Dust case, (American Textile Manufacturers Institute v. Donovan, 452 U.S. 490 (1981)) found that Section 6(b)(5) of the OSH Act places benefits to worker health above all other considerations except those making attainment of the health benefits unachievable and, therefore, only feasibility analysis of OSHA health standards is required and not cost-benefit analysis. It reaffirmed its previous position in the “benzene” case, however, that a risk assessment is not only appropriate but should be used to identify significant health risk in workers and to determine if a proposed standard will achieve a reduction in that risk. Although the Court did not require OSHA to perform a quantitative risk assessment in every case, the Court implied, and OSHA as a matter of policy agrees, that assessments should be put into quantitative terms to the extent possible.

The determining factor in the decision to perform a quantitative risk assessment is the availability of suitable data for such an assessment. As reviewed in section V.B. on Carcinogenic Effects, there are a substantial number of occupational cohort studies that reported excess lung cancer mortality in workers exposed to Cr(VI) in several industrial operations. Many of these found that workers exposed to higher levels of airborne Cr(VI) for a longer period of time had greater standardized mortality ratios (SMRs) for lung cancer.

OSHA believes that two recently studied occupational cohorts by Gibb et al. (Ex. 31-22-11) and Luippold et al. (Ex. 33-10) have the strongest data sets on which to quantify lung cancer risk from cumulative Cr(VI) exposure (i.e., air concentration x exposure duration). A variety of exposure-response models were fit to these data, including linear relative risk, quadratic relative risk, log-linear relative risk, additive risk, and Cox proportional hazards models. Using a linear relative risk model on these data to predict excess lifetime risk, OSHA estimated that the lung cancer risk from a 45 year occupational exposure to Cr(VI) at an 8-hour TWA at the previous PEL of 52 μg/m3 is 101 to 351 excess deaths per 1000. Quantitative lifetime risk estimates from a working lifetime exposure at several lower alternative PELs under consideration by the Agency were also estimated. The sections below discuss the selection of the appropriate data sets and risk models, the estimation of lung cancer risks based on the selected data sets and models, the uncertainty in the risk estimates, and the key issues that were raised in comments received during the public hearing process.

A preliminary quantitative risk assessment was previously published in the Notice of Proposed Rulemaking (69 FR at 59306, 10/4/2004). This was peer-reviewed by three outside experts in the fields of occupational epidemiology and risk assessment. Their comments were discussed in the NPRM (69 FR at 59385-59388). They commented on the suitability of several occupational data sets for exposure-response analysis, the choice of exposure metric and risk model, the appropriateness of the risk estimates, and the characterization of key issues and uncertainties. The reviewers agreed that the soluble chromate production cohorts described by Gibb et al. and Luippold et al. provided the strongest data sets for quantitative risk assessment. They concurred that a linear model using cumulative exposure based on time-weighted average Cr(VI) air concentrations by job title and employment history was the most reasonable risk assessment approach. The experts showed less enthusiasm for average monthly Cr(VI) air concentrations as an appropriate exposure metric or for an exposure threshold below which there is no lung cancer risk. They found the range of excess lifetime lung cancer risks presented by OSHA to be sound and reasonable. They offered suggestions regarding issues such as the impact of cigarette smoking and the healthy worker effect on the assessment of risk. OSHA revised the preliminary quantitative risk assessment in several respects based on these peer review comments.

In contrast to the more extensive occupational cohort data on Cr(VI) exposure-response, data from experimental animal studies are less suitable for quantitative risk assessment of lung cancer. Besides the obvious species difference, most of the animal studies administered Cr(VI) to the respiratory tract by less relevant routes, such as instillation or implantation. The few available inhalation studies in animals were limited by a combination of inadequate exposure levels, abbreviated durations, and small numbers of animals per dose group. Despite these limitations, the animal data do provide semi-quantitative information with regard to the relative carcinogenic potency of different Cr(VI) compounds. A more detailed discussion can be found in sections V.B.7 and V.B.9.

The data that relate non-cancer health impairments, such as damage to the respiratory tract and skin, to Cr(VI) exposure are also not well suited for quantitative assessment. There are some data from cross-sectional studies and worker surveys that group the prevalence and severity of nasal damage by contemporary time-weighted average (TWA) Cr(VI) air measurements. However, there are no studies that track either incidence or characterize exposure over time. Nasal damage is also more likely influenced by shorter-term peak exposures that have not been well characterized. While difficult to quantify, the data indicate that the risk of damage to the nasal mucosa will be significantly reduced by lowering the previous PEL, discussed further in section VII on Significance of Risk.

There are even less suitable exposure-response data to assess risk for other Cr(VI)-induced impairments (e.g., mild renal damage, gastrointestinal ulceration). With the possible exception of respiratory tract effects (e.g., nasal damage, occupational asthma), the risk of non-cancer adverse effects that result from inhaling Cr(VI) are expected to be very low, except as a result of long-term regular airborne exposure around or above the previous PEL (52 μg/m3). Since the non-cancer effects occur at relatively high Cr(VI) air concentrations, OSHA has concluded that lowering the PEL to reduce the risk of developing lung cancer over a working lifetime will also eliminate or reduce the risk of developing these other health impairments. As discussed in section V.E., adverse effects to the skin primarily result from dermal rather than airborne exposure.

B. Study Selection

The more than 40 occupational cohort studies reviewed in Section VI.B on carcinogenic effects were evaluated to determine the adequacy of the exposure-response information for the quantitative assessment of lung cancer risk associated with Cr(VI) exposure. The key criteria were data that allowed for estimation of input variables, Start Printed Page 10176specifically levels of exposure and duration of exposure (e.g., cumulative exposure in mg/m3-yr); observed numbers of cancers (deaths or incident cases) by exposure category; and expected (background) numbers of cancer deaths by exposure category.

Additional criteria were applied to evaluate the strengths and weaknesses of the available epidemiological data sets. Studies needed to have well-defined cohorts with identifiable cases. Features such as cohort size and length of follow-up affect the ability of the studies to detect any possible effect of Cr(VI) exposure. Potential confounding of the responses due to other exposures was considered. Study evaluation also considered whether disease rates from an appropriate reference population were used to derive expected numbers of lung cancers. One of the most important factors in study evaluation was the ascertainment and use of exposure information (i.e., well-documented historical exposure data). Both level and duration of exposure are important in determining cumulative dose, and studies are often deficient with respect to the availability or use of such information.

Two recently studied cohorts of chromate production workers, the Gibb cohort and the Luippold cohort, were found to be the strongest data sets for quantitative assessment (Exs. 31-22-11; 33-10). Of the various studies, these two had the most extensive and best documented Cr(VI) exposures spanning three or four decades. Both cohort studies characterized observed and expected lung cancer mortality and reported a statistically significant positive association between lung cancer risk and cumulative Cr(VI) exposure. For the remainder of this preamble the Gibb and Luippold cohorts are referred to as the “preferred cohorts”, denoting that they are the cohorts used to derive OSHA's model of lung cancer risk from exposure to Cr(VI).

Four other cohorts (Mancuso, Hayes et al., Gerin et al., and Alexander et al.) had less satisfactory data for quantitative assessments of lung cancer risk (Exs. 7-11; 23; 7-14; 7-120; 31-16-3). These cohorts include chromate production workers, stainless steel welders, and aerospace manufacturing workers. While the lung cancer response in these cohorts was stratified across multiple exposure groups, there were limitations to these data that affected their reliability for quantitative risk assessment. OSHA therefore did not consider them to be preferred cohorts (i.e., they were not used to derive OSHA's model of lung cancer risk from exposure to Cr(VI)). However, OSHA believes that quantitative analysis of these cohorts provides valuable information to the risk assessment, especially for the purpose of comparison with OSHA's risk model based on the preferred Gibb and Luippold cohorts. Analyses based on the Mancuso, Hayes et al., Gerin et al., and Alexander et al. cohorts, referred to as “additional cohorts” for the remainder of this preamble, were compared with the assessments based on the Gibb and Luippold cohorts. The strengths and weaknesses of all six cohorts as a basis for exposure-response analysis are discussed in more detail below.

1. Gibb Cohort

The Gibb et al. study was a particularly strong study for quantitative risk assessment, especially in terms of cohort size and historical exposure data (Exs. 31-22-11; 33-11). Gibb et al. studied an updated cohort from the same Baltimore chromate production plant previously studied by Hayes et al. (see section VI.B.4). The cohort included 2357 male workers (white and non-white) first employed between 1950 and 1974. Follow-up was through the end of 1992 for a total of 70,736 person-years and an average length of 30 years per cohort member. Smoking status and amount smoked in packs per day at the start of employment was available for the majority of the cohort members.

A significant advantage of the Gibb data was the availability of a large number of personal and area sampling measurements from a variety of locations and job titles which were collected over the years during which the cohort members were exposed (from 1950 to 1985, when the plant closed). Using these concentration estimates, a job exposure matrix was constructed giving annual average exposures by job title. Based on the job exposure matrix and work histories for the cohort members, Gibb et al. computed the person-years of observation, the observed numbers of lung cancer deaths, and the expected numbers of lung cancer deaths categorized by cumulative Cr(VI) exposure and age of death. They found that cumulative Cr(VI) exposure was a significant predictor of lung cancer risk over the exposure range of 0 to 2.76 (mean±SD = 0.70±2.75) mg/m3-yr. This included a greater than expected number of lung cancer deaths among relatively young workers. For example, chromate production workers between 40 and 50 years of age with mean cumulative Cr(VI) exposure of 0.41 mg CrO3/m3-yr (equivalent to 0.21 mg Cr(VI)/m3-yr) were about four times more likely to die of lung cancer than a State of Maryland resident of similar age (Ex. 31-22-11, Table V).

The data file containing the demographic, exposure, smoking, and mortality data for the individual cohort members was made available to OSHA (Ex. 295). These data were used in several reanalyses to produce several different statistical exposure-response models and to explore various issues raised in comments to OSHA, such as the use of linear and nonlinear exposure-response models, the difference between modern and historical levels of Cr(VI) exposure, and the impact of including or excluding short-term workers from the exposure-response analysis. The Agency's access to the dataset and to reanalyses of it performed by several different analysts has been a tremendous advantage in its consideration of these and other issues in the development of the final risk assessment.

2. Luippold Cohort

The other well-documented exposure-response data set comes from a second cohort of chromate production workers. Luippold et al. studied a cohort of 482 predominantly white, male employees who started work between 1940 and 1972 at the same Painesville, Ohio plant studied earlier by Mancuso (Ex. 33-10) (see subsection VI.B.3). Mortality status was followed through 1997 for a total of 14,048 person-years. The average worker had 30 years of follow-up. Cr(VI) exposures for the Luippold cohort were based on 21 industrial hygiene surveys conducted at the plant between 1943 and 1971, yielding a total of more than 800 area samples (Ex. 35-61). A job exposure matrix was computed for 22 exposure areas for each month of plant operation starting in 1940 and, coupled with detailed work histories available for the cohort members, cumulative exposures were calculated for each person-year of observation. Luippold et al. found significant dose-related trends for lung cancer SMRs as a function of year of hire, duration of employment, and cumulative Cr(VI) exposure. Risk assessments on the Luippold et al. study data performed by Crump et al. had access to the individual data and, therefore, had the best basis for analysis of this cohort (Exs. 31-18-1; 35-205; 35-58).

While the Luippold cohort was smaller and less racially diverse than the Gibb cohort, the workforce contained fewer transient, short-term employees. The Luippold cohort consisted entirely of workers employed over one year. Fifty-five percent worked Start Printed Page 10177for more than five years. In comparison, 65 percent of the Gibb cohort worked for less than a year and 15 percent for more than five years at the Baltimore plant. There was less information about the smoking behavior (smoking status available for only 35 percent of members) of the Luippold cohort than the Gibb cohort.

One aspect that the Luippold cohort had in common with the Gibb cohort was extensive and well-documented air monitoring of Cr(VI). The quality of exposure information for both the Gibb and Luippold cohorts was considerably better than that for the Mancuso, Hayes et al., Gerin et al., and Alexander et al. cohorts. The cumulative Cr(VI) exposures for the Luippold cohort, which ranged from 0.003 to 23 (mean±SD = 1.58±2.50) mg Cr(VI)/m3-yr, were generally higher but overlapped those of the Gibb cohort. The use of individual work histories to define exposure categories and presentation of mean cumulative doses in the exposure groups provided a strong basis for a quantitative risk assessment. The higher cumulative exposure range and the longer work duration of the Luippold cohort serve to complement quantitative data available on the Gibb cohort.

3. Mancuso Cohort

Mancuso (Ex. 7-11) studied the lung cancer incidence of an earlier cohort of 332 white male employees drawn from the same plant in Painesville, Ohio that was evaluated by the Luippold group. The Mancuso cohort was first employed at the facility between 1931 and 1937 and followed up through 1972, when the plant closed. Mancuso (Ex. 23) later extended the follow-up period through 1993, yielding a total of 12,881 person-years of observation for an average length of 38.8 years and a total of 66 lung cancer deaths. Since the Mancuso workers were first employed in the 1930s and the Luippold workers were first employed after 1940, the two cohorts are completely different sets of individuals.

A major limitation of the Mancuso study is the uncertainty of the exposure data. Mancuso relied exclusively on the air monitoring reported by Bourne and Yee (Ex. 7-98) conducted over a single short period of time during 1949. Bourne and Yee presented monitoring data as airborne insoluble chromium, airborne soluble chromium, and total airborne chromium by production department at the Painesville plant. The insoluble chromium was probably Cr(III) compounds with some slightly water-soluble and insoluble chromates. The soluble chromium was probably highly water-soluble Cr(VI). Mancuso (Exs. 7-11; 23) calculated cumulative exposures (mg/m3-yr) for each cohort member based on the 1949 mean chromium concentrations, by production department, under the assumption that those levels reflect exposures during the entire duration of employment for each cohort member, even though employment may have begun as early as 1931 and may have extended to 1972. Due to the lack of air measurements spanning the full period of worker exposure and the lack of adequate methodology to distinguish chromium valence states (i.e., Cr(VI) vs. Cr(III)), the exposure data associated with the Mancuso cohort were not as well characterized as data from the Luippold or Gibb cohorts.

Mancuso (Exs. 7-11; 23)reported cumulative exposure-related increases in age-adjusted lung cancer death rates for soluble, insoluble, or total chromium. Within a particular range of exposures to insoluble chromium, lung cancer death rates also tended to increase with increasing total cumulative chromium. However, the study did not report whether these tendencies were statistically significant, nor did it report the extent to which exposures to soluble and insoluble chromium were correlated. Thus, it is possible that the apparent relationship between insoluble chromium (e.g., primarily Cr(III)) and lung cancer may have arisen because both insoluble chromium concentrations and lung cancer death rates were positively correlated with Cr(VI) concentrations. Further discussion with respect to quantitative risk estimation from the Mancuso cohort is provided in section VI.E.1 on additional risk assessments.

4. Hayes Cohort

Hayes et al. (Ex. 7-14) studied a cohort of employees at the same chromate production site in Baltimore examined by Gibb et al. The Hayes cohort consisted of 2101 male workers who were first hired between 1945 and 1974, excluding those employed for less than 90 days. The Gibb cohort had different but partially overlapping date criteria for first employment (1950-1974) and no 90 day exclusion. Hayes et al. reported SMRs for respiratory tract cancer based on workers grouped by time of hire, employment duration, and high or low exposure groups. Workers who had ever worked at an older plant facility and workers whose location of employment could not be determined were combined into a single exposure group referred to as “high or questionable” exposure. Workers known to have been employed exclusively at a newer renovated facility built in 1950 and 1951 were considered to have had “low” exposure. A dose-response was observed in the sense that higher SMRs for respiratory cancer were observed among long-term workers (workers who had worked for three or more years) than among short-term workers.

Hayes et al. did not quantify occupational exposure to Cr(VI) at the time the cohort was studied, but Braver et al. (Ex. 7-17) later estimated average cumulative soluble chromium (presumed by the authors to be Cr(VI)) exposures for four subgroups of the Hayes cohort first employed between 1945 and 1959. The TWA Cr(VI) concentrations were determined from a total of 555 midget impinger air measurements that were collected at the older plant from 1945 to 1950. The cumulative exposures for the subgroups were estimated from the yearly average Cr(VI) exposure for the entire plant and the subgroups' average duration of employment rather than job-specific Cr(VI) concentrations and individual work histories. Such “group level” estimation of cumulative exposure is less appropriate than the estimation based on individual experiences as was done for the Gibb and Luippold cohorts.

A more severe limitation of this study is that exposures attributed to many workers in the newly renovated facility at the Baltimore site throughout the 1950s were based on chromium measurements from an earlier period (i.e., 1949-1950) at an older facility. Samples collected at the new facility and reviewed by Gibb et al. (Exs. 25, 31-22-12) show that the exposures in the new facility were substantially lower than assumed by Braver et al. Braver et al. (Ex. 7-17) discussed a number of other potential sources of uncertainty in the Cr(VI) exposure estimates, such as the possible conversion to Cr(III) during sample collection and the likelihood that samples may have been collected mainly in potential problem areas.

5. Gerin Cohort

Gerin et al. (Ex. 7-120) developed a job exposure matrix that was used to estimate cumulative Cr(VI) exposures for male stainless steel welders who were part of the International Agency for Research on Cancer's (IARC) multi-center historical cohort study (Ex. 7-114). The IARC cohort included 11,092 welders. However, the number of cohort members who were stainless steel welders, for which Cr(VI) exposures were estimated, could not be determined from their report. Gerin et al. used occupational hygiene surveys reported in the published literature, including a limited amount of data collected from 8 of the 135 companies Start Printed Page 10178that employed welders in the cohort, to estimate typical eight-hour TWA Cr(VI) breathing zone concentrations for various combinations of welding processes and base metal. The resulting exposure matrix was then combined with information about individual work history, including time and length of employment, type of welding, base metal welded, and information on typical ventilation status for each company (e.g., confined area, use of local exhaust ventilation, etc.) to estimate the cumulative Cr(VI) exposure. Individual work histories were not available for about 25 percent of the stainless steel welders. In these cases, information was assumed based on the average distribution of welding practices within the company. The lack of Cr(VI) air measurements from most of the companies in the study and the limitations in individual work practice information for this cohort raise questions concerning the accuracy of the exposure estimates.

Gerin et al. reported no upward trend in lung cancer mortality across four cumulative Cr(VI) exposure categories for stainless steel welders, each accumulating between 7,000 and 10,000 person-years of observation. The welders were also known to be exposed to nickel, another potential lung carcinogen. Co-exposure to nickel may obscure or confound the Cr(VI) exposure-response relationship. As discussed further in Sections VI.E.3 and VI.G.4, exposure misclassification in this cohort may obscure an exposure-response relationship. This is the primary reason that the Gerin et al. cohort was not considered a preferred cohort (i.e., it was not used to derive OSHA's quantitative risk estimates), although a quantitative analysis of this cohort was performed for comparison with the preferred cohorts.

6. Alexander Cohort

Alexander et al. (Ex. 31-16-3) conducted a retrospective cohort study of 2429 aerospace workers employed in jobs entailing chromate exposure (e.g., spray painting, sanding/polishing, chrome plating, etc.) between 1974 and 1994. The cohort included workers employed as early as 1940. Follow-up time was short, averaging 8.9 years per cohort member; in contrast, the Gibb and Luippold cohorts accumulated an average 30 or more years of follow-up. Long-term follow-up of cohort members is particularly important for determining the risk of lung cancer, which typically has an extended latency period of twenty years or more.

Industrial hygiene data collected between 1974 and 1994 were used to classify jobs in categories of “high” exposure, “moderate” exposure, or “low” exposure to Cr(VI). The use of respiratory protection was accounted for when setting up the job exposure matrix. These exposure categories were assigned summary TWA concentrations and combined with individual job history records to estimate cumulative exposures for cohort members over time. As further discussed in section VI.E.4, it was not clear from the study whether exposures are expressed in units of Cr(VI) or chromate (CrO3). Exposures occurring before 1974 were assumed to be at TWA levels assigned to the interval from 1974 to 1985.

Alexander et al. presented lung cancer incidence data for four cumulative chromate exposure categories based on worker duration and the three (high, moderate, low) exposure levels. Lung cancer incidence rates were determined using a local cancer registry, part of the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) program. The authors reported no positive trend in lung cancer incidence with increasing Cr(VI) exposure. Limitations of this cohort study include the young age of the cohort members (median = 42) and lack of information on smoking. As discussed above, the follow-up time (average < 9 years) was probably too short to capture lung cancers resulting from Cr(VI) exposure. Finally, the available Cr(VI) air measurement data did not span the entire employment period of the cohort (e.g., no data for 1940 to 1974) and was heavily grouped into a relatively small number of “summary” TWA concentrations that may not have fully captured individual differences in workplace exposures to Cr(VI). For the above reasons, in particular the insufficient follow-up time for most cohort members, the Alexander cohort was not considered a preferred dataset for OSHA's quantitative risk analysis. However, a quantitative analysis of this cohort was performed for comparison with the preferred cohorts.

7. Studies Selected for the Quantitative Risk Assessment

The epidemiologic database is quite extensive and contains several studies with exposure and response data that could potentially be used for quantitative risk assessment. OSHA considers certain studies to be better suited for quantitative assessment than others. The Gibb and Luippold cohorts are the preferred sources for quantitative risk assessment because they are large, have extensive follow-up, and have documentation of historical Cr(VI) exposure levels superior to the Mancuso, Hayes, Gerin and Alexander cohorts. In addition, analysts have had access to the individual job histories of cohort members and associated exposure matrices. OSHA's selection of the Gibb and Luippold cohorts as the best basis of exposure-response analysis for lung cancer associated with Cr(VI) exposure was supported by a variety of commenters, including for example NIOSH (Tr. 314; Ex. 40-10-2, p. 4), EPRI (Ex. 38-8, p.6), and Exponent (Ex. 38-215-2, p. 15). It was also supported by the three external peer reviewers who reviewed OSHA's preliminary risk assessment, Dr. Gaylor (Ex. 36-1-4-1, p. 24), Dr. Smith (Ex. 36-1-4-2 p. 28), and Dr. Hertz-Picciotto (Ex. 36-1-4-4, pp. 41-42).

The Mancuso cohort and the Hayes cohort were derived from workers at the same plants as Luippold and Gibb, respectively, but have limitations associated with the reporting of quantitative information and exposure estimates that make them less suitable for risk assessment. Similarly, the Gerin and Alexander cohorts are less suitable, due to limitations in exposure estimation and short follow-up, respectively. For these reasons, OSHA did not rely upon the Mancuso, Hayes, Gerin, and Alexander cohorts to derive its exposure-response model for the risk of lung cancer from Cr(VI).

Although the Agency did not rely on the Mancuso, Hayes, Gerin, and Alexander studies to develop its exposure-response model, OSHA believes that evaluating risk among several different worker cohorts and examining similarities and differences between them adds to the overall completeness and quality of the assessment. The Agency therefore analyzed these datasets and compared the results with the preferred Gibb and Luippold cohorts. This comparative analysis is discussed in Section VI.E. In light of the extensive worker exposure-response data, there is little additional value in deriving quantitative risk estimates from tumor incidence results in rodents, especially considering the concerns with regard to route of exposure and study design.

OSHA received a variety of public comments regarding the overall quality of the Gibb and Luippold cohorts and their suitability as the preferred cohorts in OSHA's quantitative risk analysis. Some commenters raised concerns about the possible impact of short-term workers in the Gibb cohort on the risk assessment (Tr. 123; Exs. 38-106, p. 10, 21; 40-12-5, p. 9). The Gibb cohort's inclusion of many workers employed for short periods of time was cited as a Start Printed Page 10179“serious flaw” by one commenter, who suggested that many lung cancers among short-term workers in the study were caused by unspecified other factors (Ex. 38-106, p. 10, p. 21). Another commenter stated that the Davies cohort of British chromate production workers “gives greater credence to the Painesville cohort as it showed that brief exposures (as seen in a large portion of the Baltimore cohort) did not have an increased risk of lung cancer” (Ex. 39-43, p. 1). However, separate analyses of the short-term (< 1 year employment) and longer-term ( 1 year) Gibb cohort members indicated that restriction of the cohort to workers with tenures of at least one year did not substantially impact estimates of excess lung cancer mortality (Ex. 31-18-15-1 , p. 29). At the public hearing, Ms. Deborah Proctor of Exponent, Inc. stated that “the short term workers did not affect the results of the study” (Tr. 1848). OSHA agrees with Ms. Proctor's conclusion, and does not believe that the inclusion of short term workers in the Gibb cohort is a source of substantial uncertainty in the Agency's risk estimates.

Some commenters expressed concern that the Gibb study did not control for smoking (Exs. 38-218, pp. 20-21; 38-265, p. 28; 39-74, p. 3). However, smoking status at the time of employment was ascertained for approximately 90% of the cohort (Ex. 35-435) and was used in statistical analyses by Gibb et al., Environ Inc., and Exponent Inc. to adjust for the effect of smoking on lung cancer in the cohort (Exs. 25; 31-18-15-1; 35-435). NIOSH performed similar analyses using more detailed information on smoking level (packs per day) that was available for 70% of the cohort (Ex. 35-435, p.1100). OSHA believes that these analyses appropriately addressed the potential confounding effect of smoking in the Gibb cohort. Issues and analyses related to smoking are further discussed in Section VI.G.3.

Other issues and uncertainties raised about the Gibb and Luippold cohorts include a lack of information necessary to estimate deposited dose of Cr(VI) for workers in either cohort and a concern that the Luippold exposure data were based on exposures to “airborne total soluble and insoluble chromium* * * rather than exposures to Cr(VI)” (Ex. 38-218, pp. 20-21). However, the exposure estimates for the Luippold (2003) cohort were recently developed by Proctor et al. using measurements of airborne Cr(VI), not the total chromium measurements used previously in Mancuso et al.’s analysis (Exs. 35-58, p. 1149; 35-61). And, while it is true that the Gibb and Luippold (2003) datasets do not lend themselves to construction of deposited dose measures, the extensive Cr(VI) air monitoring data available on these cohorts are more than adequate for quantitative risk assessment. In the case of the Gibb cohort, the exposure dataset is extraordinarily comprehensive and well-documented (Tr. 709-710; Ex. 44-4, p.2), even “exquisite” according to one NIOSH expert (Tr. 312). Further discussion of the quality and reliability of the Gibb and Luippold (2003) exposure data and related comments appears in Section VI.G.1.

OSHA received several comments regarding a new epidemiological study conducted by Environ, Inc. for the Industrial Health Foundation, Inc. of workers hired after the institution of process changes and industrial hygiene practices designed to limit exposure to Cr(VI) in two chromate production plants in the United States and two plants in Germany (Exs. 47-24-1; 47-27, pp. 15-16; 47-35-1, pp. 7-8). These commenters suggested that OSHA should use these cohorts to model risk of lung cancer from low exposures to Cr(VI). Unfortunately, the public did not have a chance to comment on this study because documents related to it were submitted to the docket after the time period when new information should have been submitted. However, OSHA reviewed the study and comments that were submitted to the docket. Based on the information submitted, the Agency does not believe that quantitative analysis of these studies would provide additional information on risk from low exposures to Cr(VI).

A cohort analysis based on the U.S. plants is presented in an April 2005 publication by Luippold et al. (Ex. 47-24-2). Luippold et al. studied a total of 617 workers with at least one year of employment, including 430 at a plant built in the early 1970s (“Plant 1”) and 187 hired after the 1980 institution of exposure-reducing process and work practice changes in a second plant (“Plant 2”). Workers were followed through 1998. Personal air-monitoring measures available from 1974 to 1988 for the first plant and from 1981 to 1998 for the second plant indicated that exposure levels at both plants were low, with overall geometric mean concentrations below 1.5 μg/m3 and area-specific average personal air sampling values not exceeding 10 μg/m3 for most years (Ex. 47-24-2, p. 383). By the end of follow-up, which lasted an average of 20.1 years for workers at Plant 1 and 10.1 years at Plant 2, 27 cohort members (4%) were deceased. There was a 41% deficit in all-cause mortality when compared to all-cause mortality from age-specific state reference rates, suggesting a strong healthy worker effect. Lung cancer was 16% lower than expected based on three observed vs. 3.59 expected cases, also using age-specific state reference rates (Ex. 47-24-2, p. 383). The authors concluded that “[t]he absence of an elevated lung cancer risk may be a favorable reflection of the postchange environment. However, longer follow-up allowing an appropriate latency for the entire cohort will be needed to confirm this conclusion” (Ex. 47-24-2, p. 381).

OSHA agrees with the study authors that the follow-up in this study was not sufficiently long to allow potential Cr(VI)-related lung cancer deaths to occur among many cohort members. The mean times since first exposure of 10 and 20 years for Plant 1 and Plant 2 employees, respectively, suggest that most workers in the cohort may not have completed the “ * * * typical latency period of 20 years or more” that Luippold et al. suggest is required for occupational lung cancer to emerge (Ex. 47-24-2, p. 384). Other important limitations of this study include the striking healthy worker effect on the SMR analysis, and the relatively young age of most workers at the end of follow-up (approximately 90% < 60 years old) (Ex. 47-24-2, p. 383). OSHA also agrees with the study authors' statements that “ * * * the few lung cancer deaths in this cohort precluded * * * [analyses to] evaluate exposure-response relationships * * * ” (Ex. 47-24-2, p. 384).

Although OSHA's model predicts high excess lung cancer risk for highly exposed individuals (e.g., workers exposed for 45 years at the previous PEL of 52 μg/m3), the model would predict much lower risks for workers with low exposures, as in the Luippold (2005) cohorts. To provide a point of comparison between the results of the Luippold et al. (2005) ‘post-change’ study and OSHA's risk model, the Agency used its risk model to generate an estimate of lung cancer risk for a population with exposure characteristics approximately similar to the ‘post-change’ cohorts described in Luippold et al. (2005). It should be noted that since this comparative analysis used year 2000 U.S. reference rates were rather than the state-, race-, and gender-specific historical reference mortality rates used by Luippold et al. (2005), this risk calculation provides only a rough estimate of expected excess lung cancer risk for the cohort. The derivation of OSHA's risk model (based on the preferred Gibb and Luippold Start Printed Page 10180(2003) cohorts) is described in Sections VI.C.1 and VI.C.2.

It is difficult to tell from the publication what the average level or duration of exposure was for the cohort. However, personal sampling data reported by Luippold et al. (2005) had annual geometric mean 8-hour TWA concentrations “much less” than 1.5 μg/m3 in most years (Ex. 47-24-2, p. 383). Most workers also probably had less than 20 years of exposure, given the average follow-up periods of 20 and 10 years reported for the Luippold (2005) Plant 1 and Plant 2, respectively. OSHA assumed that workers had TWA exposures of 1.5 μg/m3 for 20 years, with the understanding that this assumption would lead to somewhat higher estimates of risk than OSHA s model would predict if the average exposure of the cohort was known. Using these assumptions, OSHA's model predicts a 2-9% excess lung cancer risk due to Cr(VI) exposure, or less than four cancers in the population the size and age of the Luippold 2005 cohort.

Since this analysis used year 2000 U.S. reference rates rather than the state-, race-, and gender-specific historical reference mortality rates used by Luippold et al. (2005), this risk calculation provides only a rough estimate of the lung cancer risk that OSHA's model would predict for the cohort. Nevertheless, it illustrates that for a relatively young population with low exposures, OSHA's risk model (derived from the preferred Gibb and Luippold 2003 cohorts) predicts lung cancer risk similar to that observed in the low-exposure Luippold 2005 cohort. The small number of lung cancer deaths observed in Luippold 2005 should not be considered inconsistent with the risk estimates derived using models developed by OSHA based on the Gibb and Luippold (2003) cohorts (Ex. 47-24-2, p. 383).

Some commenters believed that analysis of the unpublished German cohorts would demonstrate that lung cancer risk was only increased at the highest Cr(VI) levels and, therefore, could form the basis for an exposure threshold (Exs. 47-24-1; 47-35-1). Although no data were provided to corroborate their comments, the Society of the Plastics Industry requested that OSHA obtain and evaluate the German study as “new and available evidence which may suggest a higher PEL than proposed” (Ex. 47-24-1, p. 4).

Following the close of the comment period, OSHA gained access to a 2002 final contract report by Applied Epidemiology Inc. prepared for the Industrial Health Foundation (Ex. 48-1-1; 48-1-2) and a 2005 prepublication by ENVIRON Germany (Ex. 48-4). The 2002 report contained detailed cohort descriptions, exposure assessments, and mortality analyses of ‘post-change’ workers from the two German chromate production plants referred to above and two U.S. chromate production plants, one of which is plant 1 discussed in the 2005 study by Luippold et al. The mortality and multivariate analyses were performed on a single combined cohort from all four plants. The 2005 prepublication contained a more abbreviated description and analysis of a smaller cohort restricted to the two German plants only. The cohorts are referred to as ‘post-change’ because the study only selected workers employed after the participating plants switched from a high-lime to a no-lime (or very low lime facility, in the case of U.S. plant 1) chromate production process and implemented industrial hygiene improvements that considerably reduced Cr(VI) air levels in the workplace.

The German cohort consisted of 901 post-change male workers from two chromate production plants employed for at least one year. Mortality experience of the cohort was evaluated through 1998. The study found elevated lung cancer mortality (SMR=1.48 95% CI: 0.93-2.25) when compared to the age- and calendar year-adjusted German national population rates (Ex. 48-4). The cohort lacked sufficient job history information and air monitoring data to develop an adequate job-exposure matrix required to estimate individual airborne exposures (Ex. 48-1-2). Instead, the researchers used the large amount of urinary chromium data from routine biomonitoring of plant employees to analyze lung cancer mortality using cumulative urinary chromium as an exposure surrogate, rather than the conventional cumulative Cr(VI) air concentrations. The study reported a statistically significant two-fold excess lung cancer mortality (SMR=2.09; 95% CI: 1.08-3.65; 12 observed lung cancer deaths) among workers in the highest cumulative exposure grouping (i.e. >200 μg Cr/L—yr). There was no increase in lung cancer mortality in the lower exposure groups, but the number of lung cancer deaths was small (i.e. < 5 deaths) and the confidence intervals were wide. Logistic regression modeling in the multi-plant cohort (i.e. German and U.S. plants combined) showed an increased risk of lung cancer in the high (OR=20.2; 95% CI: 6.2-65.4; 10 observed deaths) and intermediate (OR=4.9; 95% CI: 1.5-16.0; 9 deaths) cumulative exposure groups when compared to the low exposure group (Ex. 48-1-2, Table 18). The lung cancer risks remained unchanged when smoking status was controlled for in the model, indicating that the elevated risks were unlikely to be confounded by smoking in this study.

OSHA does not believe that the results of the German study provide a basis on which to establish a threshold exposure below which no lung cancer risk exists. Like the U.S. post-change cohort (i.e., Luippold (2005) cohort) discussed above, small cohort size, few lung cancer cases (e.g., 10 deaths in the three lowest exposure groups combined) and limited follow-up (average 17 years) severely limit the power to detect small increases in risk that may be present with low cumulative exposures. The limited power of the study is reflected in the wide confidence intervals associated with the SMRs. For example, there is no apparent evidence of excess lung cancer (SMR=0.95; 95% CI: 0.26-2.44) in workers exposed to low cumulative urine chromium levels between 40-100 μg Cr/L—yr. However, the lack of precision in this estimate is such that a two-fold increase in lung cancer mortality can not be ruled out with a high degree of confidence. Although the study authors state that the data suggest a possible threshold effect, they acknowledge that “demonstrating a clear (and statistically significant) threshold response in epidemiological studies is difficult especially [where], as in this study, the number of available cases is relatively small, and the precise estimation of small risks requires large numbers” (Ex. 48-4, p. 8). OSHA agrees that the number of lung cancer cases in the study is too small to clearly demonstrate a threshold response or precisely estimate small risks.

OSHA has relied upon a larger, more robust cohort study for its risk assessment than the German cohort. In comparison, the Gibb cohort has about five times the person-years of observation (70736 vs. 14684) and number of lung cancer cases (122 vs. 22). The workers, on average, were followed longer (30 vs. 17 years) and a greater proportion of the cohort is deceased (36% vs. 14%). Limited air monitoring from the German plants indicate that average plant-wide airborne Cr(VI) roughly declined from about 35 μg Cr(VI)/m3 in the mid 1970s to 5 μg Cr(VI)/m3 in the 1990s (2002 report; Ex. 7-91). This overlaps the Cr(VI) air levels in the Baltimore plant studied by Gibb et al. (Ex. 47-8). Furthermore, cumulative exposure estimates for members of the Gibb cohort were individually reconstructed Start Printed Page 10181from job histories and Cr(VI) air monitoring data. These airborne Cr(VI) exposures are better suited than urinary chromium for evaluating occupational risk at the permissible exposure limits under consideration by OSHA. An appropriate conversion procedure that credibly predicts time-weighted average Cr(VI) air concentrations in the workplace from urinary chromium measurements is not evident and, thus, would undoubtedly generate additional uncertainty in the risk estimates. For the above reasons, OSHA believes the Gibb cohort provides a stronger dataset than the German cohort on which to assess the existence of a threshold exposure. This and other issues pertaining to the relationship between the cumulative exposure and lung cancer risk are further discussed in section VI.G.1.a.

C. Quantitative Risk Assessments Based on the Gibb Cohort

Quantitative risk assessments were performed on the exposure-response data from the Gibb cohort by three groups: Environ International (Exs. 33-15; 33-12) under contract with OSHA; the National Institute for Occupational Safety and Health (Ex. 33-13); and Exponent (Ex. 31-18-15-1) for the Chrome Coalition. All reported similar risks for Cr(VI) exposure over a working lifetime despite using somewhat different modeling approaches. The exposure-response data, risk models, statistical evaluation, and risk estimates reported by each group are discussed below.

1. Environ Risk Assessments

In 2002, Environ International (Environ) prepared a quantitative analysis of the association between Cr(VI) exposure and lung cancer (Ex. 33-15) , which was described in detail in the Preamble to the Proposed Rule (69 FR at 59364-59365). After the completion of the 2002 Environ analysis, individual data for the 2357 men in the Gibb et al. cohort became available. The new data included cumulative Cr(VI) exposure estimates, smoking information, date of birth, race, date of hire, date of termination, cause of death, and date of the end of follow-up for each individual (Ex. 35-295). The individual data allowed Environ to do quantitative risk assessments based on (1) redefined exposure categories, (2) alternate background reference rates for lung cancer mortality, and (3) Cox proportional hazards modeling (Ex. 33-12). These are discussed below and in the 2003 Environ analysis (Ex. 33-12).

The 2003 Environ analysis presented two alternate groupings with ten cumulative Cr(VI) exposure groups each, six more than reported by Gibb et al. and used in the 2002 analysis. One alternative grouping was designed to divide the person-years of follow-up fairly evenly across groups. The other alternative allocated roughly the same number of observed lung cancers to each group. These two alternatives were designed to remedy the uneven distribution of observed and expected cases in the Gibb et al. categories, which may have caused parameter estimation problems due to the small number of cases in some groups. The new groupings assigned adequate numbers of observed and expected lung cancer cases to all groups and are presented in Table VI-1.

Environ used a five-year lag to calculate cumulative exposure for both groupings. This means that at any point in time after exposure began, an individual's cumulative exposure would equal the product of chromate concentration and duration of exposure, summed over all jobs held up to five years prior to that point in time. An exposure lag is commonly used in exposure-response analysis for lung cancer since there is a long latency period between first exposure and the development of disease. Gibb et al. found that models using five- and ten-year lags provided better fit to the mortality data than lags of zero, two and twenty years (Ex. 31-22-11).

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The 2003 Environ analysis also derived expected cases using lung cancer rates from alternative reference populations. In addition to the State of Maryland lung cancer rates that were used by Gibb et al., Environ used age- and race-specific rates from the city of Baltimore, where the plant was located. Baltimore may represent a more appropriate reference population because most of the cohort members Start Printed Page 10183resided in Baltimore and Baltimore residents may be more similar to the cohort members than the Maryland or U.S. populations in their co-exposures and lifestyle characteristics, especially smoking habits and urban-related risk factors. On the other hand, Baltimore may not be the more appropriate reference population if the higher lung cancer rates in the Baltimore population primarily reflect extensive exposure to industrial carcinogens. This could lead to underestimation of risk attributable to Cr(VI) exposure.

The 2003 analysis used two externally standardized models, a relative risk model (model E1 below) and an additive risk model (model E2) defined as follows:

E1. Ni = C0 * Ei * (1 + C1 Di + C2 Di2)

E2. Ni = C0 * Ei + PYi * (C1 Di + C2 Di2)

where Ni is the predicted number of lung cancers in the i th group; PYi is the number of person-years for group i; Ei is the expected number of lung cancers in that group, based on the reference population; Di is the mean cumulative dose for that group; and C0, C1, and C2 are parameters to be estimated. Both models initially included quadratic exposure terms (C2 Di2 ) as one way to test for nonlinearity in the exposure-response. Model E1 is a relative risk model, whereas Model E2 is an additive risk model. In the case of additive risk models, the exposure-related estimate of excess risk is the same regardless of the age- and race-specific background rate of lung cancer. For relative risk models, a dose term is multiplied by the appropriate background rate of lung cancer to derive an exposure-related estimate of risk, so that excess risk always depends on the background.

Maximum likelihood techniques were used to estimate the parameters C0, C1, and C2. Likelihood ratio tests were used to determine which of the model parameters contributed significantly to the fit of the model. Parameters were sequentially added to the model, starting with C1, when they contributed significantly (p < 0.05) to improving the fit. Parameters that did not contribute significantly, including the quadratic exposure terms (C2 Di2 ), were removed from the models.

Two Cox proportional hazards models were also fit to the individual exposure-response data. The model forms were:

C1. h(t;z;D) = h0 (t)*exp(β1 z + β2 D)

C2. h(t;z;D) = h0 (t)*[exp(β1 z)][1 + β2 D]

where h is the hazard function, which expresses the age-specific rate of lung cancer among workers, as estimated by the model. In addition, t is age, z is a vector of possible explanatory variables other than cumulative dose, D is cumulative dose, h0 (t) is the baseline hazard function (a function of age only), β2 is the cumulative dose coefficient, and β1 is a vector of coefficients for other possible explanatory variables—here, cigarette smoking status, race, and calendar year of death (Ex. 35-57). Cox modeling is an approach that uses the experience of the cohort to estimate an exposure-related effect, irrespective of an external reference population or exposure categorization. Because they are internally standardized, Cox models can sometimes eliminate concerns about choosing an appropriate reference population and may be advantageous when the characteristics of the cohort under study are not well matched against reference populations for which age-related background rates have been tabulated. Model C1 assumes the lung cancer response is nonlinear with cumulative Cr(VI) exposure, whereas C2 assumes a linear lung cancer response with Cr(VI) exposure. For the Cox proportional hazards models, C1 and C2, the other possible explanatory variables considered were cigarette smoking status, race, and calendar year of death.

The externally standardized models E1 and E2 provided a good fit to the data (p≥0.40). The choice of exposure grouping had little effect on the parameter estimates of either model E1 or E2. However, the choice of reference rates had some effect, notably on the “background” parameter, C0, which was included as a fitted parameter in the models to adjust for differences in background lung cancer rates between cohort members and the reference populations. For example, values of C0 greater than one “inflate” the base reference rates, reducing the magnitude of excess risks in the model. Such an adjustment was necessary for the Maryland reference population (the maximum likelihood estimate of C0 was significantly higher than one), but not for the Baltimore city reference population (C0 was not significantly different from one). This result suggests that the Maryland lung cancer rates may be lower than the cohort's background lung cancer rates, but the Baltimore city rates may adequately reflect the cohort background rates. The inclusion of the C0 parameter yielded a cumulative dose coefficient that reflected the effect of exposure and not the effect of differences in background rates, and was appropriate.

The model results indicated a relatively consistent cumulative dose coefficient, regardless of reference population. The coefficient for cumulative dose in the models ranged from 2.87 to 3.48 per mg/m3-yr for the relative risk model, E1, and from 0.0061 to 0.0071 per mg/m3-person-yr for the additive risk model, E2. These coefficients determine the slope of the linear cumulative Cr(VI) exposure-lung cancer response relationship. In no case did a quadratic model fit the data better than a linear model.

Based on comparison of the models' AIC values, Environ indicated that the linear relative risk model E1 was preferred over the additive risk model E2. OSHA agrees with Environ's conclusion. The relative risk model is also preferred over an additive risk model because the background rate of lung cancer varies with age. It may not be appropriate to assume, as an additive model does, that increased lung cancer risk at age 25, where background risk is relatively low, would be the same (for the same cumulative dose) as at age 65, where background rates are much higher.

The Cox proportional hazards models, C1 and C2, also fit the data well (although the fit was slightly better for model C2 than C1). Recall that for the Cox proportional hazards models, C1 and C2, the other possible explanatory variables considered were cigarette smoking status, race, and calendar year of death. For both models, addition of a term for smoking status significantly improved the fit of the models to the data (p<0.00001). The experience with model C1 indicated that race (p=0.15) and year of death (p=0.4) were not significant contributors when cumulative dose and smoking status were included in the model. Based on results for model C1, race and year of death were not considered by Environ in the linear model C2. The cumulative dose coefficient, β2, was 1.00 for model C1 and 2.68 for model C2. A more complete description of the models and variables can be found in the 2003 Environ analysis (Ex. 33-12, p. 10).

Lifetable calculations were made of the number of extra lung cancers per 1000 workers exposed to Cr(VI) based on models E1, E2, C1, and C2, assuming a constant exposure from age 20 through a maximum of age 65. The lifetable accounted for both lung cancer risk and competing mortality through age 100. Rates of lung cancer and other mortality for the lifetable calculations were based, respectively, on 2000 U.S. lung cancer and all-cause mortality rates for both sexes and all races. In addition to the maximum likelihood estimates, 95% confidence intervals for the excess lifetime risk were derived. Details about the procedures used to estimate parameters, model fit, lifetable calculations, and confidence intervals Start Printed Page 10184are described in the 2003 Environ report (Ex. 33-12, p. 8-9).

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Table VI-2 shows each model's predictions of excess lifetime lung cancer risk from a working lifetime of exposure to various Cr(VI) air levels. The estimates are very consistent regardless of model, exposure grouping, or reference population. The model that appears to generate results least similar to the others is C1, which yielded one of the higher risk estimates at 52 μg/m3, but estimated the lowest risks for exposure levels of 10 μg/m3 or lower. The change in magnitude, relative to the other models, is a result of the nonlinearity of this model. Confidence limits for all models, including C1, tend to overlap, suggesting a fair degree of statistical consistency.

2. National Institute for Occupational Safety and Health (NIOSH) Risk Assessment

NIOSH (Ex. 33-13) developed a risk assessment from the Gibb cohort. The NIOSH analysis, like the 2003 Environ assessment, used the cohort individual data files to compute cumulative Cr(VI) exposure. However, NIOSH also explored some other exposure-related assumptions. For example, they performed the dose-response analysis with lag times in addition to the 5-year lag used by Environ. NIOSH also analyzed dose-response using as many as 50 exposure categories, although their report presents data in five cumulative Cr(VI) exposure groupings.

NIOSH incorporated information on the cohort smoking behavior in their quantitative assessments. They estimated (packs/day)-years of cumulative smoking for each individual in the cohort, using information from a questionnaire that was administered at the time of each cohort member's date of hire. To estimate cumulative smoking, NIOSH assumed that the cohort members maintained the level of smoking reported in the questionnaire from the age of 18 through the end of follow-up. Individuals with unknown smoking status were assigned a value equal to the average smoking level among all individuals with known smoking levels (presumably including non-smokers). Individuals who were known to smoke but for whom the amount was unknown were assigned a smoking level equal to the average of all smokers.

NIOSH considered six different relative risk models, fit to the Gibb cohort data by Poisson regression methods. They did not consider additive risk models. The six relative risk models were externally standardized using age- and race-specific U.S. lung cancer rates. Their background coefficients, C0, explicitly included smoking, race, and age terms to adjust for differences between the cohort and the reference population. These models are described as follows:

NIOSH1a: Ni = C0 * Ei * exp(C1 Di)

NIOSH1b: Ni = C0 * Ei * exp(C1 Di 1/2\ )

NIOSH1c: Ni = C0 * Ei * exp(1 + C1 Di + C2 Di2)

NIOSH1d: Ni = C0 * Ei * (1 + D i)α

NIOSH1e: Ni = C0 * Ei * (1 + C1 Di)

NIOSH1f: Ni = C0 * Ei * (1 + C1 Diα)

where the form of the equation has been modified to match the format used in the Environ reports. In addition, NIOSH fit Cox proportional hazard models (not presented) to the lung cancer mortality data using the individual cumulative Cr(VI) exposure estimates.

NIOSH reported that the linear relative risk model 1e generally provided a superior fit to the exposure-response data when compared to the various log linear models, 1a-d. Allowing some non-linearity (e.g., model 1f) did not significantly improve the goodness-of-fit, therefore, they considered the linear relative risk model form 1e (analogous to the Environ model E1) to be the most appropriate for determining their lifetime risk calculations. A similar fit could be achieved with a log-linear power model (model 1d) using log-transformed cumulative Cr(VI) and a piece-wise linear specification for the cumulative smoking term.

The dose coefficient (C1) for the linear relative risk model 1e was estimated by NIOSH to be 1.444 per μg CrO3/m3-yr (Ex. 33-13, Table 4). If the exposures were converted to units of μg Cr(VI)/m3-yr, the estimated cumulative dose coefficient would be 2.78 (95% CI: 1.04 to 5.44) per μg/m3-yr. This value is very close to the estimates derived in the Environ 2003 analysis (maximum likelihood estimates ranging from 2.87 to 3.48 for model E1, depending on the exposure grouping and the reference population). Lifetime risk estimates based on the NIOSH-estimated dose coefficient and the Environ lifetable method using 2000 U.S. rates for lung cancer and all cause mortality are shown in Table VI-3. The values are very similar to the estimates predicted by the Environ 2003 analysis (Table VI-3). The small difference may be due to the NIOSH adjustment for smoking in the background coefficient. NIOSH found that excess lifetime risks for a 45-year occupational exposure to Cr(VI) predicted by the best-fitting power model gave very similar risks to the preferred linear relative risk model at TWA Cr(VI) concentrations between 0.52 and 52 μg/m3 (Ex. 33-13, Table 5). Although NIOSH did not report the results, they stated that Cox modeling produced risk estimates similar to the Poisson regression. The consistency between Cox and Poisson regression modeling is discussed further in section VI.C.4.

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NIOSH reported a significantly higher dose-response coefficient for nonwhite workers than for white workers. That is, nonwhite workers in the Gibb cohort are estimated to have a higher excess risk of lung cancer than white workers, given equal cumulative exposure to Cr(VI). In contrast, no significant race difference was found in the Cox proportional hazards analysis reported by 2003 Environ. Start Printed Page 10187

3. Exponent Risk Assessment

In response to OSHA's Request For Information, Exponent prepared an analysis of lung cancer mortality from the Gibb cohort. Like the 2003 Environ and NIOSH analyses, the Exponent analysis relied on the individual worker data. Exponent performed their dose-response analyses based on three different sets of exposure categories using two reference populations and 70,808 person-years of follow-up. A total of four analyses were completed, using (1) Maryland reference rates and the four Gibb et al. exposure categories; (2) Baltimore reference rates and the four Gibb et al. exposure categories; (3) Baltimore reference rates and six exposure groups defined by Exponent; and (4) Baltimore City reference rates and five exposure categories, obtained by removing the highest of the six groups defined by Exponent from the dose-response analysis. A linear relative risk model without a background correction term (the term C0 used by Environ and NIOSH) was applied in all of these cases and cumulative exposures were lagged five years (as done by Environ and NIOSH). The analyses showed excess lifetime risk between 6 and 14 per 1000 for workers exposed to 1 μg/m3 Cr(VI) for 45 years.

The analysis using Maryland reference lung cancer rates and the Gibb et al. four-category exposure grouping yielded an excess lifetime risk of 14 per 1000. This risk, which is higher than the excess lifetime risk estimates by Environ and NIOSH for the same occupational exposure, probably results from the absence of a background rate coefficient (C0) in Exponent's model. As reported in the Environ 2002 and 2003 analyses, the Maryland reference lung cancer rates require a background rate coefficient greater than 1 to achieve the best fit to the exposure-response data. The unadjusted Maryland rates probably underestimate the cohort's background lung cancer rate, leading to overestimation of the risk attributable to cumulative Cr(VI) exposure.

The two analyses that used Baltimore reference rates and either Exponent's six-category exposure grouping or the Gibb et al. four-category grouping both resulted in an excess lifetime unit risk of 9 per 1000 for workers exposed to 1 μg/m3 Cr(VI) for 45 years (Ex. 31-18-15-1, p. 41). This risk is close to estimates reported by Environ using their relative risk model (E1) and Baltimore reference rates for the same occupational exposure (Table VI-2). The Environ analysis showed that, unlike the Maryland-standardized model discussed above, the Baltimore-standardized models had background rate coefficients very close to 1, the “default” value assumed by the Exponent relative risk model. This suggests that the Baltimore reference rates may represent the background lung cancer rate for this cohort more accurately than the Maryland reference rates.

The lowest excess lifetime unit risk for workers exposed to 1 μg/m3 Cr(VI) for 45 years reported by Exponent, at 6 per 1000, was derived from the analysis that excluded the highest of Exponent's six exposure groups. While this risk value is close to the Environ and NIOSH unit risk estimates, the analysis merits some concern. Exponent eliminated the highest exposure group on the basis that most cumulative exposures in this group were higher than exposures usually found in current workplace conditions. However, eliminating this group could exclude possible long-term exposures (e.g., >15 years) below the previous OSHA PEL (52 μg/m3 ) from the risk analysis. Moreover, no matter what current exposures might be, data on higher cumulative exposures are relevant for understanding the dose-response relationships.

In addition, the Exponent six category cumulative exposure grouping may have led to an underestimate of the dose effect. The definition of Exponent's six exposure groups was not related to the distribution of cumulative exposure associated with individual person-years, but rather to the distribution of cumulative exposure among the workers at the end of their employment. This division does not result in either a uniform distribution of person-years or observed lung cancer cases among exposure categories. In fact, the six category exposure groupings of both person-years and observed lung cancers were very uneven, with a preponderance of both allocated to the lowest exposure group. This skewed distribution of person-years and observed cases puts most of the power for detecting significant differences from background cancer rates at low exposure levels, where these differences are expected to be small, and reduces the power to detect any significant differences from background at higher exposure concentrations.

4. Summary of Risk Assessments Based on the Gibb Cohort

OSHA finds remarkable consistency among the risk estimates from the various quantitative analyses of the Gibb cohort. Both Environ and NIOSH determined that linear relative risk models generally provided a superior fit to the data when compared to other relative risk models, although the confidence intervals in the non-linear Cox model reported by Environ overlapped with the confidence intervals in their linear models. The Environ 2003 analysis further suggested that a linear additive risk model could adequately describe the observed dose-response data. The risk estimates for NIOSH and Environ's best-fitting models were statistically consistent (compare Tables VI-2 and VI-3).

The choice of reference population had little impact on the risk estimates. NIOSH used the entire U.S. population as the reference, but included adjustment terms for smoking, age and race in its models. The Environ 2003 analysis used both Maryland and Baltimore reference lung cancer rates, and included a generic background coefficient C0 to adjust for potential differences in background risk between the reference population and the worker cohort. This term was significant in the fitted model when Maryland rates were used for external standardization, but not when Baltimore rates were used. Since no adjustment in the model background term was required to better fit the exposure-response data using Baltimore City lung cancer rates, they may best represent the cohort's true background lung cancer incidence. OSHA considers the inclusion of such adjustment factors, whether specific to smoking, race, and age (as defined by NIOSH), or generic (as defined by Environ), to be appropriate and believes they contribute to accurate risk estimation by helping to correct for confounding risk factors. The Cox proportional hazard models, especially the linear Cox model, yielded risk estimates that were generally consistent with the externally standardized models.

Finally, the number of exposure categories used in the analysis had little impact on the risk estimates. When an appropriate adjustment to the background rates was included, the four exposure groups originally defined by Gibb et al. and analyzed in the 2002 Environ report, the six exposure groups defined by Exponent, the two alternate sets of ten exposure categories as defined in the 2003 Environ analysis, and the fifty groups defined and aggregated by NIOSH all gave essentially the same risk estimates. The robustness of the results to various categorizations of cumulative exposure adds credence to the risk projections.

Having reviewed the analyses described in this section, OSHA finds that the best estimates of excess lung cancer risk to workers exposed to the previous PEL (52 μg Cr(VI)/m3) for a Start Printed Page 10188working lifetime are about 300 to 400 per thousand based on data from the Gibb cohort. The best estimates of excess lung cancer risks to workers exposed to other TWA exposure concentrations are presented in Table VI-2. These estimates are consistent with predictions from Environ, NIOSH and Exponent models that applied linear relative and additive risk models based on the full range of cumulative Cr(VI) exposures experienced by the Gibb cohort and used appropriate adjustment terms for the background lung cancer mortality rates.

D. Quantitative Risk Assessments Based on the Luippold Cohort

As discussed earlier, Luippold et al. (Exs. 35-204; 33-10) provided information about the cohort of workers employed in a chromate production plant in Painesville, Ohio. Follow-up for the 482 members of the Luippold cohort started in 1940 and lasted through 1997, with accumulation of person-years for any individual starting one year after the beginning of his first exposure. There were 14,048 total person-years of follow-up for the cohort. The person-years were then divided into five exposure groups that had approximately equal numbers of expected lung cancers in each group. Ohio reference rates were used to compute expected numbers of deaths. White male rates were used because the number of women was small (4 out of 482) and race was known to be white for 241 of 257 members of the cohort who died and for whom death certificates were available. The 1960-64 Ohio rates (the earliest available) were assumed to hold for the time period from 1940 to 1960. Rates from 1990-94 were assumed to hold for the period after 1994. For years between 1960 and 1990, rates from the corresponding five-year summary were used. There were significant trends for lung cancer SMR as a function of year of hire, duration of employment, and cumulative Cr(VI) exposure. The cohort had a significantly increased SMR for lung cancer deaths of 241 (95% C.I. 180 to 317).

Environ conducted a risk assessment based on the cumulative Cr(VI) exposure-lung cancer mortality data from Luippold et al. and presented in Table VI-4 (Ex. 33-15). Cumulative Cr(VI) exposures were categorized into five groups with about four expected lung cancer deaths in each group. In the absence of information to the contrary, Environ assumed Luippold et al. did not employ any lag time in determining the cumulative exposures. The calculated Start Printed Page 10189and expected numbers of lung cancers were derived from Ohio reference rates. Environ applied the relative and additive risk models, E1 and E2, to the data in Table VI-4.

Linear relative and additive risk models fit the Luippold cohort data adequately (p≥0.25). The final models did not include the quadratic exposure coefficient, C2, or the background rate parameter, C0, as they did not significantly improve the fit of the models. The maximum likelihood estimates for the Cr(VI) exposure-related parameter, C1, of the linear relative and additive risk models were 0.88 per mg/m3-yr and 0.0014 per mg/m3-person-yr, respectively. The C1 estimates based on the Luippold cohort data were about 2.5-fold lower than the parameter estimates based on the Gibb cohort data. The excess lifetime risk estimate calculated by Environ for a 45-year working-lifetime exposure to 1 μg Cr(VI)/m3 (e.g., the unit risk) for both models was 2.2 per 1000 workers (95% confidence intervals from 1.3 to 3.5 per 1000 for the relative risk model and 1.2 to 3.4 per 1000 for the additive risk model) using a lifetable analysis with 1998 U.S. mortality reference rates. These risks were 2.5 to 3-fold lower than the projected unit risks based on the Gibb data set for equivalent cumulative Cr(VI) exposures.

Crump et al. (Exs. 33-15; 35-58; 31-18) also performed an exposure-response analysis from the Painesville data. In a Poisson regression analysis, cumulative exposures were grouped into ten exposure categories with approximately two expected lung cancer deaths in each group. The observed and expected lung cancer deaths by Cr(VI) exposure category are shown in Table VI-5. Ohio reference rates were used in calculating the expected lung cancer deaths and cumulative exposures were lagged five years.

The Crump et al. analysis used the same linear relative risk and additive risk models as Environ on the individual data categorized into the ten cumulative exposure groups (Ex. 35-58). Tests for systematic departure from Start Printed Page 10190linearity were non-significant for both models (p≥0.11). The cumulative dose coefficient determined by the maximum likelihood method was 0.79 (95% CI: 0.47 to 1.19) per mg/m3-yr for the relative risk model and 0.0016 (95% CI: 0.00098 to 0.0024) per mg/m3-person-yr for the additive risk model, respectively. The authors noted that application of the linear models to five and seven exposure groups resulted in no significant difference in dose coefficients, although the results were not presented. The exposure coefficients reported by Crump et al. were very similar to those obtained by Environ above, although different exposure groups were used and Crump et al. used a five-year lag for the cumulative exposure calculation. The authors noted that the linear models did not fit the exposure data grouped into ten categories very well (goodness-of-fit p≤0.01) but fit the data much better with seven exposure groups (p>0.3), replacing the many lower exposure categories where there were few observed and expected cancers with more stable exposure groupings with greater numbers of cancers. The reduction in number of exposure groups did not substantially change the fitted exposure coefficients.

The maximum likelihood estimate for the cumulative exposure coefficient using the linear Cox regression model C2 was 0.66 (90% CI: 0.11 to 1.21), which was similar to the linear [Poisson regression] relative risk model. When the Cox analysis was restricted to the 197 workers with known smoking status and a smoking variable in the model, the dose coefficient for Cr(VI) was nearly identical to the estimate without controlling for smoking. This led the authors to conclude that “the available smoking data did not suggest that exposure to Cr(VI) was confounded with smoking in this cohort, or that failure to control for smoking had an appreciable effect upon the estimated carcinogenic potency of Cr(VI)” (Ex. 35-58, p. 1156).

Given the similarity in results, OSHA believes it is reasonable to use the exposure coefficients reported by Crump et al. based on their groupings of the individual cumulative exposure data to estimate excess lifetime risk from the Luippold cohort. Table VI-6 presents the excess risk for a working lifetime exposure to various TWA Cr(VI) levels as predicted by Crump et al.’s relative and additive risk models using a lifetable analysis with 2000 U.S. rates for all causes and lung cancer mortality. The resulting maximum likelihood estimates indicate that working lifetime exposures to the previous Cr(VI) PEL would result in excess lifetime lung cancer risks around 100 per 1000 (95% C.I. approx. 60-150). The risk estimates based on the Luippold cohort are lower than the risk estimates based on the Gibb cohort, as discussed further in section VI.F.

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E. Quantitative Risk Assessments Based on the Mancuso, Hayes, Gerin, and Alexander Cohorts

In addition to the preferred data sets analyzed above, there are four other cohorts with available data sets for estimation of additional lifetime risk of lung cancer. These are the Mancuso cohort, the Hayes cohort, the Gerin cohort, and the Alexander cohort. Environ did exposure-response analysis for all but the Hayes cohort (Ex. 33-15). Several years earlier, the K.S. Crump Division did quantitative assessments on data from the Mancuso and Hayes cohort, under contract with OSHA (Ex.13-5). The U.S. EPA developed quantitative risk assessments from the Mancuso cohort data for its Integrated Risk Information System (Exs. 19-1; 35-52). The California EPA (Ex. 35-54), Public Citizen Health Research Group (Ex. 1), and the U.S. Air Force Armstrong Laboratory (AFAL) for the Department of Defense (Ex. 35-51) performed assessments from the Mancuso data using the 1984 U.S. EPA risk estimates as their starting point. The U.S. EPA also published a risk assessment based on the Hayes cohort data (Ex. 7-102). Until the cohort studies of Gibb et al. and Luippold et al. became available, these earlier assessments provided the most current projected cancer risks from airborne exposure to Cr(VI). The previous risk assessments were extensively described in the NPRM sections VI.E.1 and VI.E.2 (69 FR at 59375-59378). While the risk estimates from Mancuso, Hayes, Gerin, and Alexander data sets are associated with a greater degree of uncertainty, it is nevertheless valuable to compare them to the risk estimates from the higher quality Gibb and Luippold data sets in order to determine if serious discrepancies exist between them. OSHA believes evaluating consistency in risk among several worker cohorts adds to the overall quality of the assessment.

The Mancuso and Luippold cohorts each worked at the Painesville plant but the worker populations did not overlap due to different selection criteria. Exposure estimates were also based on different industrial hygiene surveys. The Hayes and Gibb cohorts both worked at the Baltimore plant. Even though Cr(VI) exposures were reconstructed from monitoring data measured at different facilities resulting in significantly different exposure-response functions (see section VI.F), there was some overlap in the two study populations. As a result, the projected risks from these data sets can not strictly be viewed as independent estimates. The Gerin and Alexander cohorts were not chromate production workers and are completely independent from the Gibb and Luippold data sets. The quantitative assessment of the four data sets and comparison with the risk assessments based on the Gibb and Luippold cohorts are discussed below.

1. Mancuso Cohort

As described in subsection VII.B.3, the Mancuso cohort was initially defined in 1975 and updated in 1997. The cohort members were hired between 1931 and 1937 and worked at the same Painesville facility as the Luippold cohort workers. However, there was no overlap between the two cohorts since all Luippold cohort workers were hired after 1939. The quantitative risk assessment by Environ used data reported in the 1997 update (Ex. 23, Table XII) in which lung cancer deaths and person-years of follow-up were classified into four groups of cumulative exposure to soluble chromium, assumed to represent Cr(VI) (Ex. 33-15). The mortality data and person-years were further broken down by age of death in five year increments starting with age interval 40 to 44 years and going up to >75 years. No expected numbers of lung cancers were computed, either for the cohort as a whole or for specific groups of person-years. Environ applied an indirect method based on the recorded median age and year of entry into the cohort to estimate age information necessary to derive expected numbers of age- and calendar year-adjusted lung cancers deaths required to complete the risk assessment.

Observed and expected lung cancer deaths by age and cumulative exposure (mg/m3-yr) are presented in Table 3 of the 2002 Environ report (Ex. 33-15, p. 39). The mean cumulative exposures to soluble Cr(VI) were assumed to be equal to the midpoints of the tabulated ranges. No lag was used for calculating the cumulative exposures. Environ applied externally standardized risk models to these data, similar to those described in section VI.C.1 but using an age-related parameter, as discussed in the 2002 report (Ex. 33-15, p. 39). The externally-standardized linear relative risk model with an age-dependent exposure term provided a superior fit over the other models.

The predicted excess risk of lung cancer from a 45-year working lifetime of exposure to Cr(VI) at the previous OSHA PEL using the best-fitting linear relative risk model is 293 per 1000 workers (95% C.I. 188 to 403). The maximum likelihood estimate from working lifetime exposure to new PEL of 5.0 μg/m3 Cr(VI) is 34 per 1000 workers (95% C.I. 20 to 52 per 1000). These estimates are close to those predicted from the Gibb cohort but are higher than predicted from the Luippold cohort.

There are uncertainties associated with both the exposure estimates and the estimates of expected numbers of lung cancer deaths for the 1997 Mancuso data set. The estimates of exposure were derived from a single set of measurements obtained in 1949 (Ex. 7-98). Although little prior air monitoring data were available, it is thought that the 1949 air levels probably understate the Cr(VI) concentrations in the plant during some of the 1930s and much of the 1940s when chromate production was high to support the war. The sampling methodology used by Bourne and Yee only measured soluble Cr(VI), but it is believed that the chromate production process employed at the Painesville plant in these early years yielded slightly soluble and insoluble Cr(VI) compounds that would not be fully accounted for in the sampling results (Ex. 35-61). This would imply that risks would be overestimated by use of concentration estimates that were biased low. However, it is possible that the 1949 measurements did not underestimate the Cr(VI) air levels in the early 1930s prior to the high production years. Some older cohort members were also undoubtedly exposed to less Cr(VI) in the 1950s than measured in 1949 survey.

Another uncertainty in the risk assessment for the Mancuso cohort is associated with the post-hoc estimation of expected numbers of lung cancer deaths. The expected lung cancers were derived based on approximate summaries of the ages and assumed start times of the cohort members. Several assumptions were dictated by reliance on the published groupings of results (e.g., ages at entry, calendar year of entry, age at end of follow-up, etc.) as well as by the particular choices for reference mortality rates (e.g., U.S. rates, in particular years close to the approximated time at which the person-years were accrued). Since the validity of these assumptions could not be tested, the estimates of expected numbers of lung cancer deaths are uncertain.

There is also a potential healthy worker survivor effect in the Mancuso cohort. The cohort was identified as workers first hired in the 1930s based on employment records surveyed in the late 1940s (Ex. 2-16). The historical company files in this time period were Start Printed Page 10193believed to be sparse and more likely to only identify employees still working at the plant in the 1940s (Ex. 33-10). If there was a sizable number of unidentified short-term workers who were hired but left the plant in the 1930s or who died before 1940 (i.e. prior to systematic death registration), then there may have been a selection bias (i.e., healthy worker survivor effect) toward longer-term, healthier individuals (Ex. 35-60). Since the mortality of these long-term “survivors” is often more strongly represented in the higher cumulative exposures, it can negatively confound the exposure-response and lead to an underestimation of risk, particularly to shorter-term workers (Ex. 35-63). This may be an issue with the Mancuso cohort, although the magnitude of the potential underestimation is unclear.

Earlier quantitative risk assessments by the K.S. Crump Division, EPA, and others were done on cohort data presented in the 1975 Mancuso report (Ex. 7-11). These assessments did not have access to the 20 additional years of follow-up nor did they have age-grouped lung cancer mortality stratified by cumulative soluble chromium (presumed Cr(VI)) exposure), which was presented later in the 1997 update. Instead, age-grouped lung cancer mortality was stratified by cumulative exposure to total chromium that included not only carcinogenic Cr(VI) but substantial amounts of non-carcinogenic Cr(III). OSHA believes that the Environ quantitative risk assessment is the most credible analysis from the Mancuso cohort. It relied on the updated cohort mortality data and cumulative exposure estimates derived directly from air measurements of soluble chromium.

2. Hayes Cohort

The K.S. Crump Division (Ex. 13-5) assessed risk based on the exposure-response data reported in Table IV by Braver et al. (Ex. 7-17) for the cohort studied by Hayes et al. (Ex. 7-14). The Hayes cohort overlapped with the Gibb cohort. The Hayes cohort included 734 members, not part of the Gibb cohort, who worked at an older facility from 1945 to 1950 but did not work at the newer production facility built in August 1950. The Hayes cohort excluded 990 members of the Gibb cohort who worked less than 90 days in the new production facility after August 1950. As noted in section VI.B.4, Braver et al. derived a single cumulative soluble Cr(VI) exposure estimate for each of four subcohorts of chromate production workers categorized by duration of employment and year of hire by Hayes et al. Thus, exposures were not determined for individual workers using a more comprehensive job exposure matrix procedure, as was done for the Gibb and Luippold cohorts. In addition, the exposures were estimated from air monitoring conducted only during the first five of the fifteen years the plant was in operation. Unlike the Mancuso cohort, Hayes et al. did not stratify the observed lung cancer deaths by age group. The expected number of lung cancer deaths for each subcohort was based on the mortality statistics from Baltimore.

The K.S. Crump Division applied the externally standardized linear relative risk approach to fit the exposure-response data (Ex. 13-5). The maximum likelihood estimate for the dose coefficient (e.g., projected linear slope of the Cr(VI) exposure-response curve) was 0.75 per mg Cr(VI)/m3-yr with a 90% confidence bound of between 0.45 and 1.1 per mg Cr(VI)/m3-yr. These confidence bounds are consistent with the dose coefficient estimate obtained from modeling the Luippold cohort data (0.83, 95% CI: 0.55 to 1.2) but lower than that from the Gibb cohort data (3.5, 95% CI: 1.5 to 6.0). The linear relative risk model fit the Hayes cohort data well (p=0.50). The K.S. Crump Division predicted the excess risk from occupational exposure to Cr(VI) for a 45 year working lifetime at the previous OSHA PEL (52 μg/m3) to be 88 lung cancer cases per 1000 workers (95% CI: 61 to 141). Predicted excess risk at the new PEL of 5 μg/m3 is about 9 excess lung cancer deaths per 1000 (95% CI: 6.1 to 16) for the same duration of occupational exposure. These estimates are somewhat lower than the corresponding estimates based on the Gibb cohort data, probably because of the rather high average soluble Cr(VI) level (218 μg/m3) assumed by Braver et al. for plant workers throughout the 1950s. If these assumed air levels led to an overestimate of worker exposure, the resulting risks would be underestimated.

3. Gerin Cohort

Environ (Ex. 33-15) did a quantitative assessment of the observed and expected lung cancer deaths in stainless steel welders classified into four cumulative Cr(VI) exposure groups reported in Tables 2 and 3 of Gerin et al. (Ex. 7-120). The lung cancer data came from a large combined multi-center welding study in which a statistically significant excess lung cancer risk was observed for the whole cohort and non-statistically significant elevated lung cancer mortality was found for the stainless steel welder subcohorts (Ex. 7-114). A positive relationship with time since first exposure was also observed for the stainless steel welders (the type of welding with the highest exposure to Cr(VI)) but not with duration of employment.

The exposure-response data from the Gerin study was only presented for those stainless steel welders with at least five years employment. Workers were divided into “ever stainless steel welders” and “predominantly stainless steel welders” groups. The latter group were persons known to have had extended time welding stainless steel only or to have been employed by a company that predominantly worked stainless steel. As stated in section VI.B.5, the cumulative exposure estimates were not based on Cr(VI) air levels specifically measured in the cohort workers, and therefore are subject to greater uncertainty than exposure estimates from the chromate production cohort studies. Environ restricted their analysis to the “ever stainless steel welders” since that subcohort had the greater number of eligible subjects and person-years of follow-up, especially in the important lower cumulative exposure ranges. The person-years, observed numbers of lung cancers, and expected numbers of lung cancers were computed starting 20 years after the start of employment. Gerin et al. provided exposure-response data on welders with individual work histories (about two-thirds of the workers) as well as the entire subcohort. Regardless of the subcohort examined, there was no obvious indication of a Cr(VI) exposure-related effect on lung cancer mortality. A plausible explanation for this apparent lack of exposure-response is the potentially severe exposure misclassification resulting from the use of exposure estimates based on the welding literature (rather than exposure measurements at the plants used in the study, which were not available to the authors).

Environ used externally standardized models to fit the data (Ex. 33-15). They assumed that the cumulative Cr(VI) exposure for the workers was at the midpoint of the reported range. A value of 2.5 mg/m3-yr was assumed for the highest exposure group (e.g., >0.5 mg/m3-yr), since Gerin et al. cited it as the mean value for the group, which they noted to also include the “predominantly stainless steel welders”. All models fit the data adequately (p>0.28) with exposure coefficients considerably lower than for the Gibb or Luippold cohorts (Ex. 33-15, Table 6). In fact, the 95% confidence intervals for the exposure coefficients Start Printed Page 10194overlapped 0, which would be expected when there is no exposure-related trend.

Based on the best fitting model, a linear relative risk model (Ex. 33-15, Table 9, p. 44), the projected excess risk of lung cancer from a working lifetime exposure to Cr(VI) at the previous PEL was 46 (95% CI: 0 to 130) cases per 1000 workers. The 95 percent confidence interval around the maximum likelihood estimate reflects the statistical uncertainty associated with risk estimates from the Gerin cohort.

Following the publication of the proposed rule, OSHA received comments from Exponent (on behalf of a group of steel industry representatives) stating that it is not appropriate to model exposure-response for this cohort because there was not a statistically significant trend in lung cancer risk with estimated exposure, and risk of lung cancer did not increase monotonically with estimated exposure (Ex. 38-233-4, pp. 7-8). OSHA disagrees. Because the best-fitting model tested by Environ fit the Gerin data adequately, OSHA believes that it is reasonable to generate risk estimates based on this model for comparison with the risk estimates based on the Gibb and Luippold cohorts. This allows OSHA to quantitatively assess the consistency between its preferred estimates and risk estimates derived from the Gerin cohort.

In post-hearing comments, Dr. Herman Gibb expressed support for OSHA's approach. Dr. Gibb stated:

The epidemiologic studies of welders * * * conducted to date have been limited in their ability to evaluate a lung cancer risk. It is conceivable that differences in exposure * * * between [this industry] and the chromate production industry could lead to differences in cancer risk. Because there aren't adequate data with which to evaluate these differences, it is appropriate to compare the upper bounds [on risk] derived from the Gerin et al. * * * [study] with those predicted from the chromate production workers to determine if they are consistent.

OSHA agrees with Exponent that the results of the Gerin et al. study were different from those of the Luippold (2003) and Gibb cohorts, in that a statistically significant exposure-response relationship and a monotonically increasing lung cancer risk with exposure were not found in Gerin. Also, the maximum likelihood risk estimates based on the Gerin cohort were somewhat lower than those based on the Gibb and Luippold cohorts. However, OSHA believes the lower risk estimates from the Gerin cohort may be explained by the strong potential for bias due to Cr(VI) exposure misclassification and possibly by the presence of co-exposures, as discussed in sections VI.B.5 and VI.G.4. Part of the difference may also relate to statistical uncertainty; note that the 95% confidence intervals (shown in Table VI-7) overlap the lower end of OSHA's range based on the preferred Gibb and Luippold (2003) studies.

4. Alexander Cohort

Environ (Ex. 33-15) did a quantitative assessment of the observed and expected lung cancer incidence among aerospace workers exposed to Cr(VI) classified into four cumulative chromate exposure groups, reported in Table 4 of Alexander et al. (Ex. 31-16-3). The authors stated that they derived “estimates of exposure to chromium [VI]” based on the TWA measurements, but later on referred to “the index of cumulative total chromate exposure (italics added) reported as μg/m3 chromate TWA-years” (Ex. 31-16-3, p. 1254). Alexander et al. grouped the lung cancer data by cumulative exposure with and without a ten year lag period. They found no statistically significant elevation in lung cancer incidence among the chromate-exposed workers or clear trend with cumulative chromate exposure.

For their analysis, Environ assumed that the cumulative exposures were expressed in μg/m3-yr of Cr(VI), rather than chromate (CrO4−2) or chromic acid (CrO3). Environ used an externally standardized linear relative risk model to fit the unlagged data (Ex. 33-15). An additive risk model could not be applied because person-years of observation were not reported by Alexander et al. Environ assumed that workers were exposed to a cumulative Cr(VI) exposure at the midpoint of the reported ranges. For the open-ended high exposure category, Environ assumed a cumulative exposure 1.5 times greater than the lower limit of 0.18 mg/m3-yr. The model fit the data poorly (p=0.04) and the exposure coefficient was considered to be 0 since positive values did not significantly improve the fit. Given the lack of a positive trend between lung cancer incidence and cumulative Cr(VI) exposure for this cohort, these results are not surprising.

Following the publication of the proposed rule, OSHA received comments from Exponent (on behalf of the Aerospace Industries Association) stating that the Agency should not apply a linear model to the Alexander et al. study to derive risk estimates for comparison with the estimates based on the Gibb and Luippold (2003) cohorts (Ex. 38-215-2, p. 10). Due to the poor fit of Environ's exposure-response model to the Alexander cohort data, OSHA agrees with Exponent in this matter. Risk estimates based on Alexander et al. are therefore not presented in this risk assessment.

OSHA believes that there are several possible reasons for the lack of a positive association between Cr(VI) exposure and lung cancer incidence in this cohort. First, follow-up time was extremely short, averaging 8.9 years per cohort member. Long-term follow-up of cohort members is particularly important for determining the risk of lung cancer, which typically has an extended latency period of roughly 20 years or more. One would not necessarily expect to see excess lung cancer or an exposure-response relationship among workers who had been followed less than 20 years since their first exposure to Cr(VI), as most exposure-related cancers would not yet have appeared. Other possible reasons that an exposure-response relationship was not observed in the Alexander cohort include the young age of the cohort members (median 42 years at end of follow-up), which also suggests that occupational lung cancers may not yet have appeared among many cohort members. The estimation of cumulative Cr(VI) exposure was also problematic, drawing on air measurement data that did not span the entire employment period of the cohort (there were no data for 1940 to 1974) and were heavily grouped into a relatively small number of “summary” TWA concentrations that did not capture individual differences in workplace exposures to Cr(VI).

F. Summary of Risk Estimates Based on Gibb, Luippold, and Additional Cohorts

OSHA believes that the best estimates of excess lifetime lung cancer risks are derived from the Gibb and Luippold cohorts. Due to their large size and long follow-up, these two cohorts accumulated a substantial number of lung cancer deaths that were extensively examined by several different analyses using a variety of statistical approaches. Cohort exposures were reconstructed from air measurements and job histories over three or four decades. The linear relative risk model fit the Gibb and Luippold data sets well. It adequately fit several epidemiological data sets used for comparative analysis. Environ and NIOSH explored a variety of nonlinear dose-response forms, but none provided a statistically significant improvement over the linear relative risk model.

The maximum likelihood estimates from a linear relative risk model fit to the Gibb data are three- to five-fold higher than estimates based on the Luippold data at equivalent cumulative Start Printed Page 10195Cr(VI) exposures and the confidence limits around the projected risks from the two data sets do not overlap. This indicates that the maximum likelihood estimates derived from one data set are unlikely to describe the lung cancer mortality observed in the other data set. Despite this statistical inconsistency between the risk estimates, the differences between them are not unreasonably great given the potential uncertainties involved in estimating cancer risk from the data (see section VI.G). Since the analyses based on these two cohorts are each of high quality and their projected risks are reasonably close (well within an order of magnitude), OSHA believes the excess lifetime risk of lung cancer from occupational exposure to Cr(VI) is best represented by the range of risks that lie between maximum likelihood estimates of the Gibb and Luippold data sets.

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OSHA's best estimates of excess lung cancer cases from a 45-year working lifetime exposure to Cr(VI) are presented in Table VI-7. As previously discussed, several acceptable assessments of the Gibb data set were performed, with similar results. The 2003 Environ model E1, applying the Baltimore City reference population and ten exposure categories based on a roughly equal number of person-years per group, was selected to represent the range of best risk estimates derived from the Gibb cohort, in part because this assessment employed an approach most consistent with the exposure grouping applied in the Luippold analysis (see Table VI-6). To characterize the statistical uncertainty of OSHA's risk estimates, Table VI-7 also presents the 95% confidence limits associated with the maximum likelihood risk estimates from the Gibb cohort and the Luippold cohort.

OSHA finds that the most likely lifetime excess risk at the previous PEL of 52 μg/m3 Cr(VI) lies between 101 per 1000 and 351 per 1000, as shown in Table VI-7. That is, OSHA predicts that between 101 and 351 of 1000 workers occupationally exposed for 45 years at the previous PEL would develop lung cancer as a result of their exposure. The wider range of 62 per 1000 (lower 95% confidence bound, Luippold cohort) to 493 per 1000 (upper 95% confidence bound, Gibb cohort) illustrates the range of risks considered statistically plausible based on these cohorts, and thus represents the statistical uncertainty in the estimates of lung cancer risk. This range of risks decreases roughly proportionally with exposure, as illustrated by the risk estimates shown in Table VI-7 for working lifetime exposures at various levels at and below the previous PEL.

The risk estimates for the Mancuso, Hayes, and Gerin data sets are also presented in Table VI-7. (As discussed previously, risk estimates were not derived from the Alexander data set.) The exposure-response data from these cohorts are not as strong as those from the two featured cohorts. OSHA believes that the supplemental assessments for the Mancuso and Hayes cohorts support the range of projected excess lung cancer risks from the Gibb and Luippold cohorts. This is illustrated by the maximum likelihood estimates and 95% confidence intervals shown in Table VI-7. The risk estimates and 95% confidence interval based on the Hayes cohort are similar to those based on the Luippold cohort, while the estimates based on the Mancuso cohort are more similar to those based on the Gibb cohort. Also, OSHA's range of best risk estimates based on the two primary cohorts for a given occupational Cr(VI) exposure overlap the 95 percent confidence limits for the Mancuso, Hayes, and Gerin cohorts. This indicates that the Agency's range of best estimates is statistically consistent with the risks calculated by Environ from any of these data sets, including the Gerin cohort where the lung cancers did not show a clear positive trend with cumulative Cr(VI) exposure.

Several commenters remarked on OSHA's use of both the Gibb cohort and the Luippold cohort to define a preliminary range of risk estimates associated with a working lifetime of exposure at the previous and alternative PELs. Some suggested that OSHA should instead rely exclusively on the Gibb study, due to its superior size, smoking data, completeness of follow-up, and exposure information (Tr. 709-710, 769; Exs. 40-18-1, pp. 2-3; 47-23, p. 3; 47-28, pp. 4-5). Others suggested that OSHA should devise a weighting scheme to derive risk estimates based on both studies but with greater weight assigned to the Gibb cohort (Tr. 709-710, 769, Exs. 40-18-1, pp. 2-3; 47-23, p. 3), arguing that “the use of the maximum likelihood estimate from the Luippold study as the lower bound of OSHA's risk estimates * * * has the effect of making a higher Permissible Exposure Limit (PEL) appear acceptable” (Ex. 40-18-1, p. 3). OSHA disagrees with this line of reasoning. OSHA believes that including all studies that provide a strong basis to model the relationship between Cr(VI) and lung cancer, as the Luippold study does, provides useful information and adds depth to the Agency's risk assessment. OSHA agrees that in some cases derivation of risk estimates based on a weighting scheme is an appropriate approach when differences between the results of the two or more studies are believed to primarily reflect sources of uncertainty or error in the underlying studies. A weighting scheme might then be used to reflect the degree of confidence in their respective results. However, the Gibb and Luippold cohorts were known to be quite different populations, and the difference between the risk estimates based on the two cohorts could partly reflect variability in exposure-response. In this case, OSHA's use of a range of risk defined by the two studies is appropriate for the purpose of determining significance of risk at the previous PEL and the alternative PELs that the Agency considered.

Another commenter suggested that OSHA should derive a “single ‘best’ risk estimate [taking] into account all of the six quantitative risk estimates” identified by OSHA as featured or supporting risk assessments in the preamble to the proposed rule, consisting of the Gibb and Luippold cohorts as well as studies by Mancuso (Ex. 7-11), Hayes (Ex. 7-14), Gerin (Ex. 7-120), and Alexander (Ex. 31-16-3) (Ex. 38-265, p. 76). The commenter, Mr. Stuart Sessions of Environomics, Inc., proposed that OSHA should use a weighted average of risk estimates Start Printed Page 10197derived from all six studies, weighting the Gibb and Luippold studies more heavily than the remaining four “admittedly weaker studies” (Ex. 38-265, p. 78). During the public hearing, however, he stated that OSHA may reasonably choose not to include some studies in the development of its quantitative risk model based on certain criteria or qualifications related to the principles of sound epidemiology and risk assessment (Tr. 2484-2485). Mr. Sessions agreed with OSHA that sufficient length of follow-up (≥20 years) is a critical qualification for a cohort to provide an adequate basis for lung cancer risk assessment, admitting that “if we are dealing with [a] long latency sort of effect and if you only follow them for a few years it wouldn't be showing up with anywhere near the frequency that you would need to get a statistically significant excess risk” (Tr. 2485). This criterion supports OSHA's decision to exclude the Alexander study as a primary data set for risk assessment, due in part to the inadequate length of follow-up on the cohort (average 8.9 years).

Mr. Sessions also agreed that the quality and comprehensiveness of the exposure information for a study could be a deciding factor in whether it should be used for OSHA's risk estimates (Tr. 2485-2487). As discussed in the preamble to the proposed rule, significant uncertainty in the exposure estimates for the Mancuso and Gerin studies was a primary reason they were not used in the derivation of OSHA's preliminary risk estimates (69 FR at 59362-3). Mancuso relied exclusively on the air monitoring reported by Bourne and Yee (Ex. 7-98) conducted over a single short period of time during 1949 to calculate cumulative exposures for each cohort member, although the cohort definition and follow-up period allowed inclusion of workers employed as early as 1931 and as late as 1972. In the public hearing, Mr. Sessions indicated that reliance on exposure data from a single year would not necessarily “disqualify” a study from inclusion in the weighted risk estimate he proposed, if “for some reason the exposure hasn't changed much over the period of exposure” (Tr. 2486). However, the Mancuso study provides no evidence that exposures in the Painesville plant were stable over the period of exposure. To the contrary, Mancuso stated that:

The tremendous progressive increase in production in the succeeding years from zero could have brought about a concomitant increase in the dust concentrations to 1949 that could have exceeded the level of the first years of operation. The company instituted control measures after the 1949 study which markedly reduced the exposure (Ex. 7-11, p. 4).

In the Gerin et al. study, cohort members' Cr(VI) exposures were estimated based on total fume levels and fume composition figures from “occupational hygiene literature and and welding products manufacturers' literature readily available at the time of the study”, supplemented by “[a] limited amount of industrial hygiene measurements taken in the mid 1970s in eight of the [135] companies” from which the cohort was drawn (Ex. 7-120, p. S24). Thus, cumulative exposure estimates for workers in this cohort were generally not based on data collected in their particular job or company. Gerin et al. explained that the resulting “global average” exposure estimates “obscure a number of between-plant and within-plant variations in specific factors which affect exposure levels and would dilute a dose-response relationship”, including type of activity, * * * special processes, arcing time, voltage and current characteristics, welder position, use of special electrodes or rods, presence of primer paints and background fumes coming from other activities (Ex. 7-120, p. S25).

Commenting on the available welding epidemiology, NIOSH emphasized that wide variation in exposure conditions across employers may exist, and should be a consideration in multi-employer studies (Ex. 47-19, p. 6). Gerin et al. recommended refinement and validation of their exposure estimates using “more complete and more recent quantitative data” and accounting for variability within and between plants, but did not report any such validation for their exposure-response analysis. OSHA believes that the exposure misclassification in the Gerin study could be substantial. It is therefore difficult to place a high degree of confidence in its results, and it should not be used to derive the Agency's quantitative risk estimates. Comments received from Dr. Herman Gibb support OSHA's conclusion. He stated that epidemiologic studies of welders conducted to date do not include adequate data with which to evaluate lung cancer risk (Ex. 47-8, p. 2).

Finally, Mr. Sessions agreed with OSHA that it is best to rely on “independent studies on different cohorts of workers”, rather than including the results of two or more overlapping cohorts in the weighted average he proposed (Tr. 2487). As discussed in the preamble to the proposed rule, the Hayes et al. and Gibb et al. cohorts were drawn from the same Baltimore chromate production plant (FR 69 at 59362). The workers in the subcohort of Hayes et al. analyzed by Braver were first hired between 1945 and 1959; the Gibb cohort included workers first hired between 1950 and 1974. Due to the substantial overlap between the two cohorts, it is not appropriate to use the results of the Hayes as well as the Gibb cohort in a weighted average calculation (as proposed by Mr. Sessions).

Having carefully reviewed the various comments discussed above, OSHA finds that its selection of the Gibb and Luippold cohorts to derive a range of quantitative risk estimates is the most appropriate approach for the Cr(VI) risk assessment. Support for this approach was expressed by NIOSH, which stated that “the strength is in looking at [the Gibb and Luippold studies] together * * * appreciating the strengths of each” (Tr. 313). Several commenters voiced general agreement with OSHA's study selection, even while disagreeing with OSHA's application of these studies' results to specific industries. Said one commenter, “[w]e concur with the selection of the two focus cohorts (Luippold et al. 2003 and Gibb et al. 2000) as the best data available upon which to base an estimate of the exposure-response relationship between occupational exposure to Cr(VI) and an increased lung cancer risk” (38-8, p. 6); and another, “[i]t is clear that the data from the two featured cohorts, Gibb et al. (2000) and Luippold et al. (2003), offer the best information upon which to quantify the risk due to Cr(VI) exposure and an increased risk of lung cancer” (Ex. 38-215-2, p. 16). Comments regarding the suitability of the Gibb and Luippold cohorts as a basis for risk estimates in specific industries will be addressed in later sections.

G. Issues and Uncertainties

The risk estimates presented in the previous sections include confidence limits that reflect statistical uncertainty. This statistical uncertainty concerns the limits of precision for statistical inference, given assumptions about the input parameters and risk models (e.g., exposure estimates, observed lung cancer cases, expected lung cancer cases, linear dose-response). However, there are uncertainties with regard to the above input and assumptions, not so easily quantified, that may lead to underestimation or overestimation of risk. Some of these uncertainties are discussed below. Start Printed Page 10198

1. Uncertainty With Regard to Worker Exposure to Cr(VI)

The uncertainty that may have the greatest impact on risk estimates relates to the assessment of worker exposure. Even for the Gibb cohort, whose exposures were estimated from roughly 70,000 air measurements over a 35-year period, the calculation of cumulative exposure is inherently uncertain. The methods used to measure airborne Cr(VI) did not characterize particle size that determines deposition in the respiratory tract (see section V.A). Workers typically differ from one another with respect to working habits and they may have worked in different areas in relation to where samples are taken. Inter-individual (and intra-facility) variability in cumulative exposure can only be characterized to a limited degree, even with extensive measurement. The impact of such variability is likely less for estimates of long-term average exposures when there were more extensive measurements in the Gibb and Luippold cohorts in the 1960s through 1980s, but could affect the reliability of estimates in the 1940s and 1950s when air monitoring was done less frequently. Exposure estimates that rely on annual average air concentrations are also less likely to reliably characterize the Cr(VI) exposure to workers who are employed for short periods of time. This may be particularly true for the Gibb cohort in which a sizable fraction of cohort members were employed for only a few months.

Like many retrospective cohort studies, the frequency and methods used to monitor Cr(VI) concentrations may also be a source of uncertainty in reconstructing past exposures to the Gibb and Luippold cohorts. Exposures to the Gibb cohort in the Baltimore plant from 1950 until 1961 were determined based on periodic collection of samples of airborne dust using high volume sampling pumps and impingers that were held in the breathing zone of the worker for relatively short periods of time (e.g., tens of minutes) (Ex. 31-22-11). The use of high volume sampling with impingers to collect Cr(VI) samples may have underestimated exposure since the accuracy of these devices depended on an air flow low enough to ensure efficient Cr(VI) capture, the absence of agents capable of reducing Cr(VI) to Cr(III), the proper storage of the collected samples, and the ability of short-term collections to accurately represent full-shift worker exposures. Further, impingers would not adequately capture any insoluble forms of Cr(VI) present, although other survey methods indicated minimal levels of insoluble Cr(VI) were produced at the Baltimore facility (Ex. 13-18-14).

In the 1960s, the Baltimore plant expanded its Cr(VI) air monitoring program beyond periodic high volume sampling to include extensive area monitoring in 27 exposure zones around the facility. Multiple short-term samples were collected (e.g., twelve one-hour or eight three-hour samples) on cellulose tape for an entire 24 hour period and analyzed for Cr(VI). Studies have shown that Cr(VI) can be reduced to Cr(III) on cellulose filters under certain circumstances so there is potential for underestimation of Cr(VI) using this collection method (Ex. 7-1, p. 370). Monitoring was conducted prior to 1971, but the results were misplaced and were not accessible to Gibb et al. The area monitoring was supplemented by routine full-shift personal monitoring of workers starting in 1977. The 24-hour area sampling supplemented with personal monitoring was continued until plant closure in 1985.

Some of the same uncertainties exist in reconstructing exposures from the Luippold cohort. Exposure monitoring from operations at the Painesville plant in the 1940s and early 1950s was sparse and consisted of industrial hygiene surveys conducted by various groups (Ex. 35-61). The United States Public Health Service (USPHS) conducted two industrial hygiene surveys (1943 and 1951), as did the Metropolitan Life Insurance Company (1945 and 1948). The Ohio Department of Health (ODH) conducted surveys in 1949 and 1950. The most detailed exposure information was available in annual surveys conducted by the Diamond Alkali Company (DAC) from 1955 to 1971. Exponent chose not to consider the ODH data in their analysis since the airborne Cr(VI) concentrations reported in these surveys were considerably lower than values measured at later dates by DAC. Excluding the ODH survey data in the exposure reconstruction process may have led to higher worker exposure estimates and lower predicted lung cancer risks.

There were uncertainties associated with the early Cr(VI) exposure estimates for the Painesville cohort. Like the monitoring in the Baltimore plant, Cr(VI) exposure levels were determined from periodic short-term, high volume sampling with impingers that may have underestimated exposures (Ex. 35-61). Since the Painesville plant employed a “high-lime” roasting process to produce soluble Cr(VI) from chromite ore, a significant amount of slightly soluble and insoluble Cr(VI) was formed. It was estimated that up to approximately 20 percent of the airborne Cr(VI) was in the less soluble form in some areas of the plant prior to 1950 (Ex. 35-61). The impingers were unlikely to have captured this less soluble Cr(VI) so some reported Cr(VI) air concentrations may have been underestimated for this reason.

The annual air monitoring program at the Painesville plant was upgraded in 1966 in order to evaluate a full 24 hour period (Ex. 35-61). Unlike the continuous monitoring at the Baltimore plant, twelve area air samples from sites throughout the plant were collected for only 35 minutes every two hours using two in-series midget impingers containing water. The more frequent monitoring using the in-series impinger procedure may be an improvement over previous high-volume sampling and is believed to be less susceptible to Cr(VI) reduction than cellulose filters. While the impinger collection method at the Painesville plant may have reduced one source of potential exposure uncertainty, another source of potential uncertainty was introduced by failure to collect air samples for more than 40 percent of the work period. Also, personal monitoring of workers was not conducted at any time.

Concerns about the accuracy of the Gibb and Luippold exposure data were expressed in comments following the publication of the proposed rule. Several commenters suggested that exposures of workers in both the Gibb and Luippold (2003) cohorts may have been underestimated, resulting in systematic overestimation of risk in the analyses based on these cohorts (Exs. 38-231, pp. 19-20; 38-233, p. 82; 39-74, p. 2; 47-27, p. 15; 47-27-3, p. 1). In particular, the possibility was raised that exposure measurements taken with the RAC sampler commonly used in the 1960s may have resulted in lower reported Cr(VI) levels as a result of reduction of Cr(VI) on the sample strip. Concerns were also raised that situations of exceptionally high exposure may not have been captured by the sampling plans at the Baltimore and Painesville plants and that Cr(VI) concentrations in workers' breathing zones would have been generally higher than concentrations measured in general area samples taken in the two plants (Exs. 38-231, p. 19; 40-12-1, p. 2). One commenter noted that “the exposure values identified in both the Painesville and Baltimore studies are consistently lower than those reported for a similar time period by alternative sources (Braver et al. 1985; PHS 1953)” (Exs. 38-231, p. 19; 40-12-1, p. 2). It was also suggested that impinger samples used to estimate exposures in the Painesville Start Printed Page 10199plant and the impinger and RAC samples used between 1950 and 1985 in the Baltimore plant did not efficiently capture particles smaller than 1 μm in diameter, which were believed to have constituted a substantial fraction of particles generated during the chromite ore roasting process, and thus led to an underestimate of exposures (Ex. 47-27-3, pp. 1-4).

In his written testimony for the public hearing, Dr. Herman Gibb addressed concerns about the type of samples on which the Gibb cohort exposure estimates were based. Dr. Gibb stated, “[a] comparison of the area and personal samples [collected during 1978-1985] found essentially no difference for approximately two-thirds of the job titles with a sufficient number of samples to make this comparison.” An adjustment was made for the remaining job titles, in which the area samples were found to underestimate the breathing zone exposure, so that the potential for underestimation of exposures based on general area samples “ * * * was accounted for and corrected * * * ” in the Gibb cohort exposure estimates (Ex. 44-4, pp. 5-6). Dr. Gibb also noted that the publications claimed by commenters to have reported consistently higher levels of exposure than those specified by the authors of the Gibb et al. and Luippold et al. studies, in fact did not report exposures in sufficient detail to provide a meaningful comparison. In particular, Dr. Gibb said that the Public Health Service (PHS) publication did not report plant-specific exposure levels, and that Braver et al. did not report the locations or sampling strategies used (Ex. 44-4, pp. 5-6).

OSHA agrees with Dr. Gibb that the use of RAC general area samples in the Baltimore plant are unlikely to have caused substantial error in risk estimates based on the Gibb cohort. A similar comparison and adjustment between area and personal samples could not be performed for the Luippold et al. cohort, for which only area samples were available. The fact that most general area samples were similar to personal breathing zone samples in the Gibb cohort does not support the contention that reduction on the RAC sample strip or small particle capture issues would have caused substantial error in OSHA's risk estimates. Speculation regarding unusually high exposures that may not have been accounted for in sampling at the Baltimore and Painesville plants raises an uncertainty common to many epidemiological studies and quantitative risk analysis, but does not provide evidence that occasional high exposures would have substantially affected the results of this risk assessment.

OSHA received comments from the Small Business Administration's Office of Advocacy and others suggesting that, in addition to water-soluble sodium dichromate, sodium chromate, potassium dichromate, and chromic acid, some members of the Gibb and Luippold cohorts may have been exposed to less soluble compounds such as calcium chromate (Tr. 1825, Exs. 38-7, p. 4; 38-8, p. 12; 40-12-5, p. 5). These less soluble compounds are believed to be more carcinogenic than Cr(VI) compounds that are water-soluble or water-insoluble (e.g. lead chromate). The Painesville plant used a high-lime process to roast chromite ore, which is known to form calcium chromate and lesser amounts of other less water-soluble Cr(VI) compounds (Ex. 35-61). The 1953 USPHS survey estimated that approximately 20 percent of the total Cr(VI) in the roasting residue at the Painesville plant consisted of the less water-soluble chromates (Ex. 2-14). The high lime roasting process is no longer used in the production of chromate compounds.

Proctor et al. estimated that a portion of the Luippold cohort prior to 1950 were probably exposed to the less water-soluble Cr(VI) compounds due to the use of a high-lime roasting process, but that it would amount to less than 20 percent of their total Cr(VI) exposure (Ex. 35-61). The Painesville plant subsequently reduced and eliminated exposure to Cr(VI) roasting residue through improvements in the production process. A small proportion of workers in the Special Products Division of the Baltimore plant may have been exposed to less water-soluble Cr(VI) compounds during the occasional production of these compounds over the years. However, the high-lime process believed to generate less soluble compounds at the Painesville plant was not used at the Baltimore plant, and the 1953 USPHS survey detected minimal levels of less soluble Cr(VI) at this facility (Braver et al. 1985, Ex. 7-17).

OSHA agrees that some workers in the Luippold 2003 cohort (Painesville plant) and perhaps in the Gibb cohort (Baltimore plant) may have been exposed to minor amounts of calcium chromate and other less-soluble Cr(VI) compounds. However, these exposures would have been limited for most workers due to the nature of the production process and controls that were instituted after the early production period at the Painesville plant. The primary operation at the plants in Painesville and Baltimore was the production of the water-soluble sodium dichromate from which other primarily water-soluble chromates such as sodium chromate, potassium dichromate, and chromic acid could be made (Exs. 7-14; 35-61). Therefore, the Gibb and Luippold cohorts were principally exposed to water-soluble Cr(VI). Risk of lung cancer in these cohorts is therefore likely to reflect exposure to sodium chromate and sodium dichromate, rather than calcium chromate.

The results of the recent German post-change cohort showed that excess lung cancer mortality occurred among chromate-exposed workers in plants exclusively using a no-lime production process (Ex. 48-4). Like the Gibb cohort, the German cohort was exposed to average full-shift Cr(VI) exposures well below the previous PEL of 52 μg/m3 but without the possible contribution from the more carcinogenic calcium chromate (Exs. 48-1-2; Ex. 7-91). OSHA believes the elevated lung cancer mortality in these post-change workers are further evidence that occupational exposure to the less carcinogenic water-soluble Cr(VI) present a lung cancer risk.

In their post-hearing brief, the Aerospace Industries Association of America (AIA) stated:

OSHA's quantitative risk estimates are based on exposure estimates derived from impinger and RAC samplers in the Painesville and Baltimore chromate production plants. It is likely that these devices substantially underestimated airborne levels of Cr(VI), especially considering that particles were typically <1 μm. If exposure in these studies were underestimated, the risk per unit exposure was overestimated, and the risk estimates provided in the proposed rule overstate lung cancer risks (Ex. 47-29-2, p. 4).

AIA supports its statements by citing a study by Spanne et al. (Ex. 48-2) that found very low collection efficiencies (e.g. <20 percent) of submicron particles (i.e. <1 μm) using midget impingers. OSHA does not dispute that liquid impinger devices, primarily used to measure Cr(VI) air levels at the Painesville plant, are less effective at collecting small submicron particles. However, OSHA does not believe AIA has adequately demonstrated that the majority of Cr(VI) particles generated during soluble chromate production are submicron in size. This issue is further discussed in preamble section VI.G.4.a. Briefly, the AIA evidence is principally based on a particle size distribution from two airborne dust samples collected at the Painesville plant by an outdated sampling device under conditions that essentially excludes particles >5 μm (Ex. 47-29-2, Figure 4). Start Printed Page 10200OSHA believes it is more likely that Cr(VI) production workers in the Gibb and Luippold cohorts were exposed to Cr(VI) mass as respirable dust (i.e. <10 μm) mostly over 1 μm in size. The Spanne et al. study found that the impinger efficiency for particles greater than 2 μm is above 80 percent. Cr(VI) exposure not only occurs during roasting of chromite ore, where the smallest particles are probably generated, but also during the leaching of water-soluble Cr(VI) and packaging sodium dichromate crystals where particle sizes are likely larger. Based on this information, OSHA does not have reason to believe that the impinger device would substantially underestimate Cr(VI) exposures during the chromate production process or lead to a serious overprediction of risk.

The RAC samplers employed at the Baltimore plant collected airborne particles on filter media, not liquid media. AIA provided no data on the submicron particle size efficiency of these devices. For reasons explained earlier in this section, OSHA finds it unlikely that use of the RAC samplers led to substantial error in worker exposure estimates for the Gibb cohort.

In summary, uncertainties associated with the exposure estimates are a primary source of uncertainty in any assessment of risk. However, the cumulative Cr(VI) exposure estimates derived from the Luippold (2003) and Gibb cohorts are much more extensive than usually available for a cancer cohort and are more than adequate as a basis for quantitative risk assessment. OSHA does not believe the potential inaccuracies in the exposure assessment for the Gibb and Luippold (2003) cohorts are large enough to result in serious overprediction or underprediction of risk.

2. Model Uncertainty, Exposure Threshold, and Dose Rate Effects

The models used to fit the observed data may also introduce uncertainty into the quantitative predictions of risk. In the Preamble to the Proposed Rule, OSHA solicited comments on whether the linear relative risk model is the most appropriate approach on which to estimate risk associated with occupational exposure to Cr(VI) (FR 69 at 59307). OSHA expressed particular interest in whether there is convincing scientific evidence of a non-linear exposure-response relationship and, if so, whether there are sufficient data to develop a non-linear model that would provide more reliable risk estimates than the linear approach that was used in the preliminary risk assessment.

OSHA received a variety of comments regarding the uncertainties associated with using the risk model based on the Gibb and Luippold cohorts to predict risk to individuals exposed over a working lifetime to low levels of Cr(VI). OSHA's model assumes that the risk associated with a cumulative exposure resulting from long-term, low-level exposure is similar to the risk associated with the same cumulative exposure from briefer exposures to higher concentrations, and that a linear relative risk model adequately describes the cumulative exposure-response relationship. These assumptions are common in cancer risk assessment, and are based on scientifically accepted models of genotoxic carcinogenesis. However, OSHA received comments from the Small Business Administation's Office of Advocacy and others that questioned the Agency's reliance on these assumptions in the case of Cr(VI) (see e.g. Exs. 38-7, p. 2; 38-231, p. 18; 39-74, p. 2; 40-12-1, p. 2; 38-106, p. 10, p. 23; 38-185, p. 4; 38-233, p. 87; 38-265-1, pp. 27-29; 43-2, pp. 2-3). Some comments suggested that a nonlinear or threshold exposure-response model is an appropriate approach to estimate lung cancer risk from Cr(VI) exposures. Evidence cited in support of this approach rely on: (1) The lack of a statistically significant increased lung cancer risk for workers exposed below a cumulative Cr(VI) exposure of 1.0 mg/m3=yr (e.g., roughly equivalent to 20 μg/m3 TWA for a 45 year working lifetime) and below “a highest reported eight hour average” Cr(VI) concentration of 52 μg/m3; (2) the lack of observed lung tumors at lower dose levels in rats chronically exposed to Cr(VI) by inhalation and repeated intratracheal installations; and (3) the existence of physiological defense mechanisms within the lung, such as extracellular reduction of Cr(VI) to Cr(III) and repair of DNA damage. These commenters argue that the evidence suggests a sublinear nonlinearity or threshold in exposure-response at exposures in the range of interest to OSHA.

The Small Business Administration's Office of Advocacy and several other commenters stated that OSHA's risk model may overestimate the risk to individuals exposed for a working lifetime at “low” concentrations (Exs. 38-7, p. 2; 38-231, p. 18; 39-74, p. 2; 40-12-1, p. 2) or at concentrations as high as 20-23 μg/m3 (Exs. 38-7, p. 6; 38-106, p. 10, p. 23; 38-185, p. 4; 38-233, p. 87; 38-265-1, pp. 27-29; 43-2, pp. 2-3), due to possible nonlinear features in the exposure-response relationship for Cr(VI). These comments cited various published analyses of the Luippold and Gibb cohorts, including the Luippold et al. 2003 publication (Exs. 38-106, p. 10, p. 22; 38-233-4, p. 17), the Proctor et al. 2004 publication (Ex. 38-233-4, p. 17), the Crump et al. 2003 publication (Exs. 38-106, p. 22; 38-265-1, p. 27), and an analysis conducted by Exponent on behalf of chromium industry representatives (Ex. 31-18-15-1). The following discussion considers each of these analyses, as well as the overall weight of evidence with respect to cancer risk from low exposure to Cr(VI).

a. Linearity of the Relationship Between Lung Cancer Risk and Cumulative Exposure

In the Luippold et al. 2003 publication (Ex. 33-10) and the Proctor et al. 2004 publication (Ex. 38-216-10), the authors reported observed and expected lung cancer deaths for five categories of cumulative exposure. Lung cancer mortality was significantly elevated in categories above 1.05 mg/m3-yr Cr(VI) (p < 0.05), and was non-significantly elevated in the category spanning 0.20-0.48 mg/m3-yr (8 observed lung cancer deaths vs. 4.4 expected), with a slight deficit in lung cancer mortality for the first and third categories (3 observed vs. 4.5 expected below 0.2 mg/m3-yr, 4 observed vs. 4.4 expected at 0.48-1.04 mg/m3-yr) (Ex. 33-10, p. 455). This analysis is cited by commenters who suggest that the lack of a significantly elevated lung cancer risk in the range below 1.05 mg/m3-yr may reflect the existence of a threshold or other nonlinearity in the exposure-response for Cr(VI), and that OSHA's use of a linear relative risk model in the preliminary risk assessment may not be appropriate (Exs. 38-106, pp. 10-11; 38-233-4, p. 18). OSHA received similar comments citing the Crump et al. (2003) publication, in which the authors found a “consistently significant” trend of increasing risk with increasing cumulative exposure for categories of exposure above 1 mg/m3-yr (Ex. 35-58, p. 1157). The Exponent analysis of the Gibb et al. cohort was also cited, which found that lung cancer SMRs were not significantly elevated for workers with cumulative exposures below 0.42 mg/m3-yrs Cr(VI) when Baltimore reference rates and a six-category exposure grouping were used (Ex. 31-18-15-1, Table 6).

Some commenters have interpreted these analyses to indicate uncertainty about the exposure-response relationship at low exposure levels. Others have asserted that “[c]redible health experts assessing the same data Start Printed Page 10201as OSHA have concluded that 23 μg/m3 is a protective workplace standard (Ex. 38-185, p. 4) or that “[t]he Crump study concluded that 23 μg/m3 would be a standard that is protective of workers health” (Ex. 47-35-1, p. 5). Contrary to these assertions, it should be noted that the Gibb et al., Luippold et al., and Crump et al. publications do not include any statements concluding that 23 μg/m3 or any other exposure level is protective against occupational lung cancer. OSHA has reviewed these analyses to determine whether they provide sufficient evidence to support the use of a nonlinear or threshold-based exposure-response model for the Cr(VI) risk assessment, and whether they support the assertion that a PEL higher than that proposed would protect workers against a significant risk of lung cancer.

In discussing their results, Luippold et al. reported that evaluation of a linear dose-response model using a chi-squared test showed no significant departure from linearity and concluded that the data are consistent with a linear dose-response model. They noted that the results were also consistent with threshold or nonlinear effects at low cumulative exposures, as they observed substantial increases in cumulative exposure levels above approximately 1 mg/m3-yrs (Ex. 33-10, p. 456). Ms. Deborah Proctor, lead author of the Proctor et al. (2004) publication, confirmed these conclusions at the public hearing, stating her belief that nonlinearities may exist but that the data were also consistent with a linear dose response (Tr. 1845). The authors of the Crump et al. 2003 publication (Ex. 35-58), in which trend analyses were used to examine the exposure-response relationship for cumulative exposure, stated that the data were “ * * * neutral with respect to these competing hypotheses” (Ex. 35-58, pp. 1159-1160). Crump et al. concluded that their study of the Luippold cohort “ * * * had limited power to detect increases [in lung cancer risk] at these low exposure levels” (Ex. 35-58, p. 1147). OSHA agrees with Crump et al.'s conclusion that their study could not detect the relatively small increases in risk that would be expected at low exposures. With approximately 3000 person-years of observation time and 4.5 expected lung cancers in each of the three cumulative exposure categories lower than 0.19 mg/m3-yrs Cr(VI) (Ex. 33-10, p. 455), analyses of the Luippold cohort cannot effectively discriminate between alternative risk models for cumulative exposures that a worker would accrue from a 45-year working lifetime of occupational exposure at relatively low exposures (e.g., 0.045-0.225 mg/m3-yrs Cr(VI), corresponding to a working lifetime of exposure at 1-5 μg Cr(VI)/m3).

The Exponent reanalysis of the Gibb cohort found that lung cancer rates associated with exposures around 0.045 mg/m3-yrs Cr(VI) and below were not significantly elevated in some analyses (Ex. 31-18-15-1, Table 6 p. 26). However, OSHA believes that this result is likely due to the limited power of the study to detect small increases in risk, rather than a threshold or nonlinearity in exposure-response. In written testimony, Dr. Gibb explained that “[l]ack of a statistically elevated lung cancer risk at lower exposures does not imply that a threshold of response exists. As exposure decreases, so does the statistical power of a given sample size to detect a significantly elevated risk” (Ex. 44-4, p. 6). Exponent's analyses found (non-significant) elevated risks for all exposure groups above approximately 0.1 mg/m3-yrs, equivalent to 45 years of occupational exposure at about 2.25 μg/m3 Cr(VI) (Ex. 31-18-15-1, p. 20, Table 3). Furthermore, Gibb et al.'s SMR analysis based on exposure quartiles found statistically significantly elevated lung cancer risks among workers with cumulative exposures well below the equivalent of 45 years at the proposed PEL of 1 μg/m3. As Dr. Gibb commented at the hearing, the proposed PEL “ * * * is within the range of observation [of the studies] * * * In a sense, you don't even need risk models” to show that workers exposed to cumulative exposures equivalent to a working lifetime of exposure at or above the proposed PEL have excess risk of lung cancer as a result of their occupational exposure to Cr(VI)” (Tr. 121-122).

Furthermore, Robert Park of NIOSH reminded OSHA that “[a]nalysts of both the Painesville and the Baltimore cohorts * * * did test for deviation or departure from linearity in the exposure response and found no significant effect. If there was a large threshold, you would expect to see some deviance there” (Tr. 350-351). Post-hearing comments from NIOSH indicated that further analysis of the Gibb data provided no significant improvement in fit for nonlinear and threshold models compared to the linear relative risk model (Ex. 47-19, p. 7). Based on this evidence and on the previously discussed findings that (1) linear relative risk models fit both the Gibb and Luippold data sets adequately, and (2) the wide variety of nonlinear models tested by various analysts failed to fit the available data better than the linear model, OSHA believes that a linear risk model is appropriate and that there is not convincing evidence to support the use of a threshold or nonlinear exposure-response model, or to conclude that OSHA's risk assessment has seriously overestimated risk at low exposures.

b. The Cumulative Exposure Metric and Dose-Rate Effects on Risk

The Small Business Administration’s Office of Advocacy and several other commenters questioned OSHA's reliance in the preliminary risk assessment on models using cumulative exposure to estimate excess risk of lung cancer, suggesting that cumulative exposures attained from exposure to high concentrations of Cr(VI) for relatively short periods of time, as for some individuals in the Gibb and Luippold cohorts, may cause greater excess risk than equivalent cumulative exposures attained from long-term exposure to low concentrations of Cr(VI) (Exs. 38-7, pp. 3-4, 38-215-2, pp. 17-18; 38-231, p. 18; 38-233, p. 82; 38-265-1, p. 27; 39-74, p. 2, 40-12-1, p. 2, 43-2, p. 2, 47-27, p. 14; 47-27-3, p. 1). This assertion implies that OSHA’s risk assessment overestimates risk from exposures at or near the proposed PEL due to a threshold or dose-rate effect in exposure intensity. One commenter stated that “[a]pplication of a linear model estimating lung cancer risk from high-level expsoures . . . to very low-level exposure using the exposure metric of cumulative dose will inevitably overestimate risk estimates in the proposed PEL” (Ex. 47-27-3, p. 1). Comments on this subject have cited analyses by Proctor et al. (2004) (Ex. 38-233-4, p. 17), Crump et al. (2003) (Exs. 38-106, p. 22; 38-265-1, p. 27), Exponent (Ex. 31-18-15-1, pp. 31-34) and NIOSH (Ex. 47-19-1, p. 7); a new study by Luippold et al. on workers exposed to relatively low concentrations of Cr(VI) (Ex. 47-24-2); and mechanistic and animal studies examining the potential for dose-rate effects in Cr(VI)-related health effects (Exs. 31-18-7; 31-18-8; 11-7).

Of the two featured cohorts in OSHA’s preliminary risk assessment, the Gibb cohort is better suited to assess risk from exposure concentrations below the previous PEL of 52 μg Cr(VI)/m3. Contrary to some characterizations of the cohort’s exposures as too high to provide useful information about risk under modern workplace conditions (See e.g. Exs. 38-106, p. 21; 38-233, p. 82; 38-265-1, p. 28), most members of the Gibb cohort had relatively low exposures, with 42%% of the cohort Start Printed Page 10202members having a median annual average exposure value below 10 μg/m3 Cr(VI), 69%% below 20 μg/m3, and 91%% below the previous PEL (Ex. 35-295). In addition, Dr. Gibb indicated that exposures in general were lower than suggested by some commenters (Tr. 1856, Ex. 38-215-2, p. 17). For example, about half of the total time that workers were exposed was estimated to be below 14 μg/m3 Cr(VI) from 1960-1985 (Ex. 47-8, p. 1).

Exponent calculated SMRs for six groups of workers in the Gibb cohort, classified according to the level of their highest average annual exposure estimates. They found that only the group of workers whose highest exposure estimates were above approximately 95 μg/m3 Cr(VI) had statistically significantly elevated lung cancer risk when Baltimore reference rates were used (Ex. 31-18-15-1, p. 33). Exponent’s results are presented in Table VI-8 below, adapted from Table 10 in their report (Ex. 31-18-15-1, p. 33).

OSHA does not believe that Exponent's analysis of the Gibb data provides convincing evidence of a threshold in exposure-response. While the lower-exposure groups do not have statistically significantly elevated lung cancer risk (p > 0.05) when compared with a Baltimore reference population, the SMRs for all groups above 3.7 μg/m3 are consistently elevated. Moreover, the increased risk approaches statistical significance, especially for those subgroups with higher power (Groups 2 and 3). This can be seen by the lower 95% confidence bound on the SMR for these groups, which is only slightly below 1. The analysis suggests a lack of power to detect excess risk in Groups 2-5, rather than a lack of excess risk at these exposure levels.

Analyses of the Luippold cohort by Crump et al. (Ex. 35-58) and Proctor et al. (Ex. 38-216-10) used exposure estimates they called “highest average monthly exposure” to explore the effects of exposure intensity on lung cancer risk. They reported that lung cancer risk was elevated only for individuals with exposure estimates higher than the previous PEL of 52 μg/m3 Cr(VI). Crump et al. additionally found “statistically significant evidence of a dose-related increase in the relative risk of lung cancer mortality” only for groups above four times the previous PEL, using a series of Poisson regressions modeling the increase in risk across the first two subgroups and with the successive addition of higher-exposed subgroups (Ex. 35-58, p. 1154).

As with the Gibb data, OSHA does not believe that the subgroup of workers exposed at low levels is large enough to provide convincing evidence of a threshold in exposure-response. In the Crump et al. and Proctor et al. analyses, the groups for which no statistically significant elevation or dose-related trends in lung cancer risk were observed are quite small by the standards of cancer epidemiology (e.g., the Luippold cohort had only about 100 workers below the previous PEL and about 40 workers within 1-3 times the previous PEL). Crump et al. emphasized that “ * * * this study had limited power to detect increases [in lung cancer risk] at these low exposure levels” (Ex. 35-58, p. 1147). The authors did not conclude that their results indicate a threshold. They stated that their cancer potency estimates based on a linear relative risk model using the cumulative exposure metric “ * * * are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI)” (Ex. 35-58, p. 1147).

OSHA discussed the Exponent, Crump et al. and Luippold et al. SMR analyses of the Gibb and Luippold cohorts in the preamble to the proposed rule, stating that the lack of a statistically significant result for a subset of the entire cohort should not be construed to imply a threshold (69 FR at 59382). During the hearing, Robert Park of NIOSH expressed agreement with OSHA's preliminary interpretation, adding that:

[W]e think that any interpretation of threshold in these studies is basically a statistical artifact * * * It is important I think to understand that any true linear or even just monotonic exposure response that doesn't have a threshold will exhibit a threshold by the methods that they used. If you stratify the exposure metric fine enough and look at the lower levels, they will be statistically insignificant in any finite study * * * telling you nothing about whether or not in fact there is a threshold (Tr. 351).

To further explore the effects of highly exposed individuals on OSHA's risk model, The Chrome Coalition suggested that OSHA should base its exposure-response model on a subcohort of workers excluding those who were exposed to “ * * * an extraordinary exposure level for some extended period of time* * * ”, e.g., estimated exposures greater than the previous PEL for more than one year (Ex. 38-231, p. 21). The Chrome Coalition stated,

We are not aware of any study that has performed this type of analysis but we believe that it should be a way of better estimating the risk for exposures in the range that OSHA is considering for the PEL (Ex. 38-231, p. 21).

To gauge the potential utility of such an analysis, OSHA examined the subset of the Gibb cohort that was exposed for more than 365 days and had average annual exposure estimates above the previous PEL of 52 μg/m3 Cr(VI). The Agency found that the subcohort includes only 82 such individuals, of whom 37 were reported as deceased at the end of follow-up and five had died of lung cancer. In a cohort of 2357 Start Printed Page 10203workers with 122 lung cancers out of 855 deaths, it is unlikely that exclusion of a group this size would impact the results of a regression analysis significantly, especially as the proportion of mortality attributable to lung cancer is similar in the highly-exposed subgroup and the overall cohort (5/37 0.135, 122/855 ≅ 0.143). The great majority of the Gibb cohort members did not have the ‘extraordinary’ exposure levels implied by the Chrome Coalition. As discussed previously, most had relatively low exposures averaging less than 20 μg/m3.

As discussed in their post-hearing comments, NIOSH performed regression analyses designed to detect threshold or dose-rate effects in the exposure-response relationship for the Gibb dataset (Ex. 47-19-1, p. 7). NIOSH reported that “[t]he best fitting models had no threshold for exposure intensity and the study had sufficient power to rule out thresholds as large as 30 μg/m3 CrO3 (15.6 μg/m3 Cr(VI) * * * ” and that there was no statistically significant departure from dose-rate linearity when powers of annual average exposure values were used to predict lung cancer risk (Ex. 47-19-1, p. 7). This indicates that a threshold of approximately 20 μg/m3 Cr(VI) suggested in some industry comments is not consistent with the Gibb cohort data. Based on these and other analyses described in their post-hearing comments, NIOSH concluded that:

[E]xamination of non-linear features of the hexavalent chromium-lung cancer response supports the use of the traditional (lagged) “cumulative exposure paradigm * * * ”: that is, linear exposure-response with no threshold (Ex. 47-19-1, p. 7).

OSHA recognizes that, like most epidemiologic studies, neither the Luippold nor the Gibb cohort provides ideal information with which to identify a threshold or detect nonlinearities in the relationship between Cr(VI) exposure and lung cancer risk, and that it is important to consider other sources of information about the exposure-response relationship at very low levels of Cr(VI) exposure. The Agency agrees with Dr. Gibb's belief that “ * * * arguments for a ‘threshold’ should not be based on statistical arguments but rather on a biological understanding of the disease process” (Ex. 44-4, p. 7) and Crump et al.'s statement that “ * * * one needs to consider supporting data from mechanistic and animal studies” in order to determine the appropriateness of assuming that a threshold (or, presumably, other nonlinearity) in exposure-response exists (Ex. 35-58, p. 1159). Experimental and mechanistic evidence and related comments relevant to the issue of threshold and dose-rate effects are reviewed in the following discussion.

c. Animal and Mechanistic Evidence Regarding Nonlinearities in Cr(VI) Exposure-Response

In the NPRM, OSHA analyzed several animal and mechanistic studies and did not find convincing evidence of a threshold concentration in the range of interest (i.e. 0.25 to 52 μg/m3). However, the Agency recognized that evidence of dose rate effects in an animal instillation study and the existence of extracellular reduction, DNA repair, and other molecular pathways within the lung that protect against Cr(VI)-induced respiratory tract carcinogenesis could potentially introduce nonlinearities in Cr(VI) exposure-cancer response. OSHA solicited comment on the scientific evidence for a non-linear exposure-response relationship in the occupational exposure range of interest and whether there was sufficient data to develop a non-linear model that would provide more reliable risk estimates than the linear approach used in the preliminary risk assessment (69 FR at 59307).

Some commenters believed the scientific evidence from animal intratracheal instillation and inhalation of Cr(VI) compounds showed that a linear risk model based on lung cancers observed in the Gibb and Luippold cohorts seriously overpredicts lung cancer risk to workers exposed at the proposed PEL (Exs. 38-216-1; 38-233-4; 38-231). The research cited in support of this presumed non-linear response was the intratracheal instillation study of Steinhoff et al. and the inhalation study of Glaser et al. (Exs. 11-7; 10-11). For example, Elementis Chromium states that:

Considering either the Steinhoff or Glaser studies, a calculated risk based on the effect frequency at the highest daily exposure would be considerably greater than that calculated from the next lower daily exposure. We believe that the same effect occurs when humans are exposed to Cr(VI) and consideration of this should be taken when estimating risk at very low exposure levels based on effects at much higher exposure levels (Ex. 38-216-1, p. 4).

Despite the different mode of Cr(VI) administration and dosing schemes, the Steinhoff and Glaser studies both feature dose levels at which there was no observed incidence of lung tumors. The Steinhoff study found no significant lung tumor incidence in rats intratracheally administered highly soluble sodium dichromate at 87 μg Cr(VI)/kg or less regardless of whether the dose was received five times a week or once a week for 30 months. However, rats administered a higher dose of 437 μg Cr(VI)/kg of sodium dichromate or a similar amount of the slightly soluble calcium chromate once a week developed significant increases (about 17 percent incidence) in lung tumors. The study documented a ‘dose rate effect’ since the same total dose administered more frequently (i.e. five times weekly) at a five-fold lower dose level (i.e. 87 μg Cr(VI)/kg) did not increase lung tumor incidence in the highly soluble sodium dichromate-treated rats. The Glaser inhalation study reported no lung tumors in rats inhaling 50 μg Cr(VI)/m3 of sodium dichromate or lower Cr(VI) concentrations for 22 hours/day, 7 days a week. However, the next highest dose level of 100 μg Cr(VI)/m3 produced a 15 percent lung tumor incidence (i.e. 3 of 19 rats). Both studies are more fully described in Section V.B.7.a.

The apparent lack of lung tumors at lower Cr(VI) dose levels is interpreted by the commenters to be evidence of a non-linear exposure-response relationship and, possibly, an exposure threshold below which there is no risk of lung cancer.

In written testimony, Dr. Harvey Clewell of ENVIRON Health Science Institute addressed whether the Steinhoff, Glaser and other animal studies provided evidence of a threshold for Cr(VI) induced lung carcinogenicity (Ex. 44-5). He stated that the argument for the existence of a threshold rests on two faulty premises:

(1) Failure to detect an increased incidence of tumors from a given exposure indicates there is no carcinogenic activity at that exposure, and

(2) Nonlinearities in dose response imply a threshold below which there is no carcinogenic activity (Ex. 44-5, p. 13).

In terms of the first premise, Dr. Clewell states:

The ability to detect an effect depends on the power of the study design. A statistically-based No Observed Adverse Effect Level (NOAEL) in a toxicity study does not necessarily mean there is no risk of adverse effect. For example, it has been estimated that a typical animal study can actually be associated with the presence of an effect in as many as 10% to 30% of the animals. Thus the failure to observe a statistically significant increase in tumor incidence at a particular exposure does not rule out the presence of a substantial carcinogenic effect at that exposure (Ex. 44-5, p. 13-14).

Dr. Clewell also addressed the second premise as it applies to the Steinhoff instillation study as follows:

It has been suggested, for example, that the results of the Steinhoff study suggest that Start Printed Page 10204dose rate is an important factor in the carcinogenic potency of chrome (VI), and therefore, there must be a threshold. But these data, while they do provide an indication of a dose rate effect * * * they don't provide information about where and whether a threshold or even a non-linearity occurs, and to what extent it does occur at lower concentrations (Tr. 158-159).

OSHA agrees with Dr. Clewell that the absence of observed lung tumor incidence at a given exposure (i.e. a NOAEL) in an animal study should not be interpreted as evidence of a threshold effect. This is especially true for clearly genotoxic carcinogens, such as Cr(VI), where it is considered scientifically reasonable to expect some small, but finite, probability that a very few molecules may damage DNA in a single cell and eventally develop into a tumor. For this reason, it is not appropriate to regard the lack of tumors in the Steinhoff or Glaser studies as evidence for an exposure-response threshold.

Exponent, in a technical memorandum prepared for an ad hoc group of steel manufacturers, raises the possibility that the lung tumor responses in the Steinhoff and Glaser studies were the result of damage to lung tissue from excessive levels of Cr(VI). Exponent suggests that lower Cr(VI) exposures that do not cause ‘respiratory irritation’ are unlikely to lead an excess lung cancer risk (Ex. 38-233-4). Exponent went on to summarize:

In examining the weight of scientific evidence, for exposure concentrations below the level which causes irritation, lung cancer has not been reported. Not surprisingly, Cr(VI)-induced respiratory irritation is an important characteristic of Cr(VI)-induced carcinogenicity in both humans and animals * * * Based on the information reviewed herein, it appears that the no effect level for non-neoplastic respiratory irritation and lung cancer from occupational exposure to Cr(VI) is approximately 20 μg/m3. Thus establishing a PEL of 1 μg/m3 to protect against an excess lung cancer risk is unnecessarily conservative (Ex. 38-233-4, p. 24).

In support of the above hypothesis, Exponent points out that only the highest Cr(VI) dose level (i.e. 437 μg Cr(VI)/kg) of sodium dichromate employed in the Steinhoff study resulted in significant lung tumor incidence. Tracheal instillation of this dose once a week severely damaged the lungs leading to emphysematous lesions and pulmonary fibrosis in the Cr(VI)-exposed rats. Lower Cr(VI) dose levels (i.e. 87 μg Cr(VI)/kg or less) of the highly water-soluble sodium dichromate that caused minimal lung damage did not result in significant tumor incidence. However, the study also showed that a relatively low dose (i.e. 81 μg Cr(VI)/kg) of slightly soluble calcium chromate repeatedly instilled (i.e. five times a week) in the trachea of rats caused significant lung tumor incidence (about 7.5 percent) in the absence of lung tissue damage. This finding is noteworthy because it indicates that tissue damage is not an essential requirement for Cr(VI)-induced respiratory tract carcinogenesis. The same instilled dose of the slightly soluble calcium chromate would be expected to provide a more persistent and greater source of Cr(VI) in proximity to target cells within the lung than would the highly water-soluble sodium dichromate. This suggests that the internal dose of Cr(VI) at the tissue site, rather than degree of damage, may be the critical factor determining lung cancer risk from low-level Cr(VI) exposures.

Exponent applies similar logic to the results of the Glaser inhalation study of sodium dichromate in rats. Exponent states:

In all experimental groups (i.e. 25, 50, and 100 μg Cr(VI)/m3), inflammation effects were observed, but at 100 μg Cr(VI)/m3 [the high dose group with significant lung tumor incidence], effects were more severe, as expected (Ex. 38-233-4, p. 22).

This assessment contrasts with that of the study authors who remarked:

In this inhalation study, in which male Wistar rats were continuously exposed for 18 months to both water soluble sodium dichromate and slightly soluble chromium oxide mixture aerosols, no clinical signs of irritation were obvious * * * For the whole time of the study no significant effects were found from routine hematology and clinico-chemical examinations in all rats exposed to sodium dichromate aerosol (Ex. 10-11, p. 229).

The rats in the Glaser carcinogenicity study developed a focalized form of lung inflammation only evident from microscopic examination. This mild response should not be considered equivalent to the widespread bronchiolar fibrosis, collapsed/distorted alveolar spaces and severe damage found upon macroscopic examination of rat lungs instilled with the high dose (437 μg Cr(VI)/kg) of sodium dichromate in the Steinhoff study. The non-neoplastic lung pathology (e.g. accumulation of pigmentized macrophages) described following inhalation of sodium dichromate at all air concentrations of Cr(VI) in the Glaser study are more in line with the non-neoplastic responses seen in the lungs of rats intratracheally instilled with lower dose levels of sodium dichromate (i.e. 87 μg Cr(VI)/kg or less) that did not cause tumor incidence in the Steinhoff study. OSHA finds no evidence that severe pulmonary inflammation occurred following inhalation of 100 μg Cr(VI)/m3 in the Glaser carcinogenicity study or that the lung tumors observed in these rats were the result of ‘respiratory irritation’. Dr. Clewell also testified that lung damage or chronic inflammation is not a necessary and essential condition for C(VI) carcinogenesis in the Glaser study:

I didn't find any evidence that it [lung damage and chronic inflammation] was necessary and essential. In particular, I think the Glaser study was pretty good in demonstrating that there were effects where they saw no evidence of irritation, or any clinical signs of those kinds of processes (Tr. 192).

Subsequent shorter 30-day and 90-day inhalation exposures with sodium dichromate in rats were undertaken by the Glaser group to better understand the non-neoplastic changes of the lung (Ex. 31-18-11). The investigation found a transitory dose-related inflammatory response in the lungs at exposures of 50 μg Cr(VI)/m3 and above following the 30 day inhalation. This initial inflammatory response did not persist during the 90 day exposure study except at the very highest dose levels (i.e. 200 and 400 μg Cr(VI)/m3). Significant increases in biomarkers for lung tissue damage (such as albumin and lactate dehydrogenase (LDH) in bronchioalveolar lavage fluid (BALF) as well as bronchioalveolar hyperplasia) also persisted through 90 days at these higher Cr(VI) air levels, especially 400 μg Cr(VI)/m3. The study authors considered the transient 30-day responses to represent adaptive, rather than persistent pathological, responses to Cr(VI) challenge. A dose-related elevation in lung weights due to histiocytosis (i.e. accumulation of lung macrophages) was seen in all Cr(VI)-administered rats at both time periods. The macrophage accumulation is also likely to be an adaptive response that reflects lung clearance of inhaled Cr(VI). These study results are more fully described in section V.C.3.

OSHA believes that Cr(VI)-induced carcinogenesis may be influenced not only by the total Cr(VI) dose retained in the respiratory tract but also by the rate at which the dose is administered. Exponent is correct that one possible explanation for the dose rate effect observed in the Steinhoff study may be the widespread, severe damage to the lung caused by the immediate instillation of a high Cr(VI) dose to the respiratory tract repeated weekly for 30 months. It is biologically plausible that the prolonged cell proliferation in response to the tissue injury would enhance tumor development and Start Printed Page 10205progression compared to the same total Cr(VI) instilled more frequently at smaller dose levels that do not cause widespread damage to the respiratory tract. This is consistent with the opinion of Dr. Clewell who testified that:

I would not say that it [respiratory tract irritation, lung damage, or chronic inflammation] is necessary and sufficient, but rather it exacerbates an underlying process. If there is a carcinogenic process, then increased cell proliferation secondary to irritation is going to put mitogenic pressure on the cells, and this will cause more likelihood of a transformation (Tr. 192).

OSHA notes that increased lung tumor incidence was observed in animals instilled with lower dose levels of calcium chromate in the Steinhoff study and after inhalation of sodium dichromate in the Glaser study. These Cr(VI) exposures did not trigger extensive lung damage and OSHA believes it unlikely that the lung tumor response from these treatments was secondary to ‘respiratory irritation’ as suggested by Exponent. The more thorough investigation by the Glaser group did not find substantive evidence of persistent tissue damage until rats inhaled Cr(VI) at doses two- to four-fold higher than the Cr(VI) dose found to elevate lung tumor incidence in the their animal cancer bioassay.

Exponent goes on to estimate a NOAEL (no observable adverse effect level) for lung histopathology in the Steinhoff study. They chose the lowest dose level (i.e. 3.8 μg Cr(VI)/kg) in the study as their NOAEL based on the minimal accumulation of macrophages found in the lungs instilled with this dose of sodium dichromate five times weekly (Ex. 38-233-4, p. 21). Exponent calculates that this lung dose is roughly equivalent to the daily dose inhaled by a worker exposed to 27 μg Cr(VI)/m3 using standard reference values (e.g. 70 kg human inhaling 10 m3/day over a daily 8 hour work shift). Exponent considers this calculated Cr(VI) air level as a threshold below which no lung cancer risk is expected in exposed workers.

However, Steinhoff et al. instilled Cr(VI) compounds directly on the trachea rather than introducing the test compound by inhalation, and was only able to characterize a significant dose rate effect at one cumulative dose level. For these reasons, OSHA considers the data inadequate to reliably determine the human exposures where this potential dose transition might occur and to confidently predict the magnitude of the resulting non-linearity. NIOSH presents a similar view in their post-hearing comments:

NIOSH disagrees with Dr. Barnhardt's analysis [Ex. 38-216-1] and supports OSHA's view that the Steinhoff et al. [1986] rat study found a dose-rate effect in rats under the specified experimental conditions, that this effect may have implications for human exposure and that the data are insufficient to use in a human risk assessment for Cr(VI) * * * The study clearly demonstrates that, within the constraints of the experimental design, a dose rate effect was observed. This may be an important consideration for humans exposed to high levels of Cr(VI). However, quantitative extrapolation of that information to the human exposure scenario is difficult (Ex. 47-19-1, p. 8).

Exponent also relies on a case investigation of the benchmark dose methodology applied to the pulmonary biomarker data measured in the 90-day Glaser study (Ex. 40-10-2-8). In this instance, the benchmark doses represent the 95 percent lower confidence bound on the Cr(VI) air level corresponding a 10 percent increase relative to unexposed controls for a chosen biomarker (e.g. BALF total protein, albumin, or LDH). The inhaled animal doses were adjusted to reflect human inhalation and deposition in the respiratory tract as well as continuous environmental exposure (e.g. 24 hours/day, 7 days/week) rather than an occupational exposure pattern (e.g. 8 hours/day, 5 days/week). The benchmark doses were reported to range from 34 to 140 μg Cr(VI)/m3.

Exponent concludes that “these [benchmark] values are akin to a no-observed-adverse-effect level NOAEL in humans to which uncertainty factors are added to calculate an RfC [i.e. Reference Concentration below which adverse effects will not occur in most individuals]” and “taken as a whole, the studies of Glaser et al. suggest that both non-neoplastic tissue damage and carcinogenicity are not observed among rats exposed to Cr(VI) at exposure concentrations below 25 μg/m3” (Ex. 38-233-4, p. 22). Since the Exponent premise is that Cr(VI)-induced lung cancer only occurs as a secondary response to histopathological changes in the respiratory tract, the suggested 25 μg Cr(VI)/m3 is essentially being viewed as a threshold concentration below which lung cancer is presumed not to occur.

In his written testimony, Dr. Clewell indicated that the tumor data from the Glaser cancer bioassay was more appropriately analyzed using linear, no threshold exposure-response model rather than the benchmark uncertainty factor approach that presumes the existence of threshold exposure-response.

The bioassay of Glaser et al. provides an example of a related difficulty of interpreting data from carcinogenicity studies. The tumor outcome appears to be nonlinear (0/18, 0/18, and 3/19 at 0.025, 0.05, and 0.1 mg Cr/m3). However, although the outcomes are restricted to be whole numbers (of animals), they should not be evaluated as such. Because the nature of cancer as a stochastic process, each observed outcome represents a random draw from a Poisson distribution. Statistical dose-response modeling, such as the multistage model used by OSHA, is necessary to properly interpret the cancer dose-response. In the case of Glaser et al. (1986) study, such modeling would produce a maximum likelihood estimate of the risk at the middle dose that was greater than zero. In fact, the estimated risk at the middle dose would be on the order of several percent, not zero. Therefore, suggesting a lack of lung cancer risk at a similar human exposure would not be a health protective position (Ex. 44-5, p. 14).

The U.S. Environmental Protection Agency applied a linearized (no threshold) multistage model to the Glaser data (Ex. 17-101). They reported a maximum likelihood estimate for lifetime lung cancer risk of 6.3 per 1000 from continuous exposure to 1 μg Cr(VI)/m3. This risk would be somewhat less for an occupational exposure (e.g. 8 hours/day, 5 days/week) to the same air level and would be close to the excess lifetime risk predicted by OSHA (i.e. 2-9 per 1000).

In summary, OSHA does not believe the animal evidence demonstrates that respiratory irritation is required for Cr(VI)-induced carcinogenesis. Significant elevation in lung tumor incidence was reported in rats that received Cr(VI) by instillation or inhalation at dose levels that caused minimal lung damage. Consequently, OSHA believes it inappropriate to consider a NOAEL (such as 25 μg/m3) where lung tumors were not observed in a limited number of animals to be a threshold concentration below which there is no risk. Statistical analysis of the animal inhalation data using a standard dose-response model commonly employed for genotoxic carcinogens, such as Cr(VI), is reported to predict risks similar to those estimated by OSHA from the occupational cohorts of chromate production workers. While the rat intratracheal instillation study indicates that a dose rate effect may exist for Cr(VI)-induced carcinogenesis, it can not be reliably determined from the data whether the effect would occur at the occupational exposures of interest (e.g. working lifetime exposures at 0.25 to 52 μg Cr(VI)/m3) without a better quantitative understanding of Cr(VI) dosimetry within the lung. Therefore, OSHA does not believe that the animal data show that cumulative Cr(VI) Start Printed Page 10206exposure is an inappropriate metric to estimate lung cancer risk.

Exponent used the clinical findings from chromate production workers in the Gibb and Luippold cohorts to support their contention that ‘respiratory irritation’ was key to Cr(VI)-induced lung cancer (Ex. 28-233-4, p. 18-19). They noted that over 90 percent of chromate production workers employed at the Painesville plant during the 1930s and 1940s, including some Luippold cohort members, were reported to have damaged nasal septums. Based on this, Exponent concludes:

Thus, it is possible that the increased incidence of lung cancer in these workers (i.e. SMR of 365 from Luippold et al. cohort exposed during the 1940s) is at least partially due to respiratory system tissue damage resulting from high Cr(VI) concentrations to which these workers were exposed. These exposures clearly exceed a threshold for both carcinogenic and non-carcinogenic (i.e. respiratory irritation) health effects (Ex. 38-233-4, p. 18).

Exponent noted that about 60 percent of the Gibb cohort also suffered ulcerated nasal septum tissue. The mean estimated annual Cr(VI) air level at time of diagnosis was about 25 μg Cr(VI)/m3. Ulcerated nasal septum was found to be highly correlated with the average annual Cr(VI) exposure of the workers as determined by a proportional hazards model. These findings, again, led Exponent to suggest that:

It may be reasonable to surmise that the high rates of lung cancer risk observed among the featured cohorts (i.e. Gibb and Luippold) was at least partially related to respiratory irritation (Ex. 38-233-4, p. 19).

In its explanations, Exponent assumes that the irritation and damage to nasal septum tissue found in the exposed workers also occurs elsewhere in the respiratory tract. Exponent provided no evidence that Cr(VI) concentrations that damage tissue at the very front of the nose will also damage tissue in the bronchoalveolar regions where lung cancers are found. A national medical survey of U.S. chromate production workers conducted by the U.S. Public Health Service in the early 1950s found greater than half suffered nasal septum perforations (Ex. 7-3). However, there was little evidence of non-cancerous lung disease in the workers. The survey found only two percent of the chromate workers had chronic bronchitis which was only slightly higher than the prevalence in nonchromate workers at the same plants and less than had been reported for ferrous foundry workers. Just over one percent of the chromate production workers in the survey were found to have chest X-ray evidence consistent with pulmonary fibrosis. This led the U.S. Public Health Service to conclude “on the basis of X-ray data we cannot confirm the presence of pneumoconiosis from chromate exposure” (Ex. 7-3, p. 80). An earlier report noted fibrotic areas in the autopsied lungs of three Painesville chromate production workers employed during the 1940s who died of lung cancer (Ex. 7-12). The authors attributed the fibrotic lesions to the large amounts of chromite (a Cr(III) compound) ore found in the lungs.

Exponent correctly noted that prevalence of nasal septum ulceration in the Gibb cohort was “significantly associated with [average annual] Cr(VI) exposure concentrations” using a proportional hazards model (Ex. 38-233-4, p. 19). However, other related symptomatology, such as nasal irritation and perforation, was not found to be correlated with annual average Cr(VI) air levels. This led the authors to suggest that nasal septum tissue damage was more likely related to short-term, rather than annual, Cr(VI) air levels. Nasal septum ulceration was also not a significant predictor of lung cancer when the confounding effects of smoking and cumulative Cr(VI) exposure were accounted for in the proportional hazards model (Ex. 31-22-11). The authors believed the lack of correlation probably reflected cumulative Cr(VI) as the dominant exposure metric related to the elevated lung cancer risk in the workers, rather than the high, short-term Cr(VI) air levels thought to be responsible for the high rate of nasal septum damage. The modeling results are not consistent with nasal septum damage as a predictor of Cr(VI)-induced lung cancer in chromate production workers. Dr. Herman Gibb confirmed this in oral testimony:

* * * I was curious to see if [respiratory] irritation might be predictive of lung cancer. We did univariate analyses and found that a number of them were [predictive]. But whenever you looked at, when you put it into the regression model, none of them were. In other words, [respiratory] irritation was not predictive of the lung cancer response (Tr. 144).

OSHA does not believe the evidence indicates that tissue damage in the nasal septum of chromate production workers exposed to Cr(VI) air levels around 20 μg/m3 is responsible for the observed excess lung cancers. The lung cancers are found in the bronchioalveolar region, far removed from the nasal septum. Careful statistical analysis of the Gibb cohort did not find a significant relationship between clinical symptoms of nasal septum damage (e.g. ulceration, persistent bleeding, perforation) and lung cancer mortality. A 1951 U.S. Public Health Service medical survey found a high prevalence of nasal septum damage with few cases of chronic non-neoplastic lung disease (e.g. chronic bronchitis, pulmonary fibrosis). This suggests that the nasal septum damage caused by high Cr(VI) air concentrations was not mirrored by damage in lower regions of the respiratory tract where lung cancer takes place. Given these findings, it seems unlikely that the lower Cr(VI) air levels experienced by the Gibb cohort caused pervasive bronchioalveolar tissue damage that would be responsible for the clearly elevated lung cancer incidence in these workers. Therefore, the Agency does not concur with Exponent that there is credible evidence from occupational cohort studies that the high rates of lung cancer are related to tissue damage in the respiratory tract or that occupational exposure to 20 μg Cr(VI)/m3 represents a ‘no effect’ level for lung cancer.

Some commenters felt that certain physiological defense mechanisms that protect against the Cr(VI)-induced carcinogenic process introduce a threshold or sublinear dose-response (Exs. 38-233-4; 38-215-2; 38-265). Some physiological defenses are thought to reduce the amount of biologically active chromium (e.g. intracellular Cr(V), Cr(III), and reactive oxygen species) able to interact with critical molecular targets within the lung cell. A prime example is the extracellular reduction of permeable Cr(VI) to the relatively impermeable Cr(III) which reduces Cr(VI) uptake into cells. Other defense mechanisms, such as DNA repair and apoptosis, can interfere with carcinogenic transformation and progression. These defense mechanisms are presented by commenters as highly effective at low levels of Cr(VI) but are overwhelmed at high dose exposures and, thus, could “provide a biological basis for a sublinear dose-response or a threshold below which there is expected to be no increased lung cancer risk (Ex. 38-215-2, p. 29).

One study, cited in support of an exposure-response threshold, determined the amount of highly soluble Cr(VI) reduced to Cr(III) in vitro by human bronchioalveolar fluid and pulmonary macrophage fractions over a short period (Ex. 31-18-7). These specific activities were used to estimate an “overall reducing capacity” of the lung. As previously discussed, cell membranes are permeable to Cr(VI) but not Cr(III), so only Cr(VI) enters cells to any appreciable extent. The authors interpreted these data to mean that high Start Printed Page 10207levels of Cr(VI) would be required to “overwhelm” the reduction capacity before significant amounts of Cr(VI) could enter lung cells and damage DNA, thus creating a biological threshold to the exposure—response (Ex. 31-18-8).

There are several problems with this threshold interpretation. The in vitro reducing capacities were determined in the absence of cell uptake. Cr(VI) uptake into lung cells happens concurrently and in parallel with its extracellular reduction, so it cannot be concluded from the study data that a threshold reduction capacity must be exceeded before uptake occurs. The rate of Cr(VI) reduction to Cr(III) is critically dependant on the presence of adequate amounts of reductant, such as ascorbate or GSH (Ex. 35-65). It has not been established that sufficient amounts of these reductants are present throughout the thoracic and alveolar regions of the respiratory tract to create a biological threshold. Moreover, the in vitro activity of Cr(VI) reduction in epithelial lining fluid and alveolar macrophages was shown to be highly variable among individuals (Ex. 31-18-7, p. 533). It is possible that Cr(VI) is not rapidly reduced to Cr(III) in some workers or some areas of the lung. Finally, even if there was an exposure threshold created by extracellular reduction, the study data do not establish the dose range in which the putative threshold would occur.

Other commenters thought extracellular reduction and other physiological defenses were unlikely to produce a biological threshold (Exs. 44-5; 40-18-1). For example, Dr. Clewell remarked:

Although studies attempted to estimate capacities of Cr(VI) (De Flora et al., 1997) the extracellular reduction and cellular uptake of Cr(VI) are parallel and competing kinetic processes. That is, even at low concentrations where reductive capacity is undiminished, a fraction of Cr(VI) will still be taken up into cells, as determined by the relative rates of reduction and transport. For this reason, reductive capacities should not be construed to imply “thresholds” below which Cr(VI) will be completely reduced prior to uptake. Rather, they indicate that there is possibly a “dose-dependent transition”, i.e. a nonlinearity in concentration dependence of the cellular exposure to Cr(VI). Evaluation of the concentration-dependence of the cellular uptake of Cr(VI) would require more data than is currently available on the relative kinetics of dissolution, extracellular reduction, and cellular uptake as well as on the homeostatic response to depletion of reductive resources (e.g. reduction of glutathione reductase) (Ex. 44-5, p. 16)

The same logic applies to other ‘defense mechanisms’ such as DNA repair and apoptosis. Despite the ability of cells to repair DNA damage or to undergo apoptosis (i.e. a form of programmed cell death) upon exposure to low levels of Cr(VI), these protections are not absolute. Since a single error in a critical gene may trigger neoplastic transformation and DNA damage increases with intracellular concentration of Cr(VI), it stands to reason that there may be some risk of cancer even at low Cr(VI) levels. If the protective pathways are saturable (e.g. protective capacity overwhelmed) then it might be manifested as a dose transition or nonlinearity. However, as explained above, an extensive amount of kinetic modeling data would be needed to credibly predict the dose level at which a potential dose transition occurs. OSHA agrees with Dr. Clewell that “in the absence of such a biologically based [kinetic] dose-response model it is impossible to determine either the air concentration of Cr(VI) at which the nonlinearity might occur or the extent of the departure from a linear dose-response that would result. Therefore, the assumption of a linear dose-response is justified” (Ex. 44-5, p.17-18).

In conclusion, OSHA believes that examination of the Gibb and Luippold cohorts, the new U.S. cohorts analyzed in Luippold et al. (2005), and the best available animal and mechanistic evidence does not support a departure from the traditional linear, cumulative exposure-based approach to cancer risk assessment for hexavalent chromium. OSHA's conclusion is supported by several commenters (see e.g. Tr. 121, 186, Exs. 40-10-2, p. 6; 44-7). For example, NIOSH stated:

It is not appropriate to employ a threshold dose-response approach to estimate cancer risk from a genotoxic carcinogen such as Cr(VI) [Park et al. 2004]. The scientific evidence for a carcinogenicity threshold for Cr(VI) described in the Preamble [to the proposed rule] consists of the absence of an observed effect in epidemiology studies and animal studies at low exposures, and in vitro evidence of intracellular reduction. The epidemiologic and animal studies lack the statistical power to detect a low-dose threshold. In both the NIOSH and OSHA risk assessments, linear no-threshold risk models provided good fit to the observed cancer data. The in vitro extracellular reduction studies which suggested a theoretical basis for a non-linear reseponse to Cr(VI) exposure were conducted under non-physiologic conditions. These results do not demonstrate a threshold of response to Cr(VI) exposure (Ex. 40-10-2, p. 6).

OSHA's position is also supported by Dr. Herman Gibb's testimony at the hearing that a linear, no-threshold model best characterizes the relationship between Cr(VI) exposure and lung cancer risk in the Gibb cohort (Tr. 121). Statements from Ms. Deborah Proctor and Crump et al. (who conducted analyses utilizing the Luippold cohort) also indicated that these data are consistent with the traditional linear model (Tr. 1845, Exs. 33-10, p. 456; 35-58, pp. 1159-1160). The significant excess risk observed in the Gibb cohort, which was best suited to address risk from low cumulative or average exposures, contradicts comments to the effect that “[i]ncreased lung cancers have been demonstrated only at workplace exposures significantly higher than the existing standard * * * ” (Ex. 38-185, p. 4) or that characterized OSHA's risk assessment for the proposed PEL as “speculative” (Ex. 47-35-1, p. 4) or “seriously flawed” (Ex. 38-106, p. 23). OSHA believes that the clear excess risk among workers with cumulative exposures equivalent to those accrued over a 45-year working lifetime of low-level exposure to Cr(VI), combined with the good fit of linear exposure-response models to the Gibb and Luippold (2003) datasets and the lack of demonstrable nonlinearities or dose-rate effects, constitute strong evidence of risk at low exposures in the range of interest to OSHA.

3. Influence of Smoking, Race, and the Healthy Worker Survivor Effect

A common confounder in estimating lung cancer risk to workers from exposure to a specific agent such as Cr(VI) is the impact of cigarette smoking. First, cigarette smoking is known to cause lung cancer. Ideally, lung cancer risk attributable to smoking among the Cr(VI)-exposed cohorts should be controlled or adjusted for in characterizing exposure-response. Secondly, cigarette smoking may interact with the agent (i.e., Cr(VI)) or its biological target (i.e., susceptible lung cells) in a manner that enhances or even reduces the risk of developing Cr(VI)-induced lung cancer from occupational exposures, yet is not accounted for in the risk model. The Small Business Administration's Office of Advocacy commented that such an interactive effect may have improperly increased OSHA's risk estimates (Ex. 38-7, p. 4).

OSHA believes its risk estimates have adequately accounted for the potential confounding effects of cigarette smoking in the underlying exposure-lung cancer response data, particularly for the Gibb cohort. One of the key issues in this regard is whether or not the reference population utilized to derive the expected number of lung cancers appropriately reflects the smoking behavior of the cohort members. The Start Printed Page 10208risk analyses of the Gibb cohort by NIOSH and Environ indicate that cigarette smoking was properly controlled for in the exposure-response modeling. NIOSH applied a smoking-specific correction factor that included a cumulative smoking term for individual cohort members (Ex. 33-13). Environ applied a generic correction factor and used lung cancer mortality rates from Baltimore City as a reference population that was most similar to the cohort members with respect to smoking behavior and other factors that might affect lung cancer rates (Ex. 33-12). Environ also used internally standardized models that did not require use of a reference population and included a smoking-specific (yes/no) variable. All these models predicted very similar estimates of risk over a wide range of Cr(VI) exposures. There was less information about smoking status for the Luippold cohort. However, regression modeling that controlled for smoking indicated that it was not a significant confounding factor when relating Cr(VI) exposure to the lung cancer mortality (Ex. 35-58).

Smoking has been shown to interact in a synergistic manner (i.e., combined effect of two agents are greater than the sum of either agent alone) with some lung carcinogens, most notably asbestos (Ex. 35-114). NIOSH reported a slightly negative but nonsignficant interaction between cumulative Cr(VI) exposure and smoking in a model that had separate linear terms for both variables (Ex. 33-13). This means that, at any age, the smoking and Cr(VI) contributions to the lung cancer risk appeared to be additive, rather than synergistic, given the smoking information in the Gibb cohort along with the cumulative smoking assumptions of the analysis. In their final linear relative risk model, NIOSH included smoking as a multiplicative term in the background rate in order to estimate lifetime lung cancer risks attributable to Cr(VI) independent of smoking. Although this linear relative risk model makes no explicit assumptions with regard to an interaction between smoking and Cr(VI) exposure, the model does assume a multiplicative relationship between the background rate of lung cancer in the reference population and Cr(VI) exposure. Therefore, to the extent that smoking is a predominant influence on the background lung cancer risk, the linear relative risk model implicitly assumes a multiplicative (e.g., greater than additive and synergistic, in most situations) relationship between cumulative Cr(VI) exposure and smoking. Since current lung cancer rates reflect a mixture of smokers and non-smokers, OSHA agrees with the Small Business Administration's Office of Advocacy that the excess lung cancer risks from Cr(VI) exposure predicted by the linear relative risk model may overestimate the risks to non-smokers to some unknown extent. By the same token, the model may underestimate the risk from Cr(VI) exposure to heavy smokers. Because there were so few non-smokers in the study cohorts (approximately 15 percent of the exposed workers and four lung cancer deaths in the Gibb cohort), it was not possible to reliably estimate risk for the nonsmoking subpopulation.

Although OSHA is not aware of any convincing evidence of a specific interaction between cigarette smoking and Cr(VI) exposure, prolonged cigarette smoking does have profound effects on lung structure and function that may indirectly influence lung cancer risk from Cr(VI) exposure (Ex. 33-14). Cigarette smoke is known to cause chronic irritation and inflammation of the respiratory tract. This leads to decreases in airway diameter that could result in an increase in Cr(VI) particulate deposition. It also leads to increased mucous volume and decreased mucous flow, that could result in reduced Cr(VI) particulate clearance. Increased deposition and reduced clearance would mean greater residence time of Cr(VI) particulates in the respiratory tract and a potentially greater probability of developing bronchogenic cancer. Chronic cigarette smoking also leads to lung remodeling and changes in the proliferative state of lung cells that could influence susceptibility to neoplastic transformation. While the above effects are plausible consequences of cigarette smoking on Cr(VI)-induced carcinogenesis, the likelihood and magnitude of their occurrence have not been firmly established and, thus, the impact on risk of lung cancer in exposed workers is uncertain.

Differences in lung cancer incidence with race may also introduce uncertainty in risk estimates. Gibb et al. reported differing patterns for the cumulative exposure-lung cancer mortality response between whites and non-whites in their cohort of chromate production workers (Ex. 31-22-11). In the assessment of risk from the Gibb cohort, NIOSH reported a strong interaction between cumulative Cr(VI) exposure and race, such that nonwhites had a higher cumulative exposure coefficient (i.e., higher lung cancer risk) than whites based on a linear relative risk model (Ex. 33-13). If valid, this might explain the slightly lower risk estimates in the predominantly white Luippold cohort. However, Environ found that including race as an explanatory variable in the Cox proportional hazards model C1 did not significantly improve model fit (p=0.15) once cumulative Cr(VI) exposure and smoking status had been considered (Ex. 33-12).

NIOSH suggested that exposure or smoking misclassification might plausibly account for the Cr(VI) exposure-related differences in lung cancer by race seen in the Gibb cohort (Ex. 33-13, p. 15). It is possible that such misclassification might have occurred as a result of systematic differences between whites and non-whites with respect to job-specific Cr(VI) exposures at the Baltimore plant, unrecorded exposure to Cr(VI) or other lung carcinogens when not working at the plant, or in smoking behavior. Unknown differences in biological processes critical to Cr(VI)-induced carcinogenesis could also plausibly account for an exposure-race interaction. However, OSHA is not aware of evidence that convincingly supports any of these possible explanations.

Another source of uncertainty that may impact the risk estimates is the healthy worker survivor effect. Studies have consistently shown that workers with long-term employment status have lower mortality rates than short-term employed workers. This is possibly due to a higher proportion of ill individuals and those with a less healthy lifestyle in the short term group (Ex. 35-60). Similarly, worker populations tend to be healthier than the general population, which includes both employed and unemployed individuals. As a result, exposure-response analyses based on mortality of long-term healthy workers will tend to underestimate the risk to short-term workers and vice versa, even when their cumulative exposure is similar. Also, an increase in disease from occupational exposures in a working population may not be detected when workers are compared to a reference population that includes a greater proportion less healthy individuals.

The healthy worker survivor effect is generally thought to be less of a factor in diseases with a multifactorial causation and long onset, such as cancer, than in diseases with a single cause or short onset. However, there is evidence of a healthy worker effect in several studies of workers exposed to Cr(VI), as discussed further in the next section (“Suitability of Risk Estimates for Cr(VI) Exposures in Other Industries”). In these studies, the Start Printed Page 10209healthy worker survivor effect may mask increased lung cancer mortality due to occupational Cr(VI) exposure.

4. Suitability of Risk Estimates for Cr(VI) Exposures in Other Industries

At issue is whether the excess lung cancer risks derived from cohort studies of chromate production workers are representative of the risks for other Cr(VI)-exposed workers (e.g., electroplaters, painters, welders). Typically, OSHA has used epidemiologic studies from one industry to estimate risk for other industries. For example, OSHA relied on a cohort of cadmium smelter workers to estimate the excess lung cancer risk in a wide range of affected industries for its cadmium standard (57 FR at 42102, 9/14/1992). This approach is usually acceptable because exposure to a common agent of concern is the primary determinant of risk and not some other factor unique to the workplace. However, in the case of Cr(VI), workers in different industries are exposed to various Cr(VI) compounds that may differ in carcinogenic potency depending to a large extent on water solubility. The chromate production workers in the Gibb and Luippold cohorts were primarily exposed to certain highly water-soluble chromates. As more fully described in section V.B. of the Cancer Effects section, the scientific evidence indicates that all Cr(VI) compounds are carcinogenic but that the slightly soluble chromates (e.g. calcium chromate, strontium chromate, and some zinc chromates) exhibit greater carcinogenicity than the highly water soluble chromates (e.g. sodium chromate, sodium dichromate, and chromic acid) or the water insoluble chromates (e.g. lead chromates) provided the same dose is delivered and deposited in the respiratory tract of the worker. It is not clear from the available scientific evidence whether the carcinogenic potency of water-insoluble Cr(VI) compounds would be expected to be more or less than highly water-soluble Cr(VI) compounds. Therefore, OSHA finds it prudent to regard both types of Cr(VI) compounds to be of similar carcinogenic potency.

The primary operation at the chromate production plants in Painesville (Luippold cohort) and Baltimore (Gibb cohort) was the production of the highly water-soluble sodium dichromate. Sodium dichromate served as a starting material for the production of other highly water-soluble chromates such as sodium chromate, potassium dichromate, and chromic acid (Exs. 7-14; 35-61). As a result, the Gibb and Luippold cohorts were principally exposed to water-soluble Cr(VI). In the NPRM, OSHA requested comment on whether its risk estimates based on the exposure-response data from these two cohorts of chromate production workers were reasonably representative of the risks expected from equivalent exposures to different Cr(VI) compounds encountered in other industry sectors. Of particular interest was whether the preliminary risk estimates from worker cohorts primarily engaged in the production of the highly water soluble sodium chromate and sodium dichromate would substantially overpredict lung cancer risk for workers with the same level and duration of exposure to Cr(VI) but involving different Cr(VI) compounds or different operations. These operations include chromic acid aerosol in electroplating operations, the less water soluble Cr(VI) particulates encountered during pigment production and painting operations, and Cr(VI) released during welding, as well as exposure in other applications.

OSHA received comments on this issue from representatives of a wide range of industries, including chromate producers, specialty steel manufacturers, construction and electric power companies that engage in stainless steel welding, the military and aerospace industry that use anti-corrosive primers containing Cr(VI), the surface finishing industry, color pigment manufacturers, and the Small Business Administration's Office of Advocacy (Exs. 38-231, 38-233; 38-8; 47-5; 40-12-4; 38-215; 40-12-5; 38-106; 39-43; 38-7). Many industry commenters expressed concerns about the appropriateness of the underlying Gibb and Luippold data sets and the methodology (e.g. linear instead of threshold model) used to generate the lung cancer risk estimates. These issues have been addressed in other parts of section VI. The color pigment manufacturers asserted that lead chromate pigments, unlike other Cr(VI) compounds, lacked carcinogenic potential. This issue was addressed in section V.B.9 of the Health Effects section. In summary, OSHA finds lead chromate and other water-insoluble Cr(VI) compounds to be carcinogenic. The Agency further concludes that it is reasonable to regard water insoluble Cr(VI) compounds to be of similar carcinogenic potency to highly soluble Cr(VI) compounds. Based on this conclusion, OSHA no longer believes that its risk projections will underestimate the lung cancer risk for workers exposed to equivalent levels of water-insoluble Cr(VI), as suggested in the NPRM (69 FR at 59384).

Several commenters encouraged OSHA to rely on cohort studies that examined the lung cancer mortality of workers in their particular industry in lieu of the chromate production cohorts. Members of the aircraft industry and their representatives commented that OSHA failed to consider the results from several large cohort studies that showed aerospace workers were not at increased risk of lung cancer (Exs. 38-106; 38-215-2; 44-33; 47-29-2). In addition, Boeing Corporation and the Aeropspace Industries Association (AIA) provided data on the size distribution of Cr(VI) aerosols generated during primer spraying operations which showed most particles to be too large for deposition in the region of the respiratory tract where lung cancer typically occurs (Exs. 38-106-2; 38-215-2; 47-29-2). The Specialty Steel Industry maintained that epidemiological data specific to alloy manufacturing and experience within the their industry show that the lung cancer risk estimated by OSHA is unreasonably high for steel workers exposed to the proposed PEL of 1 μg Cr(VI)/m3 (Ex. 38-233, p. 82). Several comments argued that there was a lack of scientific evidence for a quantifiable exposure-response relationship between Cr(VI) exposure from stainless steel welding (Exs. 38-8; 38-233-4). The commenters went on to suggest that the OSHA quantitative Cr(VI) exposure-lung cancer response model derived from the chromate production cohorts should not be used to characterize the risk to welders. The suitability of the OSHA risk estimates for these particular industries is further discussed below.

a. Aerospace Manufacture and Maintenance. Most of the comments on suitability of OSHA risk estimates were provided by AIA (Exs. 38-215; 47-29-2), Exponent on behalf of AIA (Exs. 38-215-2; 44-33), and the Boeing Corporation (Exs. 38-106; 38-106-1). Cr(VI) is used as an anti-corrosive in primers and other coatings applied to the aluminum alloy structural surfaces of aircraft. The principal exposures to Cr(VI) occur during application of Cr(VI) primers and coatings and mechanical sanding of the painted surfaces during aircraft maintenance. Cr(VI) exposures are usually in the form of the slightly soluble strontium and zinc chromates used in primers and chromic acid found in other treatments and coatings designed to protect metal surfaces.

Cohort Studies of Aerospace Workers. AIA commented that:

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OSHA has all but ignored a substantial body of evidence of studies showing no increased risk of lung cancer in aerospace workers * * *. While epidemiologic studies show a link between lung cancer and chromium VI exposure in other industries [e.g. chromate production], that relationship is not established in the aerospace industry (Ex.38-106, p. 16).

Aerospace commenters pointed to several cohort studies from aircraft manufacturing and maintenance sites that did not find significantly elevated lung cancer mortality in workers (Exs. 31-16-3; 31-16-4; 35-213; 35-210). However, OSHA believes that the vast majority of workers in these cohorts were not routinely engaged in jobs involving potential Cr(VI) exposures.

Only two of the above studies (i.e., the Alexander and Boice cohorts) specifically investigated the relationship between Cr(VI) exposures and lung cancer mortality (Exs. 31-16-3; 31-16-4). The Alexander cohort was evaluated as a supplemental data set for quantitative risk assessment in sections VI.B.6 and VI.E.4. Briefly, there were 15 observed lung cancer cases in the Alexander et al. study with 19.5 expected (Ex. 31-16-3). There was no evidence of a positive trend between cumulative Cr(VI) exposure and lung cancer incidence. The lack of excess lung cancers was probably, in large part, due to the short follow-up period (median nine years per member) and young age of the cohort (median 42 years at the end of follow-up). Lung cancer generally occurs 20 or more years after initial exposure to a carcinogenic agent and mostly in persons aged 55 years and older. There was no Cr(VI) air monitoring data for a significant portion of the study period and reconstruction of worker exposure was reduced to a limited number of ‘summary time-weighted average exposure levels’ based on job category (Ex. 31-16-3). These limitations may have caused inaccuracies in the worker exposure estimates that could lead to potential misclassification of exposure, and, thus may also have contributed to the lack of a positive Cr(VI) exposure—lung cancer response.

In the their technical comments on behalf of the AIA, Exponent considered the Boice cohort to be “the largest, best defined, most completely ascertained, and followed for the longest duration” of the epidemiological studies examining lung cancer mortality and other health outcomes of aerospace workers (Ex. 38-215-2, p. 10). The Boice cohort (previously described in section V.B.6) consisted of 77,965 aerospace workers employed over a thirty-year period at a large aircraft manufacturing plant in California (Ex. 31-16-4). The average duration of employment was over ten years and thirty percent of the cohort was deceased. Therefore, the Boice cohort was larger, older, and had greater follow-up than the Alexander cohort. Unfortunately, Cr(VI) air measurements were sparse in recent years and entirely absent during early years of plant operation so, unlike the Alexander cohort, quantitative Cr(VI) exposure reconstruction was not attempted. Instead, all jobs were qualitatively categorized by the chemicals involved (e.g., chromates, trichloroethylene, perchloroethylene, etc.) and their frequency of chemical usage (routine, intermittent, or no exposure). Duration of potential chemical exposure, including Cr(VI), was determined for the cohort members based on work history (Ex. 47-19-15). There were 3634 workers in the cohort believed to have routine exposures to Cr(VI), mostly in painting/primer operations or operating process equipment used for plating and corrosion protection. Another 3809 workers were thought to have potential ‘intermittent exposure’ to chromates. Most workers with potential exposure to Cr(VI) also had potential exposures to the chlorinated solvents tricholoroethylene (TCE) and perchloroethylene (PCE). Because of an inadequate amount of Cr(VI) exposure data, OSHA was unable to use the Boice study for quantitative risk assessment.

The Boice et al. study did not find excess lung cancer among the 45,323 aircraft factory workers when compared against the race-, age-, calendar year-, and gender-adjusted rates for the general population of the State of California (SMR=97). This is not a surprising result considering more than 90 percent did not work in jobs that routinely involve Cr(VI) exposure. Factory workers potentially exposed to Cr(VI) also did not have significantly elevated lung cancer mortality (SMR=102; 95% CI: 82-126) relative to the California general population based on 87 observed lung cancer deaths. However, workers engaged in spray painting/priming operations that likely had the highest potential for Cr(VI) exposure did experience some excess lung cancer mortality (SMR=111; 95% CI: 80-151) based on 41 deaths, but the increase was not statistically significant.

As commonly encountered in factory work, there was evidence of a ‘healthy worker effect’ in this aerospace cohort that became increasingly pronounced in workers with long-term employment. The healthy worker effect (HWE) refers to the lower rate of disease relative to the general population sometimes observed in long-term occupational cohorts. For example, the Boice cohort factory workers employed for 20 years had statistically significant lower rates of death than a standardized California reference population for all causes (SMR=78; 95% CI: 75-81), lung cancer (SMR=70; 95% CI: 61-80), heart disease (SMR=79; 95% CI: 74-83), cerebrovascular disease (SMR=67; 95% CI: 56-78), non-malignant respiratory disease (SMR=65; 95% CI: 57-74), and cirrhosis of the liver (SMR=67; 95% CI: 51-88) among other specific causes (Ex. 31-16-4, Table 5). The study authors note that “these reductions [in disease mortality] seem in part due to the initial selection into the workforce and the continued employment of healthy people [i.e. healthy worker effect] that is often found in occupational studies” (Ex. 31-16-4, p. 592). If not properly accounted for in mortality analysis, HWE can mask evidence of disease risk. Mr. Robert Park, senior epidemiologist from NIOSH, confirmed this at the public hearing when addressing implications of HWE for Cr(VI) lung cancer risk in the Boice cohort.

This [Boice cohort] is a population where you would expect to see a very dramatic healthy worker effect * * * so just off the top, I would say any [relative risk] estimates for lung cancer in the Boice population based on SMRs, I would want to adjust upwards by 0.9, for example, if the real SMR ought to be around 0.9 due to the healthy worker effect. So if you do that in their population, they have classified some workers as [routinely] exposed to chromates, about 8 percent of the population. They observe a SMR of 1.02 in that group. If you look at some of the other groupings in that study, for example, assembly has an SMR of 0.92, fabrication, which is basically make all the parts, 0.92, maintenance, 0.79. So a lot of evidence for healthy worker effect in general in that population. So the chromate group actually is at least 10 or 12 percent higher in their lung cancer SMR. Now again, the numbers are small, you'd have to have a very huge study for an SMR of 1.1 or 1.15 to be statistically significant. So it is not. But it is a hint (Tr. 345-347).

OSHA agrees with Mr. Park that the relative risks for lung cancer in the Boice cohort are likely understated due to HWE. This is also illustrated in the study analysis of the lung cancer morality patterns by exposure duration to specific chemicals using internal cohort comparisons. The internal analysis presumably minimize any biases (e.g. smoking, HWE) that might exist from comparisons to the general population. The results for workers potentially exposed to Cr(VI), trichloroethylene (TCE), and perchloroethylene (PCE) are presented in Table VI-9.

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As shown in the table, there was a statistically significant decline in relative risk of lung cancer among factory workers with duration of TCE exposure (p<0.01) and PCE exposure (p=0.02). This mirrors the decline with increasing employment duration seen in comparison with the general California population and strongly suggests the internal cohort analysis failed to adequately adjust for HWE.

The table shows that, despite the downward influence of HWE on lung cancer risk, there was a slight nonsignificant upward trend in excess lung cancer mortality with duration of exposure to Cr(VI). The result is that aircraft workers potentially exposed to chromate for five or more years had 50 to 70 percent greater lung cancer mortality than coworkers with a similar duration of potential exposure to the chlorinated solvents. The relative excess is even more noteworthy given that the subgroups had considerable overlap (e.g., many of the same workers in the PCE and TCE groups were also in the chromate group). This implies that a subset of Cr(VI) workers not exposed to chlorinated solvents, possibly spray painters routinely applying Cr(VI) primers over many years, may be at greater lung cancer risk than other Cr(VI)-exposed members of the cohort.

The AIA and its technical representative, Exponent, objected to OSHA reliance on the non-statistically significant upward trend in excess lung cancers with increasing Cr(VI) exposure duration described above (Exs. 38-215-2; 47-29-2). Exponent stated:

Statistical tests for trend indicated there is no evidence for a trend of increasing risk of lung cancer with increasing years exposed to chromate (P<0.20). OSHA seems to have ‘eye-balled’ the estimates and felt confident accepting the slight and non-significant increases among risk estimates with overlapping confidence intervals as evidence of a “slightly positive” trend. However, OSHA's interpretation is an overstatement of the finding and should be corrected in the final rule (Ex. 38-215-2, p. 13).

OSHA does not agree with these comments and believes it has objectively interpreted the trend data in a scientifically legitimate fashion. The fact that an upward trend in lung cancer risk with Cr(VI) exposure duration fails to meet a statistical confidence of 95 percent does not mean the relationship does not exist. For example, a trend with a p-value of 0.2 means random chance will not explain the relationship 80 percent of the time. The positive trend is all the more notable given that it occurs in spite of a significant downward trend in lung cancer mortality with years of employment. In other words, aerospace workers exposed to Cr(VI) experienced a slightly greater lung cancer mortality with increasing number of years exposed even while their co-workers exposed to other chemicals were experiencing a substantially lower lung cancer mortality with increasing years exposed.

In its post-hearing comments, NIOSH calculated the observed excess lung cancer risk to the Boice spray painters expected to have the highest Cr(VI) exposures (SMR=1.11) to be 21 percent higher than the minimally Cr(VI)-exposed assembly workers (SMR=0.92). NIOSH assumed the painters were exposed to 15 μg CrO3/m3 (i.e., the arithmetic mean of Cr(VI) air sampling data in the plant between 1978 to 1991) for 10 years (i.e., the approximate average duration of employment) to derive an excess risk per mg CrO3/m3 of 1.4 (Ex. 47-19-1). NIOSH noted that this was very close to the excess risk per mg CrO3/m3 of 1.44 determined from their risk modeling of the Gibb cohort (Ex. 33-13). In a related calculation, OSHA derived the expected excess risk ratio from its linear relative risk model using a dose coefficient consistent with the Gibb and Luippold data sets. Assuming the Boice spray painters were exposed to 10 μg Cr(VI)/m3 (90th percentile of plant air sampling data converted from μg CrO3 to μg Cr(VI)) for 12 years (average employment duration of Boice factory workers), the model predicts a risk ratio 1.20 which is also very close to the observed excess risk ratio of 1.21 calculated from the observed SMR data for spray painters above. These calculations suggest that the excess lung cancer mortality observed in the Boice subcohort of Cr(VI)-exposed aerospace workers is consistent with excess risks predicted from models based on the Gibb and Luippold cohort of chromate production workers.

The other cohort studies of aerospace workers cited by AIA were not informative with regard to the association between Cr(VI) and lung cancer. A cohort study by Garabrandt et al. of 14,067 persons employed by an aircraft manufacturing company found significantly reduced excess lung cancer mortality (SMR=80; 95% CI: 68-95) compared to adjusted rates in the U.S. and San Diego County populations (Ex. 35-210). The mean duration of follow-up was only 16 years and the study authors are careful to state that the study can not rule out excess risk for diseases, such as lung cancer, that have long latencies of 20 years or more. The consistently low all-cause and cancer mortalities reported in the study strongly suggest the presence of a healthy worker effect. Another cohort study by Blair et al. of 14,457 aircraft maintenance workers at Hill Air Force base in Utah did not find elevated lung cancer mortality (SMR=90; 95% CI: 60-130) when compared to the general population of Utah (Ex. 35-213). However, the study was exclusively designed to investigate cancer incidence of chlorinated solvents (e.g. TCE, PCE, methylene chloride) and makes no mention of Cr(VI). This was also the case for a cohort study by Morgan et al. of 20,508 aerospace workers employed at a Hughes Aircraft manufacturing Start Printed Page 10212plant, which found no excess lung cancer mortality (SMR=0.96; 95% CI: 87-106) compared to the general U.S. population. However, a detailed investigation of jobs at a large aircraft manufacturing facility (i.e. facility studied by Boice et al.) found that only about 8 percent of employees had potential for routine Cr(VI) exposure (Ex. 47-19-15). If this is representative of the workforce in the other studies cited above, it is doubtful whether a Cr(VI)-related increase in lung cancer from a small proportion of workers would be reflected in the mortality experience of the entire cohort, most of whom would not have been exposed to Cr(VI).

In summary, OSHA does not find convincing evidence from the aerospace cohort studies that the Agency's quantitative risk assessment overstates the lung cancer risk to Cr(VI)-exposed workers. An association between Cr(VI) exposure and lung cancer was never addressed in most cohorts relied upon by the aerospace industry. Job analysis shows that only a minor proportion of all aerospace workers are engaged in workplace activities that routinely lead to Cr(VI) exposure. This could explain the lack of excess lung cancer mortality found in studies characterizing the mortality experience of all aerospace workers. Alexander et al. identified a cohort of Cr(VI) exposed workers, made individual worker estimates of cumulative Cr(VI) exposures, and found no exposure-related trend with lung cancer incidence. However, the absence of exposure-response could be the result of a number of study limitations including the young age of the cohort (e.g. majority of workers were under 50 years of age, when lung cancer incidence is relatively uncommon), the inadequate follow-up period (e.g. majority of workers followed < 10 years), and the potential for exposure misclassification (e.g. Cr(VI) exposure levels prior to 1975 were not monitored). Boice et al. also identified a subcohort of aerospace workers with potential Cr(VI) exposure but lacked adequate air sampling to investigate a quantitative relationship between Cr(VI) exposure and lung cancer response. There was a significant decline in relative lung cancer risk with length of employment among factory workers as well as those exposed to chlorinated solvents, indicating a strong healthy worker survivor effect among this pool of workers. The healthy worker effect may have masked a significant trend in lung cancer with Cr(VI) exposure duration. Risk projections based on the OSHA linear model were found to be statistically consistent with the relative risk ratios observed in the Boice cohort.

Cr(VI) Particle Size Distribution During Aerospace Operations. Differences in the size of Cr(VI) aerosols generated during chromate production and aerospace operations is another reason representatives of the aircraft industry believe the OSHA risk estimates overstate risk to aerospace workers (Exs. 38-106; 38-106-1; 38-215-2; 39-43; 44-33; 47-29-2). The submitted particle size data indicated that spraying Cr(VI) primers mostly generates large aerosol droplets (e.g.

> 10 μm) not expected to penetrate beyond the very upper portions of the respiratory tract (e.g. nasal passages, larynx). Some aerospace commenters also cited research showing that the few respirable primer particulates that reach the lower regions of the lung contain less Cr(VI) per particle mass than the larger non-respirable particles (Exs. 44-33; 38-106; 39-43). As a result, aerospace commenters contend that a very small proportion of Cr(VI) aerosols generated by aircraft primer operations deposit in the bronchioalveolar regions of the lung where lung cancer occurs. OSHA agrees that the particle size studies submitted to the record sufficiently demonstrate that a relatively small proportion of Cr(VI) reaches the critical regions of the lung as a result of these aircraft spraying operations. However, the Agency believes the reduction in lung cancer risk from this lower Cr(VI) particle burden is likely offset by the greater carcinogenic activity of the slightly soluble strontium and zinc chromates inhaled during spray primer application. Evaluation of the study data provided to the record and the rationale behind the OSHA position are described below.

The Agency reviewed the information provided by Boeing on the particle size of paint aerosols from typical spraying equipment used in aerospace applications. Boeing provided size characterization of paint aerosol from their in-house testing of spray paint equipment (Ex. 38-106-1, p. 8-11). They measured droplet size distributions of non-chromated polyurethane enamels generated by high volume low pressure (HVLP) and electrostatic air spray guns under typical settings. The particle size was measured 10 to 12 inches from the nozzle of the gun using laser diffraction techniques. Boeing found the median volumetric droplet diameter (Dv50) of the paint particles to be in the range of 17 to 32 μm under the test conditions. Less than 0.5 percent of droplets in the spray were 5 μm and smaller (e.g. typical of particles that deposit in the bronchioalveolar region). Boeing concluded:

In typical operations and products, the best aerosol size is a distribution with mass median diameter of about 30-40 microns, and a relatively monodisperse distribution. As a result, the fraction of the spray that is <5 micron is about 1% or less; in overspray perhaps ≉2%. Therefore the deposited dose would be far less than from exposure to an equal concentration of a smaller aerosol size, and estimates of risk based on studies of other industry sectors are not relevant to evaluation of risk in aerospace paint spraying (Ex. 38-106-1, p. 16).

Although Boeing used a non-chromated enamel paint in their studies, they contend that the results would be representative of the particle size distribution for a Cr(VI) primer using the same equipment under similar conditions.

Boeing also submitted recent publications by the UCLA Center for Occupational and Environmental Health measuring the Cr(VI) particle size distribution during spray painting operations at an aerospace manufacturing facility (Ex. 38-106-1). The UCLA group investigated particle size distributions of Cr(VI) primers sprayed from HVLP equipment in a lab bench-scale spray booth and in a field study of spray booths at an aerospace facility (Ex. 38-106-1, attachment 6). The tested primers contained the slightly soluble strontium chromate. The study data are presented in two papers by Sabty-Daily et al. The aerosol particles were collected at different locations several meters from the spray gun in the bench-scale paint booth using a cascade impactor. Full shift personal breathing zone samples from workers spraying primer were also collected with a cascade impactor in the field studies. The mass median aerodynamic diameter (MMAD) for Cr(VI) particles in the field study was reported to be 8.5 μm with a geometric standard deviation of 2.2 μm. On average, 62 percent of the Cr(VI) mass was associated with non-respirable particles >10 μm. Taking into account deposition efficiency, it was estimated that less than five percent of the Cr(VI) would potentially deposit in the lower regions of the respiratory tract where lung cancer occurs. The bench scale study gave particle distributions similar to the field studies. It was shown that particle size decreases slightly as gun atomization pressure increases. Particles in the direct spray were generally larger than the overspray. Particle size was shown to decrease with distance to the target surface due to evaporation of solvent.

Both Sabty-Daily articles and the Boeing submission made reference to Start Printed Page 10213another study that measured particle size distribution of a HVLP-generated paint aerosol in the breathing zone of the worker (Ex. 48-3). Paint droplets were collected on polycarbonate filters with 0.2 μm pore size. Aerosol size was measured using a microscopic method that minimizes bias from solvent evaporation. The breathing zone MMAD in the overspray was reported to be 15 to 19 μm with a GSD of 1.7 μm. In another study, LaPuma et al. investigated the Cr(VI) content of primer particles from an HVLP spray gun using a cascade impactor (Ex. 31-2-2). They reported that smaller particles (i.e. <7 μm) contained disproportionately less Cr(VI) per mass of dry paint than larger particles.

Boeing concluded that “the particle size distribution reported by Sabty-Daily et al. (2004a) significantly underestimate the size distribution of paint aerosol” (Ex. 38-106-1, p. 14). They state that “in typical [spraying] operations and products the best aerosol size is a distribution with mass median diameter of about 30-45 microns” (Ex. 38-106-1, p. 16). This particle size is larger than 15 to 20 μm reported in independent breathing zone measurements of spray paint aerosol collected on conventional sampling media (i.e. polycarbonate filters) (Carlton and Flynn, 1997).

The Boeing rationale for dismissing the UCLA data was that the cascade impactor had low collection efficiency for larger particles relative to the Boeing laser diffraction method, which Boeing believes is more accurate over the entire size distribution. OSHA notes, however, that Boeing did not characterize aerosol particles in the breathing zone of workers spraying Cr(VI) primer. Their study characterized droplet size from an non-chromated enamel spray directly out of the spray gun prior to contact with the target surface. While collection efficiency accounts for some of the particle size difference, other factors may also have contributed. These factors include the composition of the spray paint, the sampling location, and the degree of solvent evaporation. OSHA considers Cr(VI) primer droplets with an average MMAD of 7 to 20 μm, as measured in breathing zone studies, to best represent the particle size inhaled by a worker during spraying operations, since this range was measured in breathing zone studies. The majority of these droplet particles would not be expected to penetrate regions of the respiratory tract where lung cancers occur.

While aerosol particle size during spray application of Cr(VI) primers has been measured, AIA acknowledged that the particle size distribution during sanding procedures has not been well studied (Exs. 38-106; 47-29-2). However, they believe that most of the particles released as a result of sanding and grinding operations to remove old paint coatings from aircraft are non-respirable (e.g. >10 μm). OSHA is not aware of reliable data in the record to support or refute this claim.

The Cr(VI) particle size data from spray primer and sanding applications in aerospace need to be evaluated against Cr(VI) particle size during chromate production to determine its impact on OSHA risk estimates. Boeing observed that the high temperature calcination process that oxidizes chromite ore to sodium chromate would likely lead to a high proportion of respirable fume (Ex. 38-106). During post-hearing comments, AIA provided a figure from the 1953 U.S. Public Health Service survey report that indicated the geometric mean airborne dust particle size in a chromate production plant was 0.3 to 0.4 m in size (Ex. 47-29-2, p. 3). The data came from a thermal precipitator analysis of one-hour dust samples collected from the roasting and leaching areas of the plant (Ex. 7-3). An independent 1950 industrial hygiene survey report of the Painesville plant from the Ohio Department of Health indicates the median size of the in-plant dust was 1.7 microns and the median size of the mist generated during the leaching operations was 3.8 microns (Ex. 7-98). The measurement method used to determine this particle size was not clear from the survey report.

The thermal precipitator used by the U.S. Public Health Service survey is an older sampling device specifically used to characterize particles smaller than 5 μm. The thermal precipitator collection efficiency for particles >5 μm was considered suspect due to gravitational and inertial effects caused by the very low air flow rates (e.g. 6 ml/min) necessary to operate the device. The survey figure shows that 95 percent of collected particles were smaller than 1 μm. However, this is probably an inflated percentage given that the thermal precipitator is unable to effectively collect particles outside the fine and ultrafine range (e.g. greater than about 5 μm).

In their post-hearing brief, AIA introduced an Exponent microscopic analysis of particles claimed to be landfilled ‘roast residue’ generated as airborne dust from the Painesville plant ‘decades’ earlier (Ex. 47-29-2). AIA stated that “the particle diameters ranged from 0.11 to 9.64 μm and that 82 percent of the particles were less than 2.5 μm (Ex. 47-29-2, p. 3). OSHA was unable to verify the nature of the landfill dust or determine its relevance from the information provided by AIA.

In the same submission, AIA referenced several experimental and animal studies as evidence that small particles less than 2.5 μm in diameter cause greater lung toxicity than larger particles (Ex. 47-29-2). AIA concluded that:

It is important for OSHA to recognize in the quantitative risk assessment that the particles to which the featured chromate production workers were exposed were fine [particle diameters 0.1-2.5 μm] and ultrafine particles [particle diameters <0.1 μm] and that particles of this size range are known to be associated with greater toxicity than larger particles. Thus, the quantitative cancer risk estimates based on these studies are very conservative and likely overestimate risks for Cr(VI) exposures in other industries, most notably aerospace (Ex. 47-29-2, p. 7).

The above studies showed that fine/ultrafine particles penetrate into the alveolar region of the lung, are slowly cleared from respiratory tract, and can lead to pulmonary inflammation and non-neoplastic respiratory disease. OSHA agrees that fine/ultrafine particles can disrupt pulmonary clearance and cause chronic inflammation if sufficient amounts are inhaled. However, AIA did not provide data that demonstrated the Gibb and Luippold workers were routinely exposed to levels of small particles that would trigger serious lung toxicity.

AIA also referred to a human epidemiological study that reported the excess risk of lung cancer mortality from airborne fine/ultrafine particles (i.e. 8 percent increase per 10 μg/m3 in particles) to be similar to the excess risk of cardiopulmonary disease (i.e. 6 percent increase with each 10 μg/m3 in particles). AIA suggested these results were evidence that the excess lung cancer mortality attributed to Cr(VI) in chromate production cohorts were, in large part, due to fine/ultrafine particles. However, the Luippold cohort had an excess mortality from lung cancer (SMR=239) that was 10.6-fold higher than the excess mortality of heart disease (SMR=113) (Ex. 33-10). The Gibb cohort had an excess mortality from lung cancer that was 5.7-fold higher than the excess mortality of arteriosclerotic heart disease (SMR=114) (Ex. 33-11). These mortality patterns are not consistent with the small particle study results above and strongly indicate fine/ultrafine particles are not the primary cause of excess lung cancer among the chromate production workers in the Luippold and Gibb cohorts. Given the information provided, OSHA does not have reason to expect that exposure Start Printed Page 10214to fine/ultrafine particles in the Luippold and Gibb cohorts had a substantial quantitative impact on its estimates of lung cancer risk from exposure to Cr(VI).

Based on the evidence presented, OSHA believes the production of sodium chromate and dichromate likely generated a greater proportion of respirable Cr(VI) particles than the aerospace spray priming operations. The roasting operation that oxidizes trivalent chromite ore and soda ash to hexavalent sodium chromate salts would be expected to generate a small particle fume based on information from other high temperature calcination processes (e.g. beryllium oxide production). This is supported by a small amount of particle size information from the 1940s and 1950s (Ex. 7-98). However, there are insufficient data to reliably determine the median diameter of Cr(VI) particles or otherwise characterize the particle size distribution generated during sodium chromate production in the breathing zone of the worker. It should also be recognized that significant Cr(VI) exposures occurred during other chromate production operations, such as leaching sodium chromate from the roast, separating sodium dichromate crystals, and drying/bagging the final purified sodium dichromate product. There is no information on particle size for these operations, but it is reasonable to expect greater proportions of larger particles than generated during the roasting process. For these reasons, there is some degree of uncertainty with regard to size distribution of Cr(VI) aerosols inhaled by chromate production workers.

OSHA agrees with the aerospace industry that the reduced proportion of respirable particles from spray primer operations relative to chromate production will tend to lower the lung cancer risk from equivalent Cr(VI) exposures. This is because less Cr(VI) will reach the bronchioalveolar regions of the respiratory tract where lung cancer occurs. However, the chemical form of Cr(VI) must also be considered. Spray primer and painting operations expose workers to the slightly soluble strontium and zinc chromates while chromate production workers are exposed primarily to highly soluble sodium chromate/dichromate.

As explained earlier in section V.B.9 on carcinogenic effects, animal and mechanistic evidence suggest that the slightly soluble strontium and zinc chromates are more carcinogenic than the highly soluble Cr(VI) compounds when equivalent doses are delivered to critical regions of the respiratory tract. Slightly soluble Cr(VI) compounds produced a higher incidence of bronchogenic tumors than highly soluble Cr(VI) compounds (e.g. sodium dichromate, chromic acid) when instilled in the respiratory tract of rats at similar dosing and other experimental conditions (Ex. 11-2; 11-7). For example, intrabronchial instillation of strontium chromate produced a 40 to 60-fold greater tumor incidence than instillation of sodium dichromate in one study (Ex. 11-2). Unlike the highly soluble Cr(VI) compounds, the less water soluble Cr(VI) compounds are better able to provide a persistent source of high Cr(VI) concentration within the immediate microenvironment of the lung epithelia facilitating cellular uptake of chromate ion into target cells. The greater carcinogenicity of the slightly soluble Cr(VI) compounds have led to ACGIH TLVs that are from 5-fold (i.e. zinc chromates) to 100-fold (i.e. strontium chromates) lower than the TLV for highly water soluble Cr(VI) compounds.

For these reasons, the risk reductions achieved from the lower Cr(VI) particle burden that reaches the bronchioalveolar region of the lung may, to a large extent, be offset by the greater carcinogenic activity of the Cr(VI) compounds that are inhaled during aircraft spray painting operations. Since significant lung cancer risk exists at Cr(VI) air levels well below the new PEL (e.g. 0.5-2.5 μg/m3) based on chromate production cohorts, the risk would also likely be significant even if the lung cancer risk from similar Cr(VI) exposures in aerospace operations is slightly lower. Therefore, OSHA believes that the risk models based on the Gibb and Luippold data sets will provide reasonable estimates of lung cancer risk for aerospace workers exposed to equivalent levels of Cr(VI). However, based on the lower lung burden expected after considering the particle size distribution evidence submitted to the record, OSHA no longer believes that its risk projections will underestimate lung cancer risk for aerospace workers exposed to strontium or zinc chromates, as suggested in the NPRM (69 FR at 59384).

b. Specialty Steel Industry and Stainless Steel Welding.

Collier Shannon Scott submitted comments to OSHA on behalf of a group of steel and superalloy industry trade associations and companies including the Specialty Steel Industry of North America (SSINA), the Steel Manufacturers Association (SMA), and the American Iron and Steel Institute (AISI) as well as various individual companies. They requested that OSHA “seriously consider” the results of the Arena et al. (1998) study of workers employed in the high nickel alloys industry (Tr. 661), as well as studies by Huvinen et al. (1996, 2002) and Moulin et al. (1990) on stainless steel production workers (Exs. 38-233, p. 85; 47-5, p. 10) and by Danielsen et al. (1996) on Norweigen stainless steel welders (Ex. 47-5, p. 10). On behalf of the SSINA, Ms. Joan Fessler testified that the Arena et al. study (Ex. 38-233-2), also referred to as the “Redmond Study”, found no relationship between Cr(VI) exposure and lung cancer, and in general “ * * * no strong epidemiological evidence causally associating occupational exposures with excess risk” (Tr. 662). Ms. Fessler concluded that the study results “ * * * stand in stark contrast to the extrapolated estimates of cancer risk OSHA has developed from the chromate worker cohorts to develop the proposed rule” (Tr. 662) and “[show] that there is no significant excess risk of lung cancer for workers in the steel industry” (Ex. 40-12-4, p. 2). She cited studies conducted by Huvinen et al. as additional evidence that workers in the stainless steel production industry do not have excess risk of lung cancer from Cr(VI) exposure (Tr. 663).

OSHA reviewed the Arena et al. (1998) study, which examined mortality in a cohort of 31,165 workers employed at 13 U.S. high nickel alloy plants for at least one year between 1956 and 1967 (Ex. 38-233-2, p. 908). The focus of the study is nickel exposure; it does not report how many of the cohort members were exposed to Cr(VI) or the levels of Cr(VI) exposure to which they may have been exposed. Therefore there does not appear to be any basis for SSINA's conclusion that “[t]here was no strong epidemiological evidence causally associating occupational exposures with excess risk” in the study and that “[n]o dose response relationship was demonstrated * * * ” (Tr. 662). Ms. Fessler stated, in response to a question by Dr. Lurie of Public Citizen, that there is no information in the study on Cr(VI) exposures with which to assess a dose-response relationship between occupational exposure to Cr(VI) and excess lung cancer risk in the cohort (Tr. 685). Without any information on the proportion of workers that were exposed to Cr(VI) or the levels to which they were exposed, one cannot determine that there is no carcinogenic effect of Cr(VI) exposure, or that the results of the Arena study contradict OSHA's risk estimates.

To more meaningfully compare the lung cancer risk predicted by OSHA's risk model and that observed in the Start Printed Page 10215Arena et al. study, OSHA estimated Cr(VI) exposures for the cohort members based in part on exposures in the stainless steel industry. High-nickel alloys that contain chromium are roughly comparable to stainless steel in terms of chromium content and the temperatures at which they are melted. This in turn determines the amount of trivalent chromium that converts to hexavalent chromium in the heating process. For example, cast stainless steels with high nickel composition (e.g. Cast 18-38, Cast 12-60, Cast 15-65, and Cast 15-35) have chromium content ranging from 10-21% and have melting points between 2350 and 2450 degrees Fahrenheit. Other high-nickel alloys with chromium content, such as Hastelloy alloys C and G, Incoloy, Nimonic, and Inconel, range from 13 to 22% chromium (except Incoloy 804=29.7% Cr) with melting points of 2300-2600 degrees Fahrenheit. Stainless steels, in general, have 12-30% chromium content and melting points between 2350 and 2725 degrees Fahrenheit.

For this analysis OSHA projected that the proportion of workers in each production job category is approximately similar in stainless steel and high-nickel alloy production. For example, OSHA assumed that the percent of alloy production workers who are furnace operators is, as in steel production, about 5%. Assuming that both the Cr(VI) exposures typical of various production jobs and the proportion of workers employed in each job are roughly similar, workers in the Arena cohort producing high-nickel stainless steels and alloys containing chromium are likely to have Cr(VI) exposures comparable to those generally found in stainless steel production. Workers' exposures were estimated using the exposure profile shown in Table III-62 of the Final Economic Analysis section on steel mills (Ex. 49-1).

Not all workers in the Arena et al. cohort had Cr(VI) exposures comparable to those in stainless steel facilities. As discussed by Ms. Fessler at the hearing, exposure to “ * * * [c]hrome was not uniform in all [industries included in the study] because some of those industries * * * did only high nickel work or nickel mining or whatever specific nickel work there was” (Tr. 683). OSHA assumed that Cr(VI) exposures of workers producing high-nickel alloys without chromium content, such as Duranickel, Permanickel, Hastelloy alloys B, D, and G, and Monel alloys, are similar to those found in carbon steel mills and other non-stainless facilities, which according to comments submitted by Collier Shannon Scott:

* * * may generate Cr(VI) due to trace levels of chromium in feedstock materials or the inadvertent melting of stainless steel scrap, as well as during various maintenance and welding operations (Ex. 38-233, p. 10).

Exposure levels for Arena cohort workers producing these alloys were estimated using the carbon steel exposure profile shown in Table III-64 of the Final Economic Analysis section on steel mills (Ex. 49-1).

Table VI-10 below shows the risk ratios (ratio of excess plus background cancers to background only cancers) predicted by OSHA's model for workers producing high-nickel alloys with and without chromium content. The percentage of workers with 8-hour TWA exposures in each range shown below are calculated for Ni-Cr alloys and non-Cr alloys using profiles developed for the Final Economic Analysis sections on stainless steel and carbon steel industries, respectively (Ex. 49-1). An average exposure duration of 20 years was assumed. While it was not clear how long workers were exposed on average, the reported length of follow-up in the study indicates that the duration of exposure was probably less than 20 years for most workers. Risk ratios were calculated assuming that workers were followed through age 70. The average age at end of follow-up was not clear from the Arena et al. publication. Over half of the original cohort was under 30 as of 1978, and follow-up ended in 1988 (Ex. 38-233-2, p. 908). Follow-up through age 70 may therefore lead OSHA's model to overestimate risk in this population, but would probably not lead to underestimation of risk.

Start Printed Page 10216

The Arena et al. study reported lung cancer rates among white males (who comprised the majority of the cohort) about 2%-13% higher than background depending on the reference population used. The table above illustrates that with reasonable assumptions about exposures in the Arena cohort, OSHA's risk model predicts excess risks as low as those reported by Arena et al. OSHA's model predicts the highest risks (1-6% higher than background) among workers producing alloy mixtures similar to stainless steel in chromium content. Unfortunately, it is not clear from the Arena et al. publication how many of the workers were involved in production of chromium-containing alloys. If an even split is assumed between workers producing alloys with and without chromium content in the Arena et al. cohort, OSHA's model predicts a lung cancer rate between 0.8% and 3.8% higher than background.

More precise information about the level or duration of cohort members' exposures might increase or decrease OSHA's model predictions somewhat. For example, some workers in the historical alloy industry would have had higher exposures than their modern-day counterparts, so that better exposure information may lead to somewhat higher model predictions. On the other hand, better information on the duration of exposure and workers' age at the end of follow-up would lower the model predictions, because this analysis made assumptions likely to overestimate both. The analysis presented here should be interpreted cautiously in light of the considerable uncertainty about the actual exposures to the Arena cohort members, and the fact that OSHA's model predictions are based on a lifetable using year 2000 U.S. all-cause mortality data (rather than data from the time period during which the cohort was followed). This analysis is not intended to provide a precise estimate of risk from exposure to Cr(VI) in the Arena cohort, but rather to demonstrate that the relatively low excess risk seen in the cohort is reasonably consistent with the excess risk that OSHA's model would predict at low exposures. It illustrates that OSHA's risk model does not predict far higher risk than was observed in this cohort. Rather, the majority of workers in alloy production would be predicted to have relatively low risk of occupational lung cancer based on their relatively low exposure to Cr(VI).

Regarding the Huvinen et al. (1996, 2002) studies, the comments submitted by Collier Shannon Scott state that “there was not a significant increase in the incidence of any disease, including lung cancer, as compared to the control population” (Ex. 38-233, p. 85). However, the authors also noted that risk of cancer could not be excluded because the follow-up time was short and the exposed group was young and small (Ex. 38-233-3, p. 747).

In addition to the small size (109 workers) and young age (mean 43.3 years) of the Cr(VI)-exposed group in the Huvinen et al. study population, the design of this study limits its relevance to the issue of lung cancer risk among stainless steel workers. The subjects were all employed by the company at the time of the study. Individuals with lung cancer would be expected to leave active employment, and would not have been surveyed in the study. The authors made only a limited attempt to track former workers: Those who met the study criteria of 8 years' employment in a single production department were surveyed by mailed questionnaire (Ex. 38-233-3, p. 743), and no follow-up on nonrespondents was reported. A second study conducted on the original study group five years later was again limited to employed workers, as those who had left the company “ * * * could not be contacted” (Ex. 38-233-3, p. 204). Due to the short follow-up period and the restriction to living workers (still employed or survey respondents), these studies are not well suited to identify lung cancer cases.

Post-hearing comments stated that “ * * * OSHA has failed to even consider specific epidemiological studies performed on stainless steel production workers and welders that would be far more relevant than the chromate production studies OSHA relied upon for its analysis” (Ex. 47-5, p. 10). In particular, they suggest that OSHA should consider a study by Danielsen et al. (1996) on Norweigian boiler welders and a study by Moulin et al. (1990) on French stainless steel production workers (Ex. 47-5, p. 10). However, the Moulin et al. study (Ex. 35-282), was discussed in the Preamble to the Proposed Rule (69 FR at 59339). OSHA concluded that the association between Cr(VI) and respiratory tract cancer in this and similar studies is difficult to assess because of co-exposures to other potential carcinogens such as asbestos, polycyclic aromatic hydrocarbons, nickel, and the lack of information on smoking (69 FR at 59339).

The Danielsen et al. study was not evaluated in the NPRM, but is similar to other studies of welders evaluated by OSHA in which excess risk of lung cancer did not appear to be associated with stainless steel welding. In Danielsen et al., as in most other welding studies, no quantitative information on Cr(VI) exposure was available, there was potential confounding by smoking and asbestos exposure, and there appeared to be an overall healthy worker effect in the study (625 deaths vs. 659 expected). Therefore, OSHA does not believe that Danielsen et al. contributes significant information beyond that in the studies that are reviewed in Section V.B.4 of this preamble. OSHA's interpretation and conclusions regarding the general findings of welding cohort studies, discussed below in the context of comments submitted by the Electric Power Research Institute, apply to the results of Danielsen et al. as well.

The Electric Power Research Institute (EPRI), Exponent, and others submitted comments to OSHA that questioned whether the Agency's exposure-response model, based on the Gibb and Luippold chromate production industry cohorts, should be used to estimate lung cancer risks to welders exposed to Cr(VI) (Exs. 38-8; 38-233-4; 39-25, pp. 2-3). EPRI stated that:

OSHA's review of the toxicology, epidemiology, and mechanistic data associated with health effects among welders was thorough and accurate. We concur with the selection of the two focus cohorts (Luippold et al. 2003 and Gibb et al. 2000) as the best data available upon which to base an estimate of the exposure-response relationship between occupational exposure to Cr(VI) and an increased lung cancer risk”; however * * * it may be questionable whether that relationship should be used for stainless steel welders given that a positive relationship between exposure to Cr(VI) and lung cancer risk was not observed in most studies of welder cohorts (Ex. 38-8, pp. 6-7).

EPRI's concerns, like other comments submitted to OSHA on risk to welders, are based primarily on the results of the Gerin et al. (1993) study and on several studies comparing stainless steel and mild steel welders.

As discussed above in Section V., Gerin et al. (1993) is the only available study that attempts to relate estimated cumulative Cr(VI) exposure and lung cancer risk among welders. While excess lung cancer risks were found among stainless steel welders, there was no clear relationship observed between the estimated amount of Cr(VI) exposure and lung cancer (Ex. 38-8, p. 8). This led the authors to suggest that the elevated risks might be “ * * * related to other exposures such as cigarette smoking, background asbestos exposure at work or other occupational or environmental risks * * * ” rather than to Cr(VI) exposure. On the other hand, Gerin et al. stated that “ * * * the welding fume exposures in these Start Printed Page 10217populations may be too low to demonstrate a gradient of risk”, or misclassification of exposure might obscure the dose-response relationship (Ex. 7-120, pp. S25-S26), a point with which EPRI expressed agreement (Ex. 38-8, p. 8).

OSHA agrees with Gerin et al. that co-exposures to carcinogens such as nickel, asbestos, and cigarette smoke may have contributed to the elevated lung cancer risks among welders. OSHA also agrees with the authors that exposure misclassification may explain the absence of a clear relationship between Cr(VI) and lung cancer in this study. Gerin et al. derived their exposure data primarily from literature on welding fume, as well as from a limited number of industrial hygiene measurements taken in the mid 1970s in eight of the 135 companies participating in the study (Ex. 7-120, p. S24, p. S27). Their exposure estimates took account of the welding process used and the base metal welded by individuals in the cohort, but they apparently had no information on other important items, such as the size of the work piece and weld time, which were identified by EPRI as factors affecting the level of Cr(VI) exposure from welding (Ex. 38-8, p. 5).

EPRI also identified ventilation as a particularly important determinant of exposure (Ex. 38-8, p. 5). Gerin et al. did not appear to have individual information on ventilation use for their exposure estimates, relying instead on “information on the history of welding practice * * * obtained from each company on the basis of an ad hoc questionnaire” that described for each company the average percent of time that welders used local ventilation, operated in confined or open areas, and worked indoors or outdoors (Ex. 7-120, p. S23). The use of local ventilation, time spent welding in confined areas, and time spent welding outdoors may have varied considerably from worker to worker within any single company. In this case exposure estimates based on company average information would tend to overestimate exposure for some workers and underestimate it for others, thus weakening the appearance of an exposure-response relationship in the cohort.

Gerin et al. also stated that the average exposure values they estimated do not account for a number of factors which affect welders' exposure levels, including “ * * * type of activity (e.g. maintenance, various types of production), special processes, arcing time, voltage and current characteristics, welder position, use of special electrodes or rods, presence of primer paints and background fumes coming from other activities” (Ex. 7-120, p. S25). They noted that the resulting difficulty in the construction of individual exposure estimates is exacerbated by aggregation of data across small cohorts from many different companies that may have different exposure conditions (Ex. 7-120, p. S25). According to Gerin et al., exposure misclassification of this sort may have obscured a dose-response relationship in this cohort (Ex. 7-120, p. S25). The authors suggest that their estimates should be checked or corrected “ * * * with data coming from well-documented industrial hygiene studies or industrial hygiene data banks including information on the major relevant factors” (Ex. 7-120, p. S26). OSHA believes that there is insufficient information to determine why a clear relationship between Cr(VI) exposure and lung cancer is not observed in the Gerin et al. study, but agrees with the authors that exposure misclassification and the influence of background exposures may explain this result.

EPRI noted the apparent lack of a relationship between exposure duration and lung cancer risk in the Gerin et al. cohort (Ex. 38-8, p. 10). Duration of exposure is expected to show a relationship with cancer risk if duration serves as a reasonable proxy for a measure of exposure (e.g. cumulative exposure) that is related to risk. Since cumulative exposure is equal to exposure duration multiplied by average exposure level, duration of exposure may correlate reasonably well with cumulative exposure if average exposure levels are similar across workers, or if workers with longer employment tend to have higher average exposure levels. In a cohort where exposure duration is believed to correlate well with cumulative exposure, the absence of a relationship between exposure duration and disease risk could be interpreted as evidence against a relationship between cumulative exposure and risk.

High variation in average exposures among workers, unrelated to the duration of their employment, would tend to reduce the correlation between exposure duration and cumulative exposure. If, as EPRI states, Cr(VI) exposure depends strongly on process, base metal, and other work conditions that vary from workplace to workplace, then duration of exposure may not correlate well with cumulative exposure across the 135 companies included in the Gerin et al. study. The lack of a positive relationship between exposure duration and lung cancer in the Gerin et al. cohort may therefore signify that duration of exposure is not a good proxy for the amount of exposure accumulated by workers, and should not be interpreted as evidence against an exposure-response relationship.

In post-hearing comments Mr. Robert Park of NIOSH discussed other issues related to exposure duration in the Gerin et al. and other welding cohorts:

Several factors may impact the interpretation of [the Gerin et al. (1993) and Simonato et al. (1991) welder cohort studies] and are consistent with an underlying risk associated with duration * * *. The healthy worker survivor effect is a form of confounding in which workers with long employment durations systematically diverge from the overall worker population on risk factors for mortality. For example, because smoking is a risk factor for disease, disability and death, long duration workers would tend to have a lower smoking prevalence, and hence lower expected rates of diseases that are smoking related, like lung cancer. Not taking this into account among welders might result in long duration welders appearing to have diminished excess risk when, in fact, excess risk continues to increase with time (Ex. 47-19-1, p. 6).

Mr. Park also emphasized the special importance of detailed information for individual workers in multi-employer studies with exposure conditions that vary widely across employers. He notes that high worker turnover in highly exposed jobs “ * * * could result in long duration welding employment appearing to have lower risk than some shorter duration [welding] employment when it does not” (Ex. 47-19-1, p. 6).

EPRI compared the risk of lung cancer among a subset of workers in the Gerin cohort exposed to high cumulative levels of Cr(VI) to the risk found among chromate production workers in the Gibb et al. and Luippold et al. studies. “Focusing on the highest exposure group, SMRs for the cohorts of stainless steel workers studied by Gerin et al (1993) * * * range from 133 to 148 for exposures >1.5 mg-yrs/m3 * * *. By comparison, the SMR from the Luippold et al. (2003) cohort is 365 for cumulative exposures of 1.0 to 2.69 mg-yrs/m3”, a difference that EPRI argues “ * * * draws into question whether the exposure-specific risk estimates from the chromate production industry can be extrapolated to welders” (Ex. 38-8, p. 25). It is not clear why EPRI chose to focus on the high exposure group, which had a minimum of 1.5 mg/m3-years cumulative Cr(VI) exposure, a mean of 2.5 mg/m3-years, and no defined upper limit. Compared to the other exposure groups described by Gerin et al., this group is likely to have had more heterogenous exposure levels; may be expected to have a stronger Start Printed Page 10218healthy worker effect due to the association between high cumulative exposure and long employment history; and is the least comparable to either workers exposed for a working lifetime at the proposed PEL (1 μg/m3 * 45 years = 0.045 mg/m3-years cumulative exposure) or welders in modern-day working conditions, who according to an IARC review cited in EPRI's comments typically have exposure levels less than 10 μg/m3 (< 0.45 mg/m3-years cumulative exposure over 45 years) (Ex. 38-8, p. 4). In addition, the majority of the observation time in the Luippold et al. cohort and the vast majority in the Gibb et al. cohort is associated with exposure estimates lower than 1.5 mg/m3-years Cr(VI) (Ex. 33-10, p. 455, Table 3; 25, p. 122, Table VI).

It should be noted that the levels of excess lung cancer risk observed among welders in the Gerin et al. cohort and chromate production workers in the Gibb and Luippold cohorts are quite similar at lower cumulative exposure ranges that are more typical of Cr(VI) exposures experienced in the cohorts. For example, the group of welders with estimated cumulative exposures ranging from 50 to 500 μg-yrs/m3 has an SMR of 230. Chromate production workers from the Gibb and Luippold cohorts with cumulative exposures within this range have comparable SMRs, ranging from 184 to 234, as shown in Table VI-11 below. For reference, 45 years of occupational exposure at approximately 1.1 μg/m3 Cr(VI) would result in a cumulative exposure of 50 μg-yrs/m3; 45 years of occupational exposure at approximately 11.1 μg/m3 Cr(VI) would result in a cumulative exposure of 500 μg-yrs/m3.

OSHA performed an analysis comparing the risks predicted by OSHA's models, based on the Gibb and Luippold data collected on chromate production workers, with the lung cancer deaths reported for the welders in the Gerin et al. study. Gerin et al. presented observed and expected lung cancer deaths for four categories of cumulative exposure: <50 μg-yrs/m3, 50-500 μg-yrs/m3, 500-1500 μg-yrs/m3, and 1500+ μg-yrs/m3. The great majority of the Gerin et al. data on stainless steel welders (98% of person-years) are in the highest three categories, while the lowest category is extremely small (<300 person-years of observation). OSHA's preferred risk models (based on the Gibb and Luippold cohorts) were used to predict lung cancer risk for each of the three larger exposure categories. The OSHA predictions were derived using the mean values from each exposure range, except for the open-ended highest category, for which Gerin et al. reported a mean exposure level of 2500 μg-yrs/m3 (Ex. 7-120, p. S26). The ratio of predicted to background lung cancer deaths, which approximately characterizes the expected SMRs for these exposure groups, was calculated for each group.

The OSHA model predictions were calculated assuming that workers were first exposed to Cr(VI) at age 29, the average age at the start of employment reported by Gerin et al. (Ex. 7-120, p. S26). The SMRs reported by Gerin et al. were calculated for welders with at least five years of employment and at least 20 years of follow-up. However, the average duration of employment and follow-up was not evident from the publication. The OSHA model predictions were therefore calculated using a range of reasonable assumptions about the duration of employment over which workers were exposed (5, 10, 15, and 20 years) and the length of follow-up (30, 40, and 50 years).

Table VI-12 below presents the SMRs reported by Gerin et al. for stainless steel welders in the three highest exposure categories, together with the ratio of predicted to background lung cancer deaths from OSHA's risk models. It should be noted that the ratio was calculated using year 2000 U.S. lung cancer mortality rates, while the SMRs reported by Gerin et al. were calculated using national lung cancer mortality rates for the nine European countries represented in the study (Ex. 7-114).

Start Printed Page 10219

Table VI-12 shows that the range of risk ratios predicted by OSHA's model is higher than the ratios reported for the highest exposure group in the Gerin et al. cohort, consistent with EPRI's observations (Ex. 38-8, p. 25). However, the risk ratios predicted by OSHA's model are consistent with the Gerin SMRs for the 500-1500 μg-yrs/m3 cumulative exposure range. For the 50-500 μg-yrs/m3 cumulative exposure range, the OSHA prediction falls slightly below the lung cancer mortality ratio observed for the Gerin et al. cohort. The OSHA predictions for each group overlap with the 95% confidence intervals of the Gerin et al. SMRs, suggesting that sampling error may partly account for the discrepancies between the observed and predicted risk ratios in the lowest and highest exposure groups.

As previously discussed, OSHA believes that the lack of a clear exposure-response trend in the Gerin et al. study may be partly explained by exposure misclassification. As shown in Table VI-12, the highest exposure group has lower risk than might be expected based on OSHA's preferred risk models, while the lowest exposure group appears to have higher risk than OSHA's models would predict. This overall pattern of generally elevated but non-increasing SMRs across the three larger exposure groups in the Gerin study is consistent with potentially severe exposure misclassification. The higher-than-predicted risks among welders in the lowest exposure group could similarly reflect misclassification. However, it is not possible to determine with certainty that exposure misclassification is the cause of the differences between the risk predicted by OSHA's model and that observed in the Gerin cohort.

Finally, EPRI cites the generally similar relative risks found among stainless steel and mild steel welders as further evidence that exposure to Cr(VI) may not carry the same risk of lung cancer in welding operations as it does in the chromate production industry. EPRI states:

[I]t is reasonable to expect that if Cr(VI) were a relevant risk factor for welders in the development of lung cancer, and certain types of welding involve Cr(VI) more than other types, then subgroups of welders who are more exposed to Cr(VI) by virtue of the type of welding they do should have higher rates of lung cancer than welders not exposed to Cr(VI) in their welding occupation;

in particular, “ * * *stainless steel welders should have a higher risk of lung cancer than welders of mild steel” (Ex. 38-8, p. 13). OSHA believes that EPRI's point would be correct if the subgroups in question are similar in terms of other important risk factors for lung cancer, such as smoking, co-exposures, and overall population health. However, no analysis comparing stainless steel welders with mild steel welders has properly controlled for these factors, and in fact there have been indications that mild steel welders may be at greater risk of lung cancer than stainless steel welders from non-occupational causes. As discussed by EPRI, “[r]esults from cohort studies of stainless steel welders with SMRs much less than 100 support an argument that the healthy worker effect might be more marked among stainless steel workers compared to mild steel welders'; also “ * * *stainless steel welders are generally more qualified and paid more than other welders” (Ex. 38-8, p. 16), a socioeconomic factor that suggests possible differences in lung cancer risk due to smoking, community exposures, or occupational exposures from employment other than welding.

Comments submitted by Exponent (Ex. 38-233-4) and EPRI (Ex. 38-8) compare the Cr(VI) compounds found in welding fumes and those found in the chromate production environments of the Gibb and Luippold cohorts. Exponent stated that “[t]he forms of Cr(VI) to which chromate production workers were historically exposed are primarily the soluble potassium and sodium chromates” found in stainless steel welding fumes. Less soluble forms of Cr(VI) are also found in stainless steel welding fumes in limited amounts, as discussed in the 1990 IARC monograph on welding (Ex. 35-242, p. 460), and are believed to have been present in limited amounts at the plants where the Gibb and Luippold workers were employed (Ex. 38-233-4, p. 4). Exponent concludes that, while it is difficult to compare the exposures of welders to chromate production workers, “ * * *there is no obvious difference * * * in solubility * * * ” that would lead to a significantly lesser risk from Cr(VI) exposure in welding as compared to the Gibb and Luippold cohort exposures (Ex. 38-233-4, p. 3, p. 11). OSHA believes that the similarity in the solubility of Cr(VI) exposures to welders and chromate production workers supports the Agency's use of its risk model to describe Cr(VI)-related risks to welders.

Exponent and others (Exs. 38-8; 39-25) commented on the possibility that the bioavailability of Cr(VI) may nevertheless differ between welders and chromate production workers, stating that “ * * * bioavailability of Cr(VI)-containing particles from welding fumes may not be specifically related to solubility of the Cr(VI) chemical species in the fume” (Ex. 38-233-4, p. 11). In this case, Exponent argues,

delivered doses of Cr(VI) to the lung could be quite dissimilar among welders as compared to chromate production industry workers exposed to the same Cr(VI) chemical species at the same Cr(VI) airborne concentrations (Ex. 38-233-4, p. 11).

However, Exponent provided no data or plausible rationale that would support a Cr(VI) bioavailability difference between chromate production and welding. The low proportion of respirable Cr(VI) particles that apparently limits bioavailability of inhaled Cr(VI) during aircraft spray priming operations described previously is not an issue with welding. High temperature welding generates fumes of small Start Printed Page 10220respirable-size Cr(VI) particles able to penetrate the bronchoalveolar region of the lung. OSHA finds no evidence indicating that Cr(VI) from welding is less bioavailable than Cr(VI) from soluble chromate production.

In summary, OSHA agrees with EPRI and other commenters that evidence of an exposure-response relationship is not as strong in studies of Cr(VI)-exposed welders compared to studies of chromate production workers. OSHA believes that the available welding studies are less able to detect an exposure-response relationship, due to the potentially severe exposure misclassification, occupational exposure to other cancer causing agents, and the general lack of information with which to control for any differences in background lung cancer risk between Cr(VI)-exposed and unexposed welders. In contrast, the two featured cohorts had sufficient information on workers' Cr(VI) exposures and potential confounding exposures to support a reliable exposure-response assessment. These are the primary factors that led OSHA to determine (like EPRI and Exponent) that the Luippold and Gibb cohorts are the best data available on which to base a model of exposure-response between Cr(VI) and lung cancer (Exs. 38-8, p. 6; 38-233-4, p. 1). Moreover, EPRI admitted that examination of “ * * * the forms of Cr(VI) to which welders are exposed, exposure concentrations, and other considerations such as particle size * * * ” identified “ * * * no specific basis * * * ” for a difference in Cr(VI)-related lung cancer risk among welders and the Gibb and Luippold chromate production cohorts (Ex. 38-8, p. 7). OSHA concludes that it is reasonable and prudent to estimate welders' risk using the exposure-response model developed on the basis of the Gibb et al. and Luippold et al. datasets.

H. Conclusions

OSHA believes that the best quantitative estimates of excess lifetime lung cancer risks are those derived from the data sets described by Gibb et al. and Luippold et al. Both data sets show a significant positive trend in lung cancer mortality with increasing cumulative Cr(VI) exposure. The exposure assessments for these two cohorts were reconstructed from air measurements and job histories over three or four decades and were superior to those of other worker cohorts. The linear relative risk model generally provided the best fit among a variety of different models applied to the Gibb et al. and Luippold et al. data sets. It also provided an adequate fit to three additional data sets (Mancuso, Hayes et al., and Gerin et al.). Thus, OSHA believes the linear relative risk model is the most appropriate model to estimate excess lifetime risk from occupational exposure to Cr(VI). Using the Gibb et al. and Luippold et al. datasets and a linear relative risk model, OSHA concludes that the lifetime lung cancer risk is best expressed by the three-to five-fold range of risk projections bounded by the maximum likelihood estimates from the two featured data sets. This range of projected risks is within the 95 percent confidence intervals from all five data sets.

OSHA does not believe that it is appropriate to employ a threshold dose-response approach to estimate cancer risk from a genotoxic carcinogen, such as Cr(VI). Federal agencies, including OSHA, assume an exposure threshold for cancer risk assessments to genotoxic agents only when there is convincing evidence that such a threshold exists (see e.g. EPA, Guidelines for Carcinogen Risk Assessment, March 2005, pp. 3-21). In addition, OSHA does not consider absence of a statistically significant effect in an epidemiologic or animal study that lacks power to detect such effects to be convincing evidence of a threshold or other non-linearity. OSHA also does not consider theoretical reduction capacities determined in vitro with preparations that do not fully represent physiological conditions within the respiratory tract to be convincing evidence of a threshold. While physiological defense mechanisms (e.g. extracellular reduction, DNA repair, apoptosis) can potentially introduce dose transitions, there is no evidence of a significantly non-linear Cr(VI) dose-lung cancer response in the exposures of interest to OSHA. Finally, as previously discussed, linear no-threshold risk models adequately fit the existing exposure-response data.

The slightly soluble Cr(VI) compounds produced a higher incidence of respiratory tract tumors than highly water soluble or highly water insoluble Cr(VI) compounds in animal studies that tested Cr(VI) compounds under similar experimental conditions. This likely reflects the greater tendency for chromates of intermediate water solubility to provide a persistent high local concentration of solubilized Cr(VI) in close proximity to the target cell. Highly soluble chromates rapidly dissolve and diffuse in the aqueous fluid lining the epithelia of the lung and are more quickly cleared from the respiratory tract. Thus, these chromates are less able to achieve the higher and more persistent local concentrations within close proximity of the lung cell surface than the slightly water soluble chromates. Water insoluble Cr(VI) particulates are also able to come in close contact with the lung cell surface but do not release readily absorbed chromate ions into the biological environment as rapidly. OSHA concludes that slightly soluble Cr(VI) compounds are likely to exhibit a greater degree of carcinogenicity than highly water soluble or water insoluble Cr(VI) when the same dose is delivered to critical target cells in the respiratory tract of the exposed worker. OSHA also believes it reasonable to regard water insoluble Cr(VI) to be of similar carcinogenic potency to highly water soluble Cr(VI) compounds in the absence of convincing scientific evidence to indicate otherwise.

The Gibb and Luippold cohorts were predominantly exposed to highly water-soluble chromates, particularly sodium chromate and dichromate. After evaluating lung cancer rates in other occupational cohort studies with respect to the forms of Cr(VI) in the workplace, reliability in the Cr(VI) exposure data, and the presence of potentially confounding influences (e.g. smoking) and bias (e.g. healthy worker survivor bias) as well as information on solubility, particle size, cell uptake, and other factors influencing delivery of Cr(VI) to lung cells, OSHA finds the risks estimated from the Gibb and Luippold cohorts adequately represent risks to workers exposed to equivalent levels of Cr(VI) compounds in other industries.

As with any risk assessment, there is some degree of uncertainty in the projection of risks that results from the data, assumptions, and methodology used in the analysis. The exposure estimates in the Gibb et al. and Luippold et al. data sets relied, to some extent, on a paucity of air measurements using less desirable sampling techniques to reconstruct Cr(VI) exposures, particularly in the 1940s and 1950s. Additional uncertainty is introduced when extrapolating from the cohort exposures, which usually involved exposures to higher Cr(VI) levels for shorter periods of time to an equivalent cumulative exposure involving a lower level of exposure for a working lifetime. The study cohorts consisted mostly of smokers, but detailed information on their smoking behavior was unavailable. While the risk assessments make some adjustments for the confounding effects of smoking, it is unknown whether the assessments fully account for any interactive effects that smoking and Cr(VI) exposure may have on Start Printed Page 10221carcinogenic action. In any case, OSHA does not have reason to believe the above uncertainties would introduce errors that would result in serious overprediction or underprediction of risk.

OSHA's estimate of lung cancer risk from a 45 year occupational exposure to Cr(VI) at the previous PEL of 52 μg/m3 is 101 to 351 excess deaths per 1000 workers. This range, which is defined by maximum likelihood estimates based on the Gibb and Luippold epidemiological cohorts, is OSHA's best estimate of excess risk. It does not account for statistical uncertainty, or for other potential sources of uncertainty or bias. The wider range of 62 to 493 excess deaths per 1000 represents the statistical uncertainty associated with OSHA's excess risk estimate at the previous PEL, based on lowest and highest 95% confidence bounds on the maximum likelihood estimates for the two featured data sets. The excess lung cancer risks at alternative 8 hour TWA PELs that were under consideration by the Agency were previously shown in Table VI-7, together with the uncertainty bounds for the primary and supplemental studies at these exposure concentrations. The 45-year exposure estimates satisfy the Agency's statutory obligation to consider the risk of material impairment for an employee with regular exposure to the hazardous agent for the period of his working life (29 U.S.C. 651 et seq.). Occupational risks from Cr(VI) exposure to less than a full working lifetime are considered in Section VII on the Significance of Risk and in Section VIII on the Benefits Analysis.

VII. Significance of Risk

In promulgating health standards, OSHA uses the best available information to evaluate the risk associated with occupational exposures, to determine whether this risk is severe enough to warrant regulatory action, and to determine whether a new or revised rule will substantially reduce this risk. OSHA makes these findings, referred to as the “significant risk determination”, based on the requirements of the OSH Act and the Supreme Court's interpretation of the Act in the “benzene” decision of 1980 (Industrial Union Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607). The OSH Act directs the Secretary of Labor to:

set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard * * * for the period of his working life [6(b)(5)].

OSHA's authority to promulgate regulations to protect workers is limited by the requirement that standards be “reasonably necessary and appropriate to provide safe or healthful employment” [3(8)].

In the benzene decision, the Supreme Court's interpretation of Section 3(8) further defined OSHA's regulatory authority. The Court stated:

By empowering the Secretary to promulgate standards that are “reasonably necessary or appropriate to provide safe or healthful employment and places of employment,” the Act implies that, before promulgating any standard, the Secretary must make a finding that the workplaces in question are not safe (IUD v. API 448 U.S. at 642).

“But ‘safe’ is not the equivalent of ‘risk-free’ ”, the Court maintained. “[T]he Secretary is required to make a threshold finding that a place of employment is unsafe-in the sense that significant risks are present and can be eliminated or lessened by a change in practices” (IUD v. API, 448 U.S. at 642). It has been Agency practice in regulating health hazards to establish this finding by estimating risk to workers using quantitative risk assessment, and determining the significance of this risk based on judicial guidance, the language of the OSH Act, and Agency policy considerations.

The Agency has considerable latitude in defining significant risk and in determining the significance of any particular risk. The Court did not stipulate a means to distinguish significant from insignificant risks, but rather instructed OSHA to develop a reasonable approach to the significant risk determination. The Court stated that “it is the Agency's responsibility to determine in the first instance what it considers to be a ‘significant’ risk”, and it did not express “any opinion on the* * *difficult question of what factual determinations would warrant a conclusion that significant risks are present which make promulgation of a new standard reasonably necessary or appropriate” (448 U.S. at 659). The Court also stated that, while OSHA's significant risk determination must be supported by substantial evidence, the Agency “is not required to support the finding that a significant risk exists with anything approaching scientific certainty” (448 U.S. at 656). Furthermore,

A reviewing court [is] to give OSHA some leeway where its findings must be made on the frontiers of scientific knowledge [and] * * * the Agency is free to use conservative assumptions in interpreting the data with respect to carcinogens, risking error on the side of overprotection rather than underprotection [so long as such assumptions are based on] a body of reputable scientific thought (448 U.S. at 655, 656).

To make the significance of risk determination for a new or proposed standard, OSHA uses the best available scientific evidence to identify material health impairments associated with potentially hazardous occupational exposures, and, when possible, to provide a quantitative assessment of exposed workers' risk of these impairments. OSHA has reviewed extensive epidemiological and experimental research pertaining to adverse health effects of occupational Cr(VI) exposure, including lung cancer, and has established quantitative estimates of the excess lung cancer risk associated with previously allowable Cr(VI) exposure concentrations and the expected impact of the new PEL. OSHA has determined that long-term exposure at the previous PEL would pose a significant risk to workers' health, and that adoption of the new PEL and other provisions of the final rule will substantially reduce this risk.

A. Material Impairment of Health

As discussed in Section V of this preamble, there is convincing evidence that exposure to Cr(VI) may cause a variety of adverse health effects, including lung cancer, nasal tissue damage, asthma, and dermatitis. OSHA considers these conditions to be material impairments of health, as they are marked by significant discomfort and long-lasting adverse effects, can have adverse occupational and social consequences, and may in some cases have permanent or potentially life-threatening consequences. Based on this finding and on the scientific evidence linking occupational Cr(VI) to each of these effects, OSHA concludes that exposure to Cr(VI) causes “material impairment of health or functional capacity” within the meaning of the OSH Act.

1. Lung Cancer

OSHA considers lung cancer, an irreversible and frequently fatal disease, to be a clear material impairment of health. OSHA's finding that inhaled Cr(VI) causes lung cancer is based on the best available epidemiological data, reflects substantial evidence from animal and mechanistic research, and is consistent with the conclusions of other government and public health organizations, including NIOSH, EPA, Start Printed Page 10222ACGIH, NTP, and IARC (Exs. 35-117; 35-52; 35-158; 17-9-D; 18-3, p. 213). The Agency's primary evidence comes from two epidemiological studies that show significantly increased incidence of lung cancer among workers in the chromate production industry (Exs. 25; 33-10). The high quality of the data collected in these studies and the analyses performed on them has been confirmed by OSHA and by independent peer review. Supporting evidence of Cr(VI) carcinogenicity comes from occupational cohort studies in chromate production, chromate pigment production, and chromium plating, and by cell culture research into the processes by which Cr(VI) disrupts normal gene expression and replication. Studies demonstrating uptake, metabolism, and genotoxicity of a variety of soluble and insoluble Cr(VI) compounds support the Agency's position that all Cr(VI) compounds should be regulated as occupational carcinogens (Exs. 35-148; 35-68; 35-67; 35-66; 12-5; 35-149; 35-134).

2. Non-Cancer Impairments

While OSHA has relied primarily on the association between Cr(VI) inhalation and lung cancer to demonstrate the necessity of the standard, the Agency has also determined that several other material health impairments can result from exposure to airborne Cr(VI). As shown in several cross-sectional and cohort studies, inhalation of Cr(VI) can cause ulceration of the nasal passages and perforation of the nasal septum (Exs. 35-1; 7-3; 9-126; 35-10; 9-18; 3-84; 7-50; 31-22-12). Nasal tissue ulcerations are often accompanied by swelling and bleeding, heal slowly, and in some cases may progress to a permanent perforation of the nasal septum that can only be repaired surgically. Inhalation of Cr(VI) may also lead to asthma, a potentially life-threatening condition in which workers become allergic to Cr(VI) compounds and experience symptoms such as coughing, wheezing, and difficulty in breathing upon exposure to small amounts of airborne Cr(VI). Several case reports have documented asthma from Cr(VI) exposure in the workplace, supporting Cr(VI) as the sensitizing agent by bronchial challenge (Exs. 35-7; 35-12; 35-16; 35-21).

During the comment period, NIOSH requested that OSHA consider allergic contact dermatitis (ACD) as a material impairment of health due to occupational exposure to Cr(VI). NIOSH reasoned:

Dermal exposure to Cr(VI) through skin contact * * * may lead to sensitization or allergic contact dermatitis. This condition, while not life-threatening, is debilitating and marked by significant discomfort and long-lasting adverse effects; it can have adverse occupational and social consequences and should be a material impairment to the health of affected workers * * * Including allergic contact dermatitis in OSHA's determination of material impairment of health draws attention to the fact that Cr(VI) is both a dermal exposure hazard and an inhalation hazard, and alerts employers that they should seek to minimize exposure to both routes (Ex. 40-10-2, p. 3)

OSHA fully agrees with the NIOSH comment. There is strong evidence that unprotected skin contact with Cr(VI)-containing materials and solutions can cause ACD as well as irritant dermatitis and skin ulceration (see section V.D). ACD is a delayed hypersensitivity response. The worker initially becomes sensitized to Cr(VI) following dermal exposure. Once a worker becomes sensitized, brief exposures to small amounts of Cr(VI) can trigger symptoms such as redness, swelling, itching, and scaling. ACD is characterized by the initial appearance of small raised papules that can later develop into blisters and dry thickened, cracked skin. The allergic condition is persistent, causing some workers to leave their jobs (Ex. 35-320). Symptoms of ACD frequently continue long after occupational exposure to Cr(VI) ends, since sensitized individuals can react to contact with Cr(VI) in consumer products and other non-occupational sources.

Skin exposure to Cr(VI) compounds can also cause a non-allergic form of dermatitis. This skin impairment results from direct contact with Cr(VI) doses that damage or irritate the skin, but do not involve immune sensitization. This form of dermatitis can range from mild redness to severe burns and ulcers, known as “chrome holes”, that penetrate deep into tissues. Once the worker is removed from exposure, the skin ulcers heal slowly, often with scarring.

B. Risk Assessment

When possible, epidemiological or experimental data and statistical methods are used to characterize the risk of disease that workers may experience under the currently allowable exposure conditions, as well as the expected reduction in risk that would occur with implementation of the new PEL. The Agency finds that the available epidemiological data are sufficient to support quantitative risk assessment for lung cancer among Cr(VI)-exposed workers. Using the best available studies, OSHA has identified a range of expected risk from regular occupational exposure at the previous PEL (101-351 excess lung cancer deaths per 1000 workers) and at the new PEL of 5 μg/m3 (10-45 per 1000 workers), assuming a working lifetime of 45 years' exposure in each case. These values represent the best estimates of multiple analysts working with data from two extensively studied worker populations, and are highly consistent across analyses using a variety of modeling techniques and assumptions. While some attempts have been made to assess the relationship between Cr(VI) exposure level and noncancer adverse health effects, the Agency does not believe that a reliable quantitative risk assessment can be performed for noncancer effects at this time, and has therefore characterized noncancer risk qualitatively.

For estimates of lung cancer risk from Cr(VI) exposure, OSHA has relied upon data from two cohorts of chromate production workers. The Gibb cohort, which originates from a chromate production facility in Baltimore, Maryland, includes 2357 workers who began work between 1950 and 1974 and were followed up through 1992 (Ex. 33-11). The extensive exposure documentation available for this cohort, the high statistical power afforded by the large cohort size, and the availability of information on individual workers' race and smoking status provide a strong basis for risk analysis. The Luippold cohort, from a facility in Painesville, Ohio, includes 482 workers who began work between 1940 and 1972, worked for at least one year at the plant, and were followed up through 1997 (Ex. 33-10). This cohort also provides a strong basis for risk analysis, in that it has high-quality documentation of worker Cr(VI) exposure and mortality, a long period of follow-up, and a large proportion of relatively long-term employees (55% were employed for longer than 5 years).

1. Lung Cancer Risk Based on the Gibb Cohort

Risk assessments were performed on the Gibb cohort data by Environ International Corporation (Ex. 33-12), under contract with OSHA; Park et al., as part of an ongoing effort by NIOSH (Ex. 33-13); and Exponent on behalf of the Chrome Coalition (Ex. 31-18-15-1). A variety of statistical models were considered, allowing OSHA to identify the most appropriate models and assess the resulting risk estimates' sensitivity to alternate modeling approaches. Models were tried with additive and relative risk assumptions; various exposure groupings and lag times; linear and nonlinear exposure-response functions; external and internal Start Printed Page 10223standardization; reference lung cancer rates from city-, state-, and national-level data; inclusion and exclusion of short-term workers; and a variety of ways to control for the effects of smoking. OSHA's preferred approach, a relative risk model using Baltimore lung cancer reference rates, and NIOSH's preferred approach, a relative risk model using detailed smoking information and U.S. lung cancer reference rates, are among several models that use reasonable assumptions and provide good fits to the data. As discussed in section VI, the Environ, Park et al., and linear Exponent models yield similar predictions of excess risk from exposure at the previous PEL and the new PEL (see Tables VI-2 and VI-3). OSHA's preferred models (from the Gibb data set) predict about 300-350 excess lung cancers per 1000 workers exposed for a working lifetime of 45 years at the previous PEL and about 35-45 excess lung cancers per 1000 workers at the new PEL of 5 μg/m3.

Environ and Crump et al. performed risk assessments on the Luippold cohort, exploring additive and relative risk models, linear and quadratic exposure-response functions, and several exposure groupings (Exs. 35-59; 35-58). Additive and relative risk models by both analyst groups fit the data adequately with linear exposure-response. All linear models predicted similar excess risks, from which OSHA has selected preferred estimates based on the Crump et al. analysis of about 100 excess lung cancer deaths per 1000 workers exposed for 45 years at the previous PEL, and ten excess lung cancer deaths per 1000 workers at the new PEL.

2. Lung Cancer Risk Based on the Luippold Cohort

The risk assessments performed on the Luippold cohort yield somewhat lower estimates of lung cancer risk than those performed on the Gibb cohort. This discrepancy is probably not due to statistical error in the risk estimates, as the confidence intervals for the estimates do not overlap. The risk estimates based on the Gibb and Luippold cohorts are nonetheless reasonably close. OSHA believes that both cohorts support reasonable estimates of lung cancer risk, and based on their results has selected a representative range of 101-351 per 1000 for 45 years' occupational exposure at the previous PEL and 10-45 per 1000 for 45 years' occupational exposure at the new PEL for the significant risk determination. OSHA's confidence in these risk estimates is further strengthened by the results of the independent peer review to which the risk assessment was submitted, which supported the Agency's approach and results. OSHA also received several comments in support of its risk estimates (Exs. 44-7, 38-222; 39-73-1). A full analysis of major comments on the results of OSHA's quantitative risk assessment can be found in section VI.F.

3. Risk of Non-Cancer Impairments

Although nasal damage and asthma may be associated with occupational exposure to airborne Cr(VI), OSHA has determined that there are insufficient data to support a formal quantitative risk assessment for these effects. Available occupational studies of Cr(VI)-induced nasal damage are either of cross-sectional study design, do not provide adequate data on short-term airborne Cr(VI) exposure over an entire employment period, or do not account for possible contribution from hand-to-nose transfer of Cr(VI) (Exs. 31-22-12; 9-126; 35-10; 9-18). Occupational asthma caused by Cr(VI) has been documented in clinical case reports but asthma occurrence has not been linked to specific Cr(VI) exposures in a well-conducted epidemiological investigation. The Agency has nonetheless made careful use of the best available scientific information in its evaluation of noncancer health risks from occupational Cr(VI) exposure. In lieu of a quantitative analysis linking the risk of noncancer health effects, such as damage to nasal tissue, with specific occupational exposure conditions, the Agency has qualitatively considered information on the extent of these effects and occupational factors affecting risk, as discussed below.

Damage to the nasal mucosa and septum can occur from inhalation of airborne Cr(VI) or transfer of Cr(VI) on workers' hands to the interior of the nose. Epidemiological studies have found varying, but substantial, prevalence of nasal damage among workers exposed to high concentrations of airborne Cr(VI). In the cohort of 2357 chromate production workers studied by Gibb et al., over 60% experienced nasal tissue ulceration at some point during their employment, with half of these workers' first ulcerations occurring within 22 days from the date they were hired (Ex. 31-22-12). The authors found a statistically significant relationship between nasal ulceration and workers' contemporaneous exposures, with about half of the workers who developed ulcerations first diagnosed while employed in a job with average exposure concentrations greater than 20 μg/m3. Nasal septum perforations were reported among 17% of the Gibb cohort workers, and developed over relatively long periods of exposure (median time 172 days from hire date to diagnosis).

A high prevalence of nasal damage was also found in a study of Swedish chrome platers (Ex. 9-126). Platers exposed to average 8-hour Cr(VI) concentrations above 2 μg/m3 with short-term excursions above 20 μg/m3 from work near the chrome bath had a nearly 50 percent prevalence (i.e. 11 out of 24 workers) of nasal ulcerations and septum perforations. These data, along with that from the Gibb cohort, suggest a substantial and clearly significant risk of nasal tissue damage from regular short-term exposures above 20 μg/m3. More than half of the platers (i.e. 8 of 12 subjects) with short-term excursions to somewhat lower Cr(VI) concentrations between 2.5 and 11 μg/m3 had atrophied nasal mucosa (i.e. cellular deterioration of the nasal passages) but not ulcerations or perforations. This high occurrence of nasal atrophy was substantially greater than found among the workers with mean Cr(VI) levels less than 2 μg/m3 (4 out of 19 subjects) and short-term Cr(VI) exposures less than 1 μg/m3 (1 of 10 subjects) or among the office workers not exposed to Cr(VI) (0 of 19 subjects). This result is consistent with a concentration-dependant gradation in response from relatively mild nasal tissue atrophy to the more serious nasal tissue ulceration with short-term exposures to Cr(VI) levels above about 10 μg/m3. For this reason, OSHA believes short-term Cr(VI) exposures regularly exceeding about 10 μg/m3 may still result in a considerable risk of nasal impairment. However, the available data do not allow a precise quantitative estimation of this risk.

While dermal exposure to Cr(VI) can cause material impairment to the skin, a credible quantitative assessment of the risk is not possible because few occupational studies have measured the amounts of Cr(VI) that contact the skin during job activities; studies rarely distinguish dermatitis due to Cr(VI) from other occupational and non-occupational sources of dermatitis; and immune hypersensitivity responses, such as ACD, have an exceedingly complex dose-response.

C. Significance of Risk and Risk Reduction

The Supreme Court's benzene decision of 1980 states that “before he can promulgate any permanent health or safety standard, the Secretary [of Labor] is required to make a threshold finding that a place of employment is unsafe—in the sense that significant risks are Start Printed Page 10224present and can be eliminated or lessened by a change in practices” (IUD v. API, 448 U.S. at 642). The Court broadly describes the range of risks OSHA might determine to be significant:

It is the Agency's responsibility to determine in the first instance what it considers to be a “significant” risk. Some risks are plainly acceptable and others are plainly unacceptable. If, for example, the odds are one in a billion that a person will die from cancer by taking a drink of chlorinated water, the risk clearly could not be considered significant. On the other hand, if the odds are one in a thousand that regular inhalation of gasoline vapors that are 2 percent benzene will be fatal, a reasonable person might well consider the risk significant and take the appropriate steps to decrease or eliminate it. (IUD v. API, 448 U.S. at 655).

The Court further stated, “The requirement that a “significant” risk be identified is not a mathematical straitjacket * * *. Although the Agency has no duty to calculate the exact probability of harm, it does have an obligation to find that a significant risk is present before it can characterize a place of employment as “unsafe”' and proceed to promulgate a regulation (IUD v. API, 448 U.S. at 655).

Table VII-1 presents the estimated excess risk of lung cancer associated with various levels of Cr(VI) exposure allowed under the current rule, based on OSHA's risk assessment and assuming either 20 years' or 45 years' occupational exposure to Cr(VI) as indicated. The purpose of the OSH Act, as stated in Section 6(b), is to ensure “that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard * * * for the period of his working life.” 29 U.S.C. 655(b)(5). Taking a 45-year working life from age 20 to age 65, as OSHA has always done in significant risk determinations for previous standards, the Agency finds an excess lung cancer risk of approximately 100 to 350 per 1000 workers exposed at the previous PEL of 52 μg/m3 Cr(VI). This risk is clearly significant, falling well above the level of risk the Supreme Court indicated a reasonable person might consider acceptable. Even assuming only a 20-year working life, the excess risk of about 50 to 200 per 1000 workers is still clearly significant. The new PEL of 5 μg/m3 Cr(VI) is expected to reduce these risks substantially, to below 50 excess lung cancers per 1000 workers. However, even at the new PEL, the risk posed to workers with a lifetime of regular exposure is still clearly significant.

Workers exposed to concentrations of Cr(VI) lower than the new PEL and for shorter periods of time may also have significant excess cancer risk. The Agency's risk estimates are roughly proportional to duration for any given exposure concentration. The estimated risk to workers exposed at any fixed concentration for 10 years is about one-half the risk to workers exposed for 20 years; the risk for five years' exposure is about one-fourth the risk for 20 years. For example, about 11 to 55 out of 1000 workers exposed at the previous PEL for five years are expected to develop lung cancer as a result of their exposure. Those exposed to 10 μg/m3 Cr(VI) for 5 years have an estimated excess risk of about 2-12 lung cancer deaths per 1000 workers. It is thus not only workers exposed for many years at high levels who have significant cancer risk under the old standard; even workers exposed for shorter periods at levels below the previous PEL are at substantial risk, and will benefit from implementation of the new PEL.

To further demonstrate significant risk, OSHA compares the risk from currently permissible Cr(VI) exposures to risks found across a broad variety of occupations. The Agency has used similar occupational risk comparisons in the significant risk determination for substance-specific standards promulgated since the benzene decision. This approach is supported by evidence in the legislative record that Congress intended the Agency to regulate unacceptably severe occupational hazards, and not “to establish a utopia free from any hazards”(116 Cong. Rec. 37614 (1970), Leg. Hist 480), or to address risks comparable to those that exist in virtually any occupation or workplace. It is also consistent with Section 6(g) of the OSH Act, which states:

In determining the priority for establishing standards under this section, the Secretary shall give due regard to the urgency of the need for mandatory safety and health standards for particular industries, trades, crafts, occupations, businesses, workplaces or work environments.

Fatal injury rates for most U.S. industries and occupations may be obtained from data collected by the Bureau of Labor Statistics. Table VII-2 s