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Proposed Rule

Occupational Exposure to Beryllium and Beryllium Compounds

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AGENCY:

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

ACTION:

Proposed rule; request for comments.

SUMMARY:

The Occupational Safety and Health Administration (OSHA) proposes to amend its existing exposure limits for occupational exposure in general industry to beryllium and beryllium compounds and promulgate a substance-specific standard for general industry regulating occupational exposure to beryllium and beryllium compounds. This document proposes a new permissible exposure limit (PEL), as well as ancillary provisions for employee protection such as methods for controlling exposure, respiratory protection, medical surveillance, hazard communication, and recordkeeping. In addition, OSHA seeks comment on a number of alternatives, including a lower PEL, that could affect construction and maritime, as well as general industry.

DATES:

Written comments. Written comments, including comments on the information collection determination described in Section IX of the preamble (OMB Review under the Paperwork Reduction Act of 1995), must be submitted (postmarked, sent, or received) by November 5, 2015.

Informal public hearings. The Agency will schedule an informal public hearing on the proposed rule if requested during the comment period. The location and date of the hearing, procedures for interested parties to notify the Agency of their intention to participate, and procedures for participants to submit their testimony and documentary evidence will be announced in the Federal Register if a hearing is requested.

ADDRESSES:

Written comments. You may submit comments, identified by Docket No. OSHA-H005C-2006-0870, by any of the following methods:

Electronically: You may submit comments and attachments electronically at http://www.regulations.gov, which is the Federal e-Rulemaking Portal. Follow the instructions on-line for making electronic submissions. When uploading multiple attachments into Regulations.gov, please number all of your attachments because www.Regulations.gov will not automatically number the attachments. This will be very useful in identifying all attachments in the beryllium rule. For example, Attachment 1—title of your document, Attachment 2—title of your document, Attachment 3—title of your document, etc. Specific instructions on uploading all documents are found in the Facts, Answer, Questions portion and the commenter check list on Regulations.gov Web page.

Fax: If your submissions, including attachments, are not longer than 10 pages, you may fax them to the OSHA Docket Office at (202) 693-1648.

Mail, hand delivery, express mail, messenger, or courier service: You may submit your comments to the OSHA Docket Office, Docket No. OSHA-H005C-2006-0870, U.S. Department of Labor, Room N-2625, 200 Constitution Avenue NW., Washington, DC 20210, telephone (202) 693-2350 (OSHA's TTY number is (877) 889-5627). Deliveries (hand, express mail, messenger, or courier service) are accepted during the Docket Office's normal business hours, 8:15 a.m.-4:45 p.m., E.S.T.

Instructions: All submissions must include the Agency name and the docket number for this rulemaking (Docket No. OSHA-H005C-2006-0870). All comments, including any personal information you provide, are placed in the public docket without change and may be made available online at http://www.regulations.gov. Therefore, OSHA cautions you about submitting personal information such as Social Security numbers and birthdates.

If you submit scientific or technical studies or other results of scientific research, OSHA requests (but is not requiring) that you also provide the following information where it is available: (1) Identification of the funding source(s) and sponsoring organization(s) of the research; (2) the extent to which the research findings were reviewed by a potentially affected party prior to publication or submission to the docket, and identification of any such parties; and (3) the nature of any financial relationships (e.g., consulting agreements, expert witness support, or research funding) between investigators who conducted the research and any organization(s) or entities having an interest in the rulemaking. If you are submitting comments or testimony on the Agency's scientific or technical analyses, OSHA requests that you disclose: (1) The nature of any financial relationships you may have with any organization(s) or entities having an interest in the rulemaking; and (2) the extent to which your comments or testimony were reviewed by an interested party before you submitted them. Disclosure of such information is intended to promote transparency and scientific integrity of data and technical information submitted to the record. This request is consistent with Executive Order 13563, issued on January 18, 2011, which instructs agencies to ensure the objectivity of any scientific and technological information used to support their regulatory actions. OSHA emphasizes that all material submitted to the rulemaking record will be considered by the Agency to develop the final rule and supporting analyses.

Docket: To read or download comments and materials submitted in response to this Federal Register notice, go to Docket No. OSHA-H005C-2006-0870 at http://www.regulations.gov, or to the OSHA Docket Office at the address above. All comments and submissions are listed in the http://www.regulations.gov index; however, some information (e.g., copyrighted material) is not publicly available to read or download through that Web site. All comments and submissions are available for inspection at the OSHA Docket Office.

Electronic copies of this Federal Register document are available at http://www.regulations.gov. Copies also are available from the OSHA Office of Publications, Room N-3101, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210; telephone (202) 693-1888. This document, as well as news releases and other relevant information, is also available at OSHA's Web site at http://www.osha.gov.

OSHA has not provided the document ID numbers for all submissions in the record for this beryllium proposal. The proposal only contains a reference list for all submissions relied upon. The public can find all document ID numbers in an Excel spreadsheet that is posted on OSHA's rulemaking Web page (see www.osha.gov/​berylliumrulemaking). The public will be able to locate submissions in the record in the public docked Web page: http://www.regulations.gov. To locate a particular submission contained in http://www.regulations.gov, the public should enter the full document ID number in the search bar.

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FOR FURTHER INFORMATION CONTACT:

For general information and press inquiries, contact Frank Meilinger, Director, Office of Communications, Room N-3647, Start Printed Page 47567OSHA, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210; telephone: (202) 693-1999; email: meilinger.francis2@dol.gov . For technical inquiries, contact: William Perry or Maureen Ruskin, Directorate of Standards and Guidance, Room N-3718, OSHA, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210; telephone (202) 693-1955 or fax (202) 693-1678; email: perry.bill@dol.gov.

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SUPPLEMENTARY INFORMATION:

The preamble to the proposed standard on occupational exposure to beryllium and beryllium compounds follows this outline:

Executive Summary

I. Issues and Alternatives

II. Pertinent Legal Authority

III. Events Leading to the Proposed Standards

IV. Chemical Properties and Industrial Uses

V. Health Effects

VI. Preliminary Risk Assessment

VII. Response to Peer Review

VIII. Significance of Risk

IX. Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis

X. OMB Review under the Paperwork Reduction Act of 1995

XI. Federalism

XII. State-Plan States

XIII. Unfunded Mandates Reform Act

XIV. Protecting Children from Environmental Health and Safety Risks

XV. Environmental Impacts

XVI. Consultation and Coordination with Indian Tribal Governments

XVII. Public Participation

XVIII. Summary and Explanation of the Proposed Standard

(a) Scope and Application

(b) Definitions

(c) Permissible Exposure Limits (PELs)

(d) Exposure Assessment

(e) Beryllium Work Areas and Regulated Areas

(f) Methods of Compliance

(g) Respiratory Protection

(h) Personal Protective Clothing and Equipment

(i) Hygiene Areas and Practices

(j) Housekeeping

(k) Medical Surveillance

(l) Medical Removal

(m) Communication of Hazards to Employees

(n) Recordkeeping

(o) Dates

XIX. References

Executive Summary

OSHA currently enforces permissible exposure limits (PELs) for beryllium in general industry, construction, and shipyards. These PELs were adopted in 1971, shortly after the Agency was created, and have not been updated since then. The time-weighted average (TWA) PEL for beryllium is 2 micrograms per cubic meter of air (μg/m3) as an 8-hour time-weighted average. OSHA is proposing a new TWA PEL of 0.2 μg/m3 in general industry. OSHA is also proposing other elements of a comprehensive health standard, including requirements for exposure assessment, preferred methods for controlling exposure, respiratory protection, personal protective clothing and equipment (PPE), medical surveillance, medical removal, hazard communication, and recordkeeping.

OSHA's proposal is based on the requirements of the Occupational Safety and Health Act (OSH Act) and court interpretations of the Act. For health standards issued under section 6(b)(5) of the OSH Act, OSHA is required to promulgate a standard that reduces significant risk to the extent that it is technologically and economically feasible to do so. See Section II of this preamble, Pertinent Legal Authority, for a full discussion of OSHA legal requirements.

OSHA has conducted an extensive review of the literature on adverse health effects associated with exposure to beryllium. The Agency has also assessed the risk of beryllium-related diseases at the current TWA PEL, the proposed TWA PEL and the alternative TWA PELs. These analyses are presented in this preamble at Section V, Health Effects, Section VI, Preliminary Risk Assessment, and Section VIII, Significance of Risk. As discussed in Section VIII of this preamble, Significance of Risk, the available evidence indicates that worker exposure to beryllium at the current PEL poses a significant risk of chronic beryllium disease (CBD) and lung cancer, and that the proposed standard will substantially reduce this risk.

Section 6(b) of the OSH Act requires OSHA to determine that its standards are technologically and economically feasible. OSHA's examination of the technological and economic feasibility of the proposed rule is presented in the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis (PEA) (OSHA, 2014), and is summarized in Section IX of this preamble, Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis. OSHA has preliminarily concluded that the proposed PEL of 0.2 μg/m3 is technologically feasible for all affected industries and application groups. Thus, OSHA preliminarily concludes that engineering and work practices will be sufficient to reduce and maintain beryllium exposures to the proposed PEL of 0.2 μg/m3 or below in most operations most of the time in the affected industries. For those few operations within an industry or application group where compliance with the proposed PEL cannot be achieved even when employers implement all feasible engineering and work practice controls, the proposed standard would require employers to supplement controls with respirators.

OSHA developed quantitative estimates of the compliance costs of the proposed rule for each of the affected industry sectors. The estimated compliance costs were compared with industry revenues and profits to provide a screening analysis of the economic feasibility of complying with the revised standard and an evaluation of the potential economic impacts. Industries with unusually high costs as a percentage of revenues or profits were further analyzed for possible economic feasibility issues. After performing these analyses, OSHA has preliminarily concluded that compliance with the requirements of the proposed rule would be economically feasible in every affected industry sector.

The Regulatory Flexibility Act, as amended by the Small Business Regulatory Enforcement Fairness Act (SBREFA), requires that OSHA either certify that a rule would not have a significant economic impact on a substantial number of small entities or prepare a regulatory flexibility analysis and hold a Small Business Advocacy Review (SBAR) Panel prior to proposing the rule. OSHA has determined that a regulatory flexibility analysis is needed and has provided this analysis in Chapter IX of the PEA (OSHA, 2014). A summary is provided in Section IX of this preamble, Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis. OSHA also previously held a SBAR Panel for this rule. The recommendations of the Panel and OSHA's response to them are summarized in Section IX of this preamble.

Executive Orders 13563 and 12866 direct agencies to assess all costs and benefits of available regulatory alternatives. Executive Order 13563 emphasizes the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules, and of promoting flexibility. This rule has been designated an economically significant regulatory action under section 3(f)(1) of Executive Order 12866. Accordingly, this proposed rule has been reviewed by the Office of Management and Budget. The remainder of this section summarizes the key findings of the analysis with respect to costs and benefits of the proposed standard, presents alternatives Start Printed Page 47568to the proposed standard, and requests comments on a number of issues.

Table I-1, which is derived from material presented in the PEA, provides a summary of OSHA's best estimate of the costs and benefits of this proposed rule. As shown, this proposed rule is estimated to prevent 96 fatalities and 50 non-fatal beryllium-related illnesses annually once it is fully effective, and the monetized annualized benefits of the proposed rule are estimated to be $576 million using a 3-percent discount rate and $255 million using a 7-percent discount rate. Also as shown in Table I-1, the estimated annualized cost of the rule is $37.6 million using a 3-percent discount rate and $39.1 million using a 7-percent discount rate. This proposed rule is estimated to generate net benefits of $538 million annually using a 3-percent discount rate and $216 million annually using a 7-percent discount rate. These estimates are for informational purposes only and have not been used by OSHA as the basis for its decision concerning the choice of a PEL or of other ancillary requirements for this proposed beryllium rule. The courts have ruled that OSHA may not use benefit-cost analysis or a criterion of maximizing net benefits as a basis for setting OSHA health standards.[1]

Table I-1—Annualized Costs, Benefits and Net Benefits of OSHA's Proposed Beryllium Standard of 0.2 μg/m3

Discount rate3%7%
Annualized Costs
Engineering Controls$9,540,189$10,334,036
Respirators249,684252,281
Exposure Assessment2,208,9502,411,851
Regulated Areas and Beryllium Work Areas629,031652,823
Medical Surveillance2,882,0762,959,448
Medical Removal148,826166,054
Exposure Control Plan1,769,5061,828,766
Protective Clothing and Equipment1,407,3651,407,365
Hygiene Areas and Practices389,241389,891
Housekeeping12,574,92112,917,944
Training5,797,5355,826,975
Total Annualized Costs (Point Estimate)37,597,32539,147,434
Annual Benefits: Number of Cases Prevented
Fatal Lung Cancer4.0
CBD-Related Mortality92.0
Total Beryllium Related Mortality96.0572,981,864253,743,368
Morbidity49.52,844,7701,590,927
Monetized Annual Benefits (midpoint estimate)575,826,633255,334,295
Net Benefits538,229,308216,186,861
Source: OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis.

Both the costs and benefits of Table I-1 reflect the incremental costs and benefits associated with achieving full compliance with the proposed standard. They do not include costs and benefits associated with employers' current exposure control measures or other aspects of the proposed standard they have already implemented. For example, for employers whose exposures are already below the proposed PEL, OSHA's estimated costs and benefits for the proposed standard do not include the costs of their exposure control measures or the benefits of these employers' compliance with the proposed PEL. The costs and benefits of Table I-1 also do not include costs and benefits associated with achieving compliance with existing requirements, to the extent that some employers may currently not be fully complying with applicable regulatory requirements.

I. Issues and Alternatives

In addition to the proposed standard itself, this preamble discusses more than two dozen regulatory alternatives, including various sub-alternatives, to the proposed standard and requests comments and information on a variety of topics pertinent to the proposed standard. The regulatory alternatives OSHA is considering include alternatives to the proposed scope of the standard, regulatory alternatives to the proposed TWA PEL of 0.2 μg/m3 and proposed STEL of 2 μg/m3, a regulatory alternative that would modify the proposed methods of compliance, and regulatory alternatives that affect proposed ancillary provisions. The Agency solicits comment on the proposed phase-in schedule for the various provisions of the standard. Additional requests for comments and information follow the summaries of regulatory alternatives, under the “Issues” heading.

Regulatory Alternatives

OSHA believes that inclusion of regulatory alternatives serves two important functions. The first is to explore the possibility of less costly ways (than the proposed standard) to provide an adequate level of worker protection from exposure to beryllium. The second is tied to the Agency's statutory requirement, which underlies the proposed standard, to reduce significant risk to the extent feasible. Each regulatory alternative presented here is described and analyzed more fully elsewhere in this preamble or in the PEA. Where appropriate, the alternative is included in this preamble at the end of the relevant section of Section XVIII, Summary and Explanation of the Proposed Standard, to facilitate comparison of the alternative to the proposed standard. For example, alternative PELs under consideration by the Agency are presented in the discussion of paragraph (c) in Section XVIII. In addition, all Start Printed Page 47569alternatives are discussed in the PEA, Chapter VIII: Regulatory Alternatives (OSHA, 2014). The costs and benefits of each regulatory alternative are presented both in Section IX of this preamble and in Chapter VIII of the PEA.

The more than two dozen regulatory alternatives, including various sub-alternatives regulatory alternatives under consideration are summarized below, and are organized into the following categories: alternatives to the proposed scope of the standard; alternatives to the proposed PELs; alternatives to the proposed methods of compliance; alternatives to the proposed ancillary provisions; and the timing of the standard.

Scope

OSHA has examined three alternatives that would alter the groups of employers and employees covered by this rulemaking. Regulatory Alternative #1a would expand the scope of the proposed standard to include all operations in general industry where beryllium exists only as a trace contaminant; that is, where the materials used contain no more than 0.1% beryllium by weight. Regulatory Alternative #1b is similar to Regulatory Alternative #1a, but exempts operations where the employer can show that employees' exposures will not meet or exceed the action level or exceed the STEL. Where the employer has objective data demonstrating that a material containing beryllium or a specific process, operation, or activity involving beryllium cannot release beryllium in concentrations at or above the proposed action level or above the proposed STEL under any expected conditions of use, that employer would be exempt from the proposed standard except for recordkeeping requirements pertaining to the objective data. Alternative #1a and Alternative #1b, like the proposed rule, would not cover employers or employees in construction or shipyards.

Regulatory Alternative #2a would expand the scope of the proposed standard to also include employers in construction and maritime. For example, this alternative would cover abrasive blasters, pot tenders, and cleanup staff working in construction and shipyards who have the potential for airborne beryllium exposure during blasting operations and during cleanup of spent media. Regulatory Alternative #2b would update §§ 1910.1000 Tables Z-1 and Z-2, 1915.1000 Table Z, and 1926.55 Appendix A so that the proposed TWA PEL and STEL would apply to all employers and employees in general industry, shipyards, and construction, including occupations where beryllium exists only as a trace contaminant. However, all other provisions of the standard would be in effect only for employers and employees that fall within the scope of the proposed rule. More detailed discussion of Regulatory Alternatives #1a, #1b, #2a, and #2b appears in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, Section XVIII of this preamble, Summary and Explanation, includes a discussion of paragraph (a) that describes the scope of the proposed rule, issues with the proposed scope, and Regulatory Alternatives #1a, #1b, #2a, and #2b.

Another regulatory alternative that would impact the scope of affected industries, extending eligibility for medical surveillance to employees in shipyards, construction, and parts of general industry excluded from the scope of the proposed standard, is discussed along with other medical surveillance alternatives later in this section (Regulatory Alternative #21) and in the discussion of paragraph (k) in this preamble at Section XVIII, Summary and Explanation of the Proposed Standard.

Permissible Exposure Limits

OSHA has examined several regulatory alternatives that would modify the TWA PEL or STEL for the proposed rule. Under Regulatory Alternative #3, OSHA would adopt a STEL of 5 times the proposed PEL. Thus, this alternative STEL would be 1.0 μg/m3 if OSHA adopts a PEL of 0.2 μg/m3; it would be 0.5 μg/m3 if OSHA adopts a PEL of 0.1 μg/m3; and it would be 2.5 µg/m3 if OSHA adopts a PEL of 0.5 µg/m3 (see Regulatory Alternatives #4 and #5). Under Regulatory Alternative #4, the proposed PEL would be lowered from 0.2 μg/m3 to 0.1 μg/m3. Under Regulatory Alternative #5, the proposed PEL would be raised from 0.2 μg/m3 to 0.5 μg/m3. In addition, for informational purposes, OSHA examined a regulatory alternative that would maintain the TWA PEL at 2.0 μg/m3, but all of the other proposed provisions would be required with their triggers remaining the same as in the proposed rule. This alternative is not one OSHA could legally adopt because the absence of a more protective requirement for engineering controls would not be consistent with section 6(b)(5) of the OSH Act. More detailed discussion of these alternatives to the proposed PEL appears in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, in Section XVIII of this preamble, Summary and Explanation of the Proposed Standard, the discussion of proposed paragraph (c) describes the proposed TWA PEL and STEL, issues with the proposed exposure limits, and Regulatory Alternatives #3, #4, and #5.

Methods of Compliance

The proposed standard would require employers to implement engineering and work practice controls to reduce employees' exposures to or below the TWA PEL and STEL. Where engineering and work practice controls are insufficient to reduce exposures to or below the TWA PEL and STEL, employers would still be required to implement them to reduce exposure as much as possible, and to supplement them with a respiratory protection program. In addition, for each operation where there is airborne beryllium exposure, the employer must ensure that one or more of the engineering and work practice controls listed in paragraph (f)(2) are in place, unless all of the listed controls are infeasible, or the employer can demonstrate that exposures are below the action level based on two samples taken seven days apart. Regulatory Alternative #6 would eliminate the engineering and work practice controls provision currently specified in paragraph (f)(2). This regulatory alternative does not eliminate the need for engineering controls to lower exposure levels to or below the TWA PEL and STEL; rather, it dispenses with the mandatory use of certain engineering controls that must be installed above the action level but at or below the TWA PEL.

More detailed discussion of Regulatory Alternative #6 appears in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the discussion of paragraph (f) in Section XVIII of this preamble, Summary and Explanation, provides a more detailed explanation of the proposed methods of compliance, issues with the proposed methods of com­pli­ance, and Regulatory Alternative #6.

Ancillary Provisions

The proposed rule contains several ancillary provisions, including requirements for exposure assessment, personal protective clothing and equipment (PPE), medical surveillance, medical removal, training, and regulated areas or access control. OSHA has examined a variety of regulatory alternatives involving changes to one or more of these ancillary provisions. OSHA has preliminarily determined that several of these ancillary provisions will increase the benefits of the proposed rule, for example, by helping to ensure the TWA PEL is not exceeded Start Printed Page 47570or by lowering the risks to workers given the significant risk remaining at the proposed TWA PEL. However, except for Regulatory Alternative #7 (involving the elimination of all ancillary provisions), OSHA did not estimate changes in monetized benefits for the regulatory alternatives that affect ancillary provisions. Two regulatory alternatives that involve all ancillary provisions are presented below (#7 and #8), followed by regulatory alternatives for exposure monitoring (#9, #10, and #11), for regulated areas (#12), for personal protective clothing and equipment (#13), for medical surveillance (#14 through #21), and for medical removal (#22).

All Ancillary Provisions

During the Small Business Regulatory Fairness Act (SBREFA) process conducted in 2007, the SBAR Panel recommended that OSHA analyze a PEL-only standard as a regulatory alternative. The Panel also recommended that OSHA consider applying ancillary provisions of the standard so as to minimize costs for small businesses where exposure levels are low (OSHA, 2008b). In response to these recommendations, OSHA analyzed Regulatory Alternative #7, a PEL-only standard, and Regulatory Alternative #8, which would only apply ancillary provisions of the beryllium standard at exposures above the proposed PEL of 0.2 µg/m3 or the proposed STEL of 2 µg/m3. Regulatory Alternative #7 would update the Z tables for § 1910.1000, so that the proposed TWA PEL and STEL would apply to all workers in general industry. All other provisions of the proposed standard would be dropped.

As indicated previously, OSHA has preliminarily determined that there is significant risk remaining at the proposed PEL of 0.2 μg/m3. However, the available evidence on feasibility suggests that 0.2 μg/m3 may be the lowest feasible PEL (see Chapter IV of the PEA, OSHA 2014). Therefore, the Agency believes that it is necessary to include ancillary provisions in the proposed rule to further reduce the remaining risk. In addition, the recommended standard provided to OSHA by representatives of the primary beryllium manufacturing industry and the Steelworkers Union further supports the importance of ancillary provisions in protecting workers from the harmful effects of beryllium exposure (Materion and USW, 2012).

Under Regulatory Alternative #8, several ancillary provisions that the current proposal would require under a variety of exposure conditions (e.g., dermal contact; any airborne exposure; exposure at or above the action level) would instead only apply where exposure levels exceed the TWA PEL or STEL. Regulatory Alternative #8 affects the following provisions of the proposed standard:

—Exposure monitoring. Whereas the proposed standard requires annual monitoring where exposure levels are at or above the action level and at or below the TWA PEL, Alternative #8 would require annual exposure monitoring only where exposure levels exceed the TWA PEL or STEL;

— Written exposure control plan. Whereas the proposed standard requires written exposure control plans to be maintained in any facility covered by the standard, Alternative #8 would require only facilities with exposures above the TWA PEL or STEL to maintain a plan;

—PPE. Whereas the proposed standard requires PPE for employees under a variety of conditions, such as exposure to soluble beryllium or visible contamination with beryllium, Alternative #8 would require PPE only for employees exposed above the TWA PEL or STEL;

—Housekeeping. Whereas the proposed standard's housekeeping requirements apply across a wide variety of beryllium exposure conditions, Alternative #8 would limit housekeeping requirements to areas with exposures above the TWA PEL or STEL.

—Medical Surveillance. Whereas the proposed standard's medical surveillance provisions require employers to offer medical surveillance to employees with signs or symptoms of beryllium-related health effects regardless of their exposure level, Alternative #8 would make surveillance available to such employees only if they were exposed above the TWA PEL or STEL.

More detailed discussions of Regulatory Alternatives #7 and #8, including a description of the considerations pertinent to these alternatives, appear in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014).

Exposure Monitoring

OSHA has examined three regulatory alternatives that would modify the proposed standard's provisions on exposure monitoring, which require periodic monitoring annually where exposures are at or above the action level and at or below the TWA PEL. Under Regulatory Alternative #9, employers would be required to perform periodic exposure monitoring every 180 days where exposures are at or above the action level or above the STEL, and at or below the TWA PEL. Under Regulatory Alternative #10, employers would be required to perform periodic exposure monitoring every 180 days where exposures are at or above the action level or above the STEL, including where exposures exceed the TWA PEL. Under Regulatory Alternative #11, employers would be required to perform periodic exposure monitoring every 180 days where exposures are at or above the action level or above the STEL, and every 90 days where exposures exceed the TWA PEL. More detailed discussions of Regulatory Alternatives #9, #10, and #11 appear in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the discussion of proposed paragraph (d) in Section XVIII of this preamble, Summary and Explanation of the Proposed Standard, provides a more detailed explanation of the proposed requirements for exposure monitoring, issues with exposure monitoring, and the considerations pertinent to Regulatory Alternatives #9, #10, and #11.

Regulated Areas

The proposed standard would require employers to establish and maintain two types of areas: beryllium work areas, wherever employees are, or can reasonably be expected to be, exposed to any level of airborne beryllium; and regulated areas, wherever employees are, or can reasonably be expected to be, exposed to airborne beryllium at levels above the TWA PEL or STEL. Employers are required to demarcate beryllium work areas, but are not required to restrict access to beryllium work areas or provide respiratory protection or other forms of PPE within work areas that are not also regulated areas. Employers must demarcate regulated areas, restrict access to them, post warning signs and provide respiratory protection and other PPE within regulated areas, as well as medical surveillance for employees who work in regulated areas for more than 30 days in a 12-month period. During the SBREFA process conducted in 2007, the SBAR Panel recommended that OSHA consider dropping or limiting the provision for regulated areas (OSHA, 2008b). In response to this recommendation, OSHA analyzed Regulatory Alternative #12, which would not require employers to establish regulated areas. More detailed discussion of Regulatory Alternative #12 appears in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the discussion of Start Printed Page 47571paragraph (e) in Section XVIII of this preamble, Summary and Explanation, provides a more detailed explanation of the proposed requirements for regulated areas, issues with regulated areas, and considerations pertinent to Regulatory Alternative #12.

Personal Protective Clothing and Equipment (PPE)

Regulatory Alternative #13 would modify the proposed requirements for PPE, which require PPE where exposure exceeds the TWA PEL or STEL; where employees' clothing or skin may become visibly contaminated with beryllium; and where employees may have skin contact with soluble beryllium compounds. The requirement to use PPE where work clothing or skin may become “visibly contaminated” with beryllium differs from prior standards that do not require contamination to be visible in order for PPE to be required. In the case of beryllium, which OSHA has preliminarily concluded can sensitize through dermal exposure, the exposure levels capable of causing adverse health effects and the PELs in effect are so low that beryllium surface contamination is unlikely to be visible (see this preamble at section V, Health Effects). OSHA is therefore considering Regulatory Alternative #13, which would require appropriate PPE wherever there is potential for skin contact with beryllium or beryllium-contaminated surfaces. More detailed discussion of Regulatory Alternative #13 is provided in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the discussion of paragraph (h) in Section XVIII of this preamble, Summary and Explanation, provides a more detailed explanation of the proposed requirements for PPE, issues with PPE, and the considerations pertinent to Regulatory Alternative #13.

Medical Surveillance

The proposed requirements for medical surveillance include: (1) Medical examinations, including a test for beryllium sensitization, for employees who are exposed to beryllium above the proposed PEL for 30 days or more per year, who are exposed to beryllium in an emergency, or who show signs or symptoms of CBD; and (2) low-dose helical tomography (low-dose computed tomography, hereafter referred to as “CT scans”), for employees who were exposed above the proposed PEL for more than 30 days in a 12-month period for 5 years or more. This type of CT scan is a method of detecting tumors, and is commonly used to diagnose lung cancer. The proposed standard would require periodic medical exams to be provided for employees in the medical surveillance program annually, while tests for beryllium sensitization and CT scans would be provided to eligible employees biennially.

OSHA has examined eight regulatory alternatives (#14 through #21) that would modify the proposed rule's requirements for employee eligibility, the types of exam that must be offered, and the frequency of periodic exams. Medical surveillance was a subject of special concern to SERs during the SBREFA process, and the SBREFA Panel offered many comments and recommendations related to medical surveillance for OSHA's consideration. Some of the Panel's concerns have been addressed in this proposal, which was modified since the SBREFA Panel was convened (see this preamble at Section XVIII, Summary and Explanation of the Proposed Standard, for more detailed discussion). Several of the alternatives presented here (#16, #18, and #20) also respond to recommendations by the SBREFA Panel to reduce burdens on small businesses by dropping or reducing the frequency of medical surveillance requirements. OSHA also seeks to ensure that the requirements of the final standard offer workers adequate medical surveillance while limiting the costs to employers. Thus, OSHA requests feedback on several additional alternatives and on a variety of issues raised later in this section of the preamble.

Regulatory Alternatives #14, #15, and #21 would expand eligibility for medical surveillance to a broader group of employees than would be eligible in the proposed standard. Under Regulatory Alternative #14, medical surveillance would be available to employees who are exposed to beryllium above the proposed PEL, including employees exposed for fewer than 30 days per year. Regulatory Alternative #15 would expand eligibility for medical surveillance to employees who are exposed to beryllium above the proposed action level, including employees exposed for fewer than 30 days per year. Regulatory Alternative #21 would extend eligibility for medical surveillance as set forth in proposed paragraph (k) to all employees in shipyards, construction, and general industry who meet the criteria of proposed paragraph (k)(1) (or any of the alternative criteria under consideration). However, all other provisions of the standard would be in effect only for employers and employees that fall within the scope of the proposed rule.

Regulatory Alternatives #16 and #17 would modify the proposed standard's requirements to offer beryllium sensitization testing to eligible employees. Under Regulatory Alternative #16, employers would not be required to offer employees testing for beryllium sensitization. Regulatory Alternative #17 would increase the frequency of periodic sensitization testing, from the proposed standard's biennial requirement to annual testing. Regulatory Alternatives #18 and #19 would similarly modify the proposed standard's requirements to offer CT scans to eligible employees. Regulatory Alternative #18 would drop the CT scan requirement from the proposed rule, whereas Regulatory Alternative #19 would increase the frequency of periodic CT scans from biennial to annual scans. Finally, under Regulatory Alternative #20, all periodic components of the medical surveillance exams would be available biennially to eligible employees. Instead of requiring employers to offer eligible employees a medical examination every year, employers would be required to offer eligible employees a medical examination every other year. The frequency of testing for beryllium sensitization and CT scans would also be biennial for eligible employees, as in the proposed standard.

More detailed discussions of Regulatory Alternatives #14, #15, #16, #17, #18, #19, #20, and #21 appear in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, Section XVIII of this preamble, Summary and Explanation, paragraph (k) provides a more detailed explanation of the proposed requirements for medical surveillance, issues with medical surveillance, and the considerations pertinent to Regulatory Alternatives #14 through #21.

Medical Removal Protection (MRP)

The proposed requirements for medical removal protection provide an option for medical removal to an employee who is working in a job with exposure at or above the action level and is diagnosed with CBD or confirmed positive for beryllium sensitization. If the employee chooses removal, the employer must either remove the employee to comparable work in a work environment where exposure is below the action level, or if comparable work is not available, must place the employee on paid leave for 6 months or until such time as comparable work becomes available. In either case, the employer must maintain for 6 months the employee's base earnings, seniority, Start Printed Page 47572and other rights and benefits that existed at the time of removal. During the SBREFA process, the Panel recommended that OSHA give careful consideration to the impacts that an MRP requirement could have on small businesses (OSHA, 2008b). In response to this recommendation, OSHA analyzed Regulatory Alternative #22, which would not require employers to offer MRP. More detailed discussion of Regulatory Alternative #22 appears in Section IX of this preamble and in Chapter VIII of the PEA (OSHA, 2014). In addition, the discussion of paragraph (l) in section XVIII of this preamble, Summary and Explanation, provides a more detailed explanation of the proposed requirements for MRP, issues with MRP, and considerations pertinent to Regulatory Alternative #22.

Timing of the Standard

The proposed standard would become effective 60 days following publication of the final standard in the Federal Register. The effective date is the date on which the standard imposes compliance obligations on employers. However, the standard would not become enforceable by OSHA until 90 days following the effective date for exposure monitoring, work areas and regulated areas, written exposure control plan, respiratory protection, other personal protective clothing and equipment, hygiene areas and practices (except change rooms), housekeeping, medical surveillance, and medical removal. The proposed requirement for change rooms would not be enforceable until one year after the effective date, and the requirements for engineering controls would not be enforceable until two years after the effective date. In summary, employers will have some period of time after the standard becomes effective to come into compliance before OSHA will begin enforcing it: 90 days for most provisions, one year for change rooms, and two years for engineering controls. Beginning 90 days following the effective date, during periods necessary to install or implement feasible engineering controls where exposure exceed the TWA PEL or STEL, employers must provide employees with respiratory protection as described in the proposed standard under section (g), Respiratory Protection.

OSHA invites comment and suggestions for phasing in requirements for engineering controls, medical surveillance, and other provisions of the standard. A longer phase-in time would have several advantages, such as reducing initial costs of the standard or allowing employers to coordinate their environmental and occupational safety and health control strategies to minimize potential costs. However, a longer phase-in would also postpone and reduce the benefits of the standard. Suggestions for alternatives may apply to specific industries (e.g., industries where first-year or annualized cost impacts are highest), specific size-classes of employers (e.g., employers with fewer than 20 employees), combinations of these factors, or all firms covered by the rule.

OSHA requests comments on these regulatory alternatives, including the Agency's choice of regulatory alternatives (and whether there are other regulatory alternatives the Agency should consider) and the Agency's analysis of them. In addition, OSHA requests comments and information on a number of specific topics and issues pertinent to the proposed standard. These are summarized below.

Regulatory Issues

In this section, we solicit public feedback on issues associated with the proposed standard and request information that would help the Agency craft the final standard. In addition to the issues specified here, OSHA also raises issues for comment on technical questions and discussions of economic issues in the PEA (OSHA, 2014). OSHA requests comment on all relevant issues, including health effects, risk assessment, significance of risk, technological and economic feasibility, and the provisions of the proposed regulatory text. In addition, OSHA requests comments on all of the issues raised by the Small Business Advocacy Review (SBAR) Panel, as summarized in the SBAR report (OSHA, 2008b)

We present these issues and requests for information in the first chapter of the preamble to assist readers as they review the preamble and consider any comments they may want to submit. The issues are presented here in summary form. However, to fully understand the questions in this section and provide substantive input in response to them, the sections of the preamble relevant to these issues should be reviewed. These include: Section V, Health Effects; Section VI, the Preliminary Risk Assessment; Section VIII, Significance of Risk; Section IX, Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis; and Section XVIII, Summary and Explanation of the Proposed Standard.

OSHA requests that comments be organized, to the extent possible, around the following issues and numbered questions. Comment on particular provisions should contain a heading setting forth the section and the paragraph in the proposed standard that the comment addresses. Comments addressing more than one section or paragraph will have correspondingly more headings.

Submitting comments in an organized manner and with clear reference to the issue raised will enable all participants to easily see what issues the commenter addressed and how they were addressed. Many commenters, especially small businesses, are likely to confine their comments to the issues that affect them, and they will benefit from being able to quickly identify comments on these issues in others' submissions. The Agency welcomes comments concerning all aspects of this proposal. However, OSHA is especially interested in responses, supported by evidence and reasons, to the following questions:

Health Effects

1. OSHA has described a variety of studies addressing the major adverse health effects that have been associated with exposure to beryllium. Using currently available epidemiologic and experimental studies, OSHA has made a preliminary determination that beryllium presents risks of lung cancer; sensitization; CBD at 0.1 µg/m3; and at higher exposures acute beryllium disease, and hepatic, renal, cardiovascular and ocular diseases. Is this determination correct? Are there additional studies or other data OSHA should consider in evaluating any of these health outcomes?

2. Has OSHA adequately identified and documented all critical health impairments associated with occupational exposure to beryllium? If not, what other adverse health effects should be added? Are there additional studies or other data OSHA should consider in evaluating any of these health outcomes?

3. Are there any additional studies, other data, or information that would affect the information discussed or significantly change the determination of material health impairment?

Please submit any relevant information, data, or additional studies (or citations to studies), and explain your reasons for recommending any studies you suggest.

Risk Assessment and Significance of Risk

4. OSHA has developed an analysis of health risks associated with occupational beryllium exposure, including an analysis of sensitization and CBD based on a selection of recent Start Printed Page 47573studies in the epidemiological literature, a data set on a population of beryllium machinists provided by the National Jewish Medical Research Center (NJMRC), and an assessment of lung cancer risk using an analysis provided by NIOSH. Did OSHA rely on the best available evidence in its risk assessment? Are there additional studies or other data OSHA should consider in evaluating risk for these health outcomes? Please provide the studies, citations to studies, or data you suggest.

5. OSHA preliminarily concluded that there is significant risk of material health impairment (lung cancer or CBD) from a working lifetime of occupational exposure to beryllium at the current TWA PEL of 2 µg/m3, which would be substantially reduced by the proposed TWA PEL of 0.2 µg/m3 and the alternative TWA PEL of 0.1 µg/m3. OSHA's preliminary risk assessment also concludes that there is still significant risk of CBD and lung cancer at the proposed PEL and the alternative PELs, although substantially less than at the current PEL. Are these preliminary conclusions reasonable, based on the best available evidence? If not, please provide a detailed explanation of your position, including data to support your position and a detailed analysis of OSHA's risk assessment if appropriate.

6. Please provide comment on OSHA's analysis of risk for beryllium sensitization, CBD and lung cancer. Are there important gaps or uncertainties in the analysis, such that the Agency's preliminary conclusions regarding significance of risk at the current, proposed, and alternative PELs may be in error? If so, please provide a detailed explanation and suggestions for how OSHA's analysis should be corrected or improved.

7. OSHA has made a preliminary determination that the available data are not sufficient or suitable for risk analysis of effects other than beryllium sensitization, CBD and lung cancer. Do you have, or are you aware of, studies or data that would be suitable for a risk assessment for these adverse health effects? Please provide the studies, citations to studies, or data you suggest.

(a) Scope

8. Has OSHA defined the scope of the proposed standard appropriately? Does it currently include employers who should not be covered, or exclude employers who should be covered by a comprehensive beryllium standard? Are you aware of employees in construction or maritime, or in general industry who deal with beryllium only as a trace contaminant, who may be at significant risk from occupational beryllium exposure? Please provide the basis for your response and any applicable supporting information.

(b) Definitions

9. Has OSHA defined the Beryllium lymphocyte proliferation test appropriately? If not, please provide the definition that you believe is appropriate. Please provide rationale and citations supporting your comments.

10. Has OSHA defined CBD Diagnostic Center appropriately? In particular, should a CBD diagnostic center be required to analyze biological samples on-site, or should diagnostic centers be allowed to send samples off-site for analysis? Is the list of tests and procedures a CBD Diagnostic Center is required to be able to perform appropriate? Should any of the tests or procedures be removed from the definition? Should other tests or procedures be added to the definition? Please provide rationale and information supporting your comments.

(d) Exposure Monitoring

11. Do you currently monitor for beryllium exposures in your workplace? If so, how often? Please provide the reasoning for the frequency of your monitoring. If periodic monitoring is performed at your workplace for exposures other than beryllium, with what frequency is it repeated?

12. Is it reasonable to allow discontinuation of monitoring based on one sample below the action level? Should more than one result below the action level be required to discontinue monitoring?

(e) Work Areas and Regulated Areas

The proposed standard would require employers to establish and maintain two types of areas: beryllium work areas, wherever employees are, or can reasonably be expected to be, exposed to any level of airborne beryllium; and regulated areas, wherever employees are, or can reasonably be expected to be, exposed to airborne beryllium at levels above the TWA PEL or STEL. Employers are required to demarcate beryllium work areas, but are not required to restrict access to beryllium work areas or provide respiratory protection or other forms of PPE within work areas with exposures at or below the TWA PEL or STEL. Employers must also demarcate regulated areas, including posting warning signs; restrict access to regulated areas; and provide respiratory protection and other PPE within regulated areas.

13. Does your workplace currently have regulated areas? If so, how are regulated areas demarcated?

14. Please describe work settings where establishing regulated areas could be problematic or infeasible. If establishing regulated areas is problematic, what approaches might be used to warn employees in such work settings of high risk areas?

(f) Methods of Compliance

Paragraph (f)(2) of the proposed standard would require employers to implement engineering and work practice controls to reduce employees' exposures to or below the TWA PEL and STEL. Where engineering and work practice controls are insufficient to reduce exposures to or below the TWA PEL and STEL, employers would still be required to implement them to reduce exposure as much as possible, and to supplement them with a respiratory protection program. In addition, for each operation where there is airborne beryllium exposure, the employer must ensure that at least one of the engineering and work practice controls listed in paragraph (f)(2) is in place, unless all of the listed controls are infeasible, or the employer can demonstrate that exposures are below the action level based on no fewer than two samples taken seven days apart.

15. Do you usually use engineering or work practices controls (local exhaust ventilation, isolation, substitution) to reduce beryllium exposures? If so, which controls do you use?

16. Are the controls and processes listed in paragraph (f)(2)(i)(A) appropriate for controlling beryllium exposures? Are there additional controls or processes that should be added to paragraph (f)(2)(i)(A)?

(g) Respiratory Protection

17. OSHA's asbestos standard (CFR 1910.1001) requires employers to provide each employee with a tight-fitting, powered air-purifying respirator (PAPR) instead of a negative pressure respirator when the employee chooses to use a PAPR and it provides adequate protection to the employee. Should the beryllium standard similarly require employers to provide PAPRs (instead of allowing a negative pressure respirator) when requested by the employee? Are there other circumstances where a PAPR should be specified as the appropriate respiratory protection? Please provide the basis for your response and any applicable supporting information.Start Printed Page 47574

(h) Personal Protective Clothing and Equipment

18. Do you currently require specific PPE or respirators when employees are working with beryllium? If so, what type?

19. The proposal requires PPE wherever work clothing or skin may become visibly contaminated with beryllium; where employees' skin can reasonably be expected to be exposed to soluble beryllium compounds; or where employee exposure exceeds or can reasonably be expected to exceed the TWA PEL or STEL. The requirement to use PPE where work clothing or skin may become “visibly contaminated” with beryllium differs from prior standards which do not require contamination to be visible in order for PPE to be required. Is “visibly contaminated” an appropriate trigger for PPE? Is there reason to require PPE where employees' skin can be exposed to insoluble beryllium compounds? Please provide the basis for your response and any applicable supporting information.

(i) Hygiene Areas and Practices

20. The proposal requires employers to provide showers in their facilities if (A) Exposure exceeds or can reasonably be expected to exceed the TWA PEL or STEL; and (B) Beryllium can reasonably be expected to contaminate employees' hair or body parts other than hands, face, and neck. Is this requirement reasonable and adequately protective of beryllium-exposed workers? Should OSHA amend the provision to require showers in facilities where exposures exceed the PEL or STEL, without regard to areas of bodily contamination?

(j) Housekeeping

21. The proposed rule prohibits dry sweeping or brushing for cleaning surfaces in beryllium work areas unless HEPA-filtered vacuuming or other methods that minimize the likelihood and level of exposure have been tried and were not effective. Please comment on this provision. What methods do you use to clean work surfaces at your facility? Are HEPA-filtered vacuuming or other methods to minimize beryllium exposure used to clean surfaces at your facility? Have they been effective? Are there any circumstances under which dry sweeping or brushing are necessary? Please explain your response.

22. The proposed rule requires that materials designated for recycling that are visibly contaminated with beryllium particulate shall be cleaned to remove visible particulate, or placed in sealed, impermeable enclosures. However, small particles (<10 μg) may not be visible to the naked eye, and there are studies suggesting that small particles may penetrate the skin, beyond which beryllium sensitization can occur (Tinkle et al., 2003). OSHA requests feedback on this provision. Should OSHA require that all material to be recycled be decontaminated regardless of perceived surface cleanliness? Should OSHA require that all material disposed or discarded be in enclosures regardless of perceived surface cleanliness? Please provide explanation or data to support your comments.

(k) Medical Surveillance

The proposed requirements for medical surveillance include: (1) Medical examinations, including a test for beryllium sensitization, for employees who are exposed to beryllium above the proposed PEL for 30 days or more per year, who are exposed to beryllium in an emergency, or who show signs or symptoms of CBD; and (2) CT scans for employees who were exposed above the proposed PEL for more than 30 days in a 12-month period for 5 years or more. The proposed standard would require periodic medical exams to be provided for employees in the medical surveillance program annually, while tests for beryllium sensitization and CT scans would be provided to eligible employees biennially.

23. Is medical surveillance being provided for beryllium-exposed employees at your worksite? If so:

a. Do you provide medical surveillance to employees under another OSHA standard or as a matter of company policy? What OSHA standard(s) does the program address?

b. How many employees are included, and how do you determine which employees receive medical surveillance (e.g., by exposure level, other factors)?

c. Who administers and implements the medical surveillance (e.g., company doctor, nurse practitioner, physician assistant, or nurse; or outside doctor, nurse practitioner, physician assistant, or nurse)?

d. What examinations, tests, or evaluations are included in the medical surveillance program, and with what frequency are they administered? Does your program include a surveillance program specifically for beryllium-related health effects (e.g., the BeLPT or other tests for beryllium sensitization)?

e. If your facility offers the BeLPT, please provide feedback and data on your experience with the BeLPT, including the analytical or interpretive procedure you use and its role in your facility's exposure control program. Has identification of sensitized workers led to interventions to reduce exposures to sensitized individuals, or in the facility generally? If a worker is found to be sensitized, do you track worker health and possible progression of disease beyond sensitization? If so, how is this done?

f. What difficulties and benefits (e.g., health, reduction in absenteeism, or financial) have you experienced with your medical surveillance program? If applicable, please discuss benefits and difficulties you have experienced with the use of the BeLPT, providing detailed information or examples if possible.

g. What are the costs of your medical surveillance program? How do your costs compare with OSHA's estimated unit costs for the physical examination and employee time involved in the medical surveillance program? Are OSHA's baseline assumptions and cost estimates for medical surveillance consistent with your experiences providing medical surveillance to your employees?

24. Please review paragraph (k) of the proposed rule, Medical Surveillance, and comment on the frequency and contents of medical surveillance in the proposed rule. Is 30 days from initial assignment a reasonable time at which to provide a medical exam? Should there be a requirement for beryllium sensitization testing at time of employment? Should there be a requirement for beryllium sensitization testing at an employee's exit exam, regardless of when the employee's most recent sensitization test was administered? Are the tests required and the testing frequencies specified appropriate? Should sensitized employees have the opportunity to be examined at a CBD Diagnostic Center more than once following a confirmed positive BeLPT? Are there additional tests or alternate testing schedules you would suggest? Should the skin be examined for signs and symptoms of beryllium exposure or other medical issues, as well as for breaks and wounds? Please explain the basis for your position and provide data or studies if applicable.

25. Please provide comments on the proposed requirements regarding referral of a sensitized employee to a CBD diagnostic center, which specify referral to a diagnostic center “mutually agreed upon” by the employer and employee. Is this requirement for mutual agreement necessary and appropriate? How should a diagnostic center be chosen if the employee and employer cannot come to agreement? Should OSHA consider alternate language, such as referral for CBD Start Printed Page 47575evaluation at a diagnostic center in a reasonable location?

26. In the proposed rule, OSHA specifies that all medical examinations and procedures required by the standard must be performed by or under the direction of a licensed physician. Are physicians available in your geographic area to provide medical surveillance to workers who are covered by the proposed rule? Are other licensed health care professionals available to provide medical surveillance? Do you have access to other qualified personnel such as qualified X-ray technicians, and pulmonary specialists? Should the proposal be amended to allow examination by, or under the direction of, a physician or other licensed health care professional (PLHCP)? Please explain your position. Please note what you consider your geographic area in responding to this question.

27. The proposed standard requires the employer to obtain the Licensed Physician's Written Medical Opinion from the PLHCP within 30 days of the examination. Should OSHA revise the medical surveillance provisions of the proposed standard to allow employees to choose what, if any, medical information goes to the employer from the PLHCP? For example, the employer could instead be required to obtain a certification from the PLCHP within 30 days of the examination stating (1) when the examination took place, (2) that the examination complied with the standard, and (3) that the PLHCP provided the employee a copy of the Licensed Physician's Written Medical Opinion required by the standard. The PLHCP would need the employee's written consent to send the employer the Licensed Physician's Written Medical Opinion or any other medical information about the employee. This approach might lead to corresponding changes in proposed paragraphs (f)(1) (written exposure control program), (l) (medical removal) and (n) (recordkeeping) to reflect that employers will not automatically be receiving any medical information about employees as a result of the medical surveillance required by the proposed standard, but would instead only receive medical information the employee chooses to share with the employer. Please comment on the relative merits of the proposed standard's requirement that employers obtain the PLHCP's written opinion or an alternative that would provide employees with greater discretion over the information that goes to employers, and explain the basis for your position and the potential impact on the benefits of medical surveillance.

28. Appendix A to the proposed standard reviews procedures for conducting and interpreting the results of BeLPT testing for beryllium sensitization. Is there now, or should there be, a standard method for BeLPT laboratory procedure? If yes, please describe the existing or proposed method. Is there now, or should there be, a standard algorithm for interpreting BeLPT results to determine sensitization? Please describe the existing or proposed laboratory method or interpretation algorithm. Should OSHA require that BeLPTs performed to comply with the medical surveillance provisions of this rule adhere to the Department of Energy (DOE) analytical and interpretive specifications issued in 2001? Should interpretation of laboratory results be delegated to the employee's occupational physician or PLHCP?

29. Should OSHA require the clinical laboratories performing the BeLPT to be accredited by the College of American Pathologists or another accreditation organization approved under the Clinical Laboratory Improvement Amendments (CLIA)? What other standards, if any, should be required for clinical laboratories providing the BeLPT?

30. Are there now, or are there being developed, alternative tests to the BeLPT you would suggest? Please explain the reasons for your suggestion. How should alternative tests for beryllium sensitization be evaluated and validated? How should OSHA determine whether a test for beryllium sensitization is more reliable and accurate than the BeLPT? Please see Appendix A to the proposed standard for a discussion of the accuracy of the BeLPT.

31. The proposed rule requires employers to provide OSHA with the results of BeLPTs performed to comply with the medical surveillance provisions upon request, provided that the employer obtains a release from the tested employee. Will this requirement be unduly burdensome for employers? Are there alternative organizations that would be appropriate to send test results to?

(l) Medical Removal Protection

The proposed requirements for medical removal protection provide an option for medical removal to an employee who is working in a job with exposure at or above the action level and is diagnosed with CBD or confirmed positive for beryllium sensitization. If the employee chooses removal, the employer must remove the employee to comparable work in a work environment where exposure is below the action level, or if comparable work is not available, must place the employee on paid leave for 6 months or until such time as comparable work becomes available. In either case, the employer must maintain for 6 months the employee's base earnings, seniority, and other rights and benefits that existed at the time of removal.

32. Do you provide MRP at your facility? If so, please comment on the program's benefits, difficulties, and costs, and the extent to which eligible employees make use of MRP.

33. OSHA has included requirements for medical removal protection (MRP) in the proposed rule, which includes provisions for medical removal for employees with beryllium sensitization or CBD, and an extension of removed employees' rights and benefits for six months. Are beryllium sensitization and CBD appropriate triggers for medical removal? Are there other medical conditions or findings that should trigger medical removal? For what amount of time should a removed employee's benefits be extended?

(p) Appendices

34. Some OSHA health standards include appendices that address topics such as the hazards associated with the regulated substance, health screening considerations, occupational disease questionnaires, and PLHCP obligations. In this proposed rule, OSHA has included a non-mandatory appendix to describe and discuss the BeLPT (Appendix A), and a non-mandatory appendix presenting a non-exhaustive list of engineering controls employers may use to comply with paragraph (f) (Appendix B). What would be the advantages and disadvantages of including each appendix in the final rule? What would be the advantages and disadvantages of providing this information in guidance materials?

35. What additional information, if any, should be included in the appendices? What additional information, if any, should be provided in guidance materials?

General

36. The current beryllium proposal includes triggers that require employers to initiate certain provisions, programs, and activities to protect workers from beryllium exposure. All employers covered under an OSHA health standard are required to initiate certain activities such as initial monitoring to evaluate the potential hazard to employees. OSHA health standards typically include ancillary provisions with various triggers indicating when an Start Printed Page 47576employer covered under the standard would need to comply with a provision. The most common triggers are ones based an exposure level such as the PEL or action level. These exposure level triggers are sometimes combined with a minimum duration of exposure (e.g., ≥ 30 days per year). Other triggers may include reasonably anticipated exposure, medical surveillance findings, certain work activities, or simply the presence of the regulated substance in the workplace.

For the current Proposal, exposures to beryllium above the TWA PEL or STEL trigger the provisions for regulated areas, additional or enhanced engineering or work practice controls to reduce airborne exposures to or below the TWA PEL and STEL, personal protective clothing and equipment, medical surveillance, showers, and respiratory protection if feasible engineering and work practice controls cannot reduce airborne exposures to or below the TWA PEL and STEL. Exposures at or above the action level in turn trigger the provisions for periodic exposure monitoring, and medical removal eligibility (along with a diagnosis of CBD or confirmed positive for beryllium sensitization). Finally, an employer covered under the scope of the proposed standard must establish a beryllium work area where employees are, or can reasonably be expected to be, exposed to airborne beryllium regardless of the level of exposure. In beryllium work areas, employers must implement a written exposure control plan, provide washing facilities and change rooms (change rooms are only necessary if employees are required to remove their personal clothing), and follow housekeeping provisions. The employers must also implement at least one of the engineering and work practice controls listed in paragraph (f)(2) of the proposed standard. An employer is exempt from this requirement if he or she can demonstrate that such controls are not feasible or that exposures are below the action level.

Certain provisions are triggered by one condition and other provisions are triggered only if multiple conditions are present. For example, medical removal is only triggered if an employee has CBD or is confirmed positive AND the employee is exposed at or above the action level.

OSHA is requesting comment on the triggers in the proposed beryllium standard. Are the triggers OSHA has proposed appropriate? OSHA is also requesting comment on these triggers relative to the regulatory alternatives affecting the scope and PELs as described in this preamble in section I, Issues and Alternatives. For example, are the triggers in the proposed standard appropriate for Alternative #1a, which would expand the scope of the proposed standard to include all operations in general industry where beryllium exists only as a trace contaminant (less than 0.1% beryllium by weight)? Are the triggers appropriate for the alternatives that change the TWA PEL, STEL, and action level? Please specify the trigger and the alternative, if applicable, and why you agree or disagree with the trigger.

Relevant Federal Rules Which May Duplicate, Overlap, or Conflict With the Proposed Rule

37. In Section IX—Preliminary Economic Analysis under the Initial Regulatory Flexibility Analysis, OSHA identifies, to the extent practicable, all relevant Federal rules which may duplicate, overlap, or conflict with the proposed rule. One potential area of overlap is with the U.S. Department of Energy (DOE) beryllium program. In 1999, DOE established a chronic beryllium disease prevention program (CBDPP) to reduce the number of workers (DOE employees and DOE contractors) exposed to beryllium at DOE facilities (10 CFR part 850, published at 64 FR 68854-68914 (Dec. 8, 1999)). In establishing this program, DOE has exercised its statutory authority to prescribe and enforce occupational safety and health standards. Therefore pursuant to section 4(b)(1) of the OSH Act, 29 U.S.C. 653(b)(1), the DOE facilities are exempt from OSHA jurisdiction.

Nevertheless, under 10 CFR 850.22, DOE has included in its CBDPP regulation a requirement for compliance with the current OSHA permissible exposure limit (PEL), and any lower PEL that OSHA establishes in the future. Thus, although DOE has preempted OSHA's standard from applying at DOE facilities and OSHA cannot exercise any authority at those facilities, DOE relies on OSHA's PEL in implementing its own program. However, DOE's decision to tie its own standard to OSHA's PEL has little consequence to this rulemaking because the requirements in DOE's beryllium program (controls, medical surveillance, etc.) are triggered by DOE's action level of 0.2 µg/m3, which is much lower than DOE's existing PEL and the same as OSHA's proposed PEL. DOE's action level is not tied to OSHA's standard, so 10 CFR 850.22 would not require the CBDPP's action level or any non-PEL requirements to be automatically adjusted as a result of OSHA's rulemaking. For this reason, DOE has indicated to OSHA that OSHA's proposed rule would not have any impact on DOE's CBDPP, particularly since 10 CFR 850.25(b), Exposure reduction and minimization, requires DOE contractors to reduce exposures to below the DOE's action level of 0.2 µg/m3, if practicable.

DOE has expressed to OSHA that DOE facilities are already in compliance with 10 CFR 850 and its action level of 0.2 µg/m[3] ,[2] so the only potential impact on DOE's CBDPP that could flow from OSHA's rulemaking would be if OSHA ultimately adopted a PEL of 0.1 µg/m3, as discussed in alternative #4, instead of the proposed PEL of 0.2 µg/m3, and DOE did not make any additional adjustments to its standards. Even in that hypothetical scenario, the impact would still be limited because of the odd result that DOE's PEL would drop below its own action level, while the action level would continue to serve as the trigger for most of DOE's program requirements.

DOE also has noted some potential overlap with a separate DOE provision in 10 CFR part 851, which requires its contractors to comply with DOE's CBDPP (10 CFR 851.23(a)(1)) and also with all OSHA standards under 29 CFR part 1910 except “Ionizing Radiation” (§ 1910.1096) (10 CFR 851.23(a)(3)). These requirements, which DOE established in 2006 (71 FR 6858 (February 9, 2006)), make sense in light of OSHA's current regulation because OSHA's only beryllium protection is a PEL, so compliance with 10 CFR 851.23(a)(1) and (3) merely make OSHA's current PEL the relevant level for purposes of the CBDPP. However, its function would be less clear if OSHA adopts a beryllium standard as proposed. OSHA's proposed beryllium standard would establish additional substantive protections beyond the PEL. Consequently, notwithstanding the CBDPP's preemptive effect on the OSHA beryllium standard as a result of 29 U.S.C. 653(b)(1), 10 CFR 851.23(a)(3) could be read to require DOE contractors to comply with all provisions in OSHA's proposal (if finalized), including the ancillary provisions, creating a dual regulatory scheme for beryllium protection at DOE facilities.

DOE officials have indicated that this is not their intent. Instead, their intent is that DOE contractors comply solely with the CBDPP provisions in 10 CFR part 850 for protection from beryllium. Start Printed Page 47577Based on its discussions with DOE officials, OSHA anticipates that DOE will clarify that its contractors do not need to comply with any ancillary provisions in a beryllium standard that OSHA may promulgate.

OSHA can envision several potential scenarios developing from its rulemaking, ranging from OSHA retaining the proposed PEL of 0.2 µg/m3 and action level of 0.1 µg/m3 in the final rule to adopting the PEL of 0.1 µg/m3, as discussed in alternative #4. Because OSHA's beryllium standard does not apply directly to DOE facilities, and the only impact of its rules on those facilities is the result of DOE's regulatory choices, there is also a range of actions that DOE could take to minimize any potential impact of any change to OSHA's rules, including (1) taking no action at all, (2) simply clarifying the CBDPP, as described above, to mean that OSHA's beryllium standard (other than its PEL) does not apply to contractors, or (3) revising both parts 850 and 851 to completely disassociate DOE's regulation of beryllium at DOE facilities from OSHA's regulation of beryllium.

OSHA is aware that, in the preamble to its 1999 CBDPP rule, DOE analyzed the costs for implementing the CBDPP for action levels of 0.1 µg/m3, 0.2 µg/m3, and 0.5 µg/m3 (64 FR 68875, December 8, 1999). DOE estimated costs for periodic exposure monitoring, notifying workers of the results of such monitoring, exposure reduction and minimization, regulated areas, change rooms and showers, respiratory protection, protective clothing, and disposal of protective clothing. All of these provisions are triggered by DOE's action level (64 FR 68874, December 8, 1999). Although DOE's rule is not identical to OSHA's proposed standard, OSHA believes that DOE's costs are sufficiently representative to form the basis of a preliminary estimate of the costs that could flow from OSHA's standard, if finalized.

Based on the range of potential scenarios and the prior DOE cost estimates, OSHA estimates that the annual cost impact on DOE facilities could range from $0 to $4,065,768 (2010 dollars). The upper end of the cost range would reflect the unlikely scenario in which OSHA promulgates a final PEL of 0.1 µg/m3, 10 CFR 851.23(a)(3) is found to compel DOE contractors to comply with OSHA's comprehensive beryllium standard in addition to DOE's CBDPP, and DOE takes no action to clarify that OSHA's beryllium standard does not apply to DOE contractors. The lower end of the cost range assumes OSHA promulgates its rule as proposed with a PEL of 0.2 µg/m3 and action level of 0.1 µg/m3, and DOE clarifies that it intends its contractors to follow DOE's CBDPP and not OSHA's beryllium standard, so that the ancillary provisions of OSHA's beryllium standard do not apply to DOE facilities. Additionally, OSHA assumes that DOE contractors are in compliance with DOE's current rule and therefore took the difference in cost between implementation of an action level of 0.2 µg/m3 and an action level of 0.1 µg/m3 for the above estimates. Finally, OSHA used the GDP price deflator to present the cost estimate in 2010 dollars.

OSHA requests comment on the potential overlap of DOE's rule with OSHA's proposed rule.

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 proposed standard regulating occupational exposure to beryllium, 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. See 29 U.S.C. 655(b)(5).

The Supreme Court has held that before the Secretary can promulgate any permanent health or safety standard, he 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”). Thus, section 6(b)(5) of the Act requires health standards to reduce significant risk to the extent feasible. Id.

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.” Am. Textile Mfrs. Inst. v. Donovan, 452 U.S. 490, 509-510 (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. Id. 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 . . . [T]he 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 Indus. Union Dep't, 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 PELs may enhance economic feasibility. The Lead I case at 1265. 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 required. The Cotton Dust case, 453 U.S. at 509.

Finally, sections 6(b)(7) and 8(c) of the Act authorize OSHA to include among a standard's requirements labeling, monitoring, medical testing, and other information-gathering and -transmittal provisions. 29 U.S.C. 655(b)(7), 657(c).Start Printed Page 47578

III. Events Leading to the Proposed Standards

The first occupational exposure limit for beryllium was set in 1949 by the Atomic Energy Commission (AEC), which required that beryllium exposure in the workplaces under its jurisdiction be limited to 2 µg/m3 as an 8-hour time-weighted average (TWA), and 25 µg/m3 as a peak exposure never to be exceeded (Department of Energy, 1999). These exposure limits were adopted by all AEC installations handling beryllium, and were binding on all AEC contractors involved in the handling of beryllium.

In 1956, the American Industrial Hygiene Association (AIHA) published a Hygienic Guide which supported the AEC exposure limits. In 1959, the American Conference of Governmental Industrial Hygienists (ACGIH®) also adopted a Threshold Limit Value (TLV®) of 2 µg/m3 as an 8-hour TWA (Borak, 2006).

In 1971, OSHA adopted, under Section 6(a) of the Occupational Safety and Health Act of 1970, and made applicable to general industry, a national consensus standard (ANSI Z37.29-1970) for beryllium and beryllium compounds. The standard set a permissible exposure limit (PEL) for beryllium and beryllium compounds at 2 µg/m3 as an 8-hour TWA; 5 µg/m3 as an acceptable ceiling concentration; and 25 µg/m3 as an acceptable maximum peak above the acceptable ceiling concentration for a maximum duration of 30 minutes in an 8-hour shift (OSHA, 1971).

Section 6(a) stipulated that in the first two years after the effective date of the Act, OSHA was to promulgate “start-up” standards, on an expedited basis and without public hearing or comment, based on national consensus or established Federal standards that improved employee safety or health. Pursuant to that authority, in 1971, OSHA promulgated approximately 425 PELs for air contaminants, including beryllium, derived principally from Federal standards applicable to government contractors under the Walsh-Healey Public Contracts Act, 41 U.S.C. 35, and the Contract Work Hours and Safety Standards Act (commonly known as the Construction Safety Act), 40 U.S.C. 333. The Walsh-Healey Act and Construction Safety Act standards, in turn, had been adopted primarily from ACGIH®'s TLV®s.

The National Institute for Occupational Safety and Health (NIOSH) issued a document entitled Criteria for a Recommended Standard: Occupational Exposure to Beryllium (Criteria Document) in June 1972. OSHA reviewed the findings and recommendations contained in the Criteria Document along with the AEC control requirements for beryllium exposure. OSHA also considered existing data from animal and epidemiological studies, and studies of industrial processes of beryllium extraction, refinement, fabrication, and machining. In 1975, OSHA asked NIOSH to update the evaluation of the existing data pertaining to the carcinogenic potential of beryllium. In response to OSHA's request, the Director of NIOSH stated that, based on animal data and through all possible routes of exposure including inhalation, “beryllium in all likelihood represents a carcinogenic risk to man.”

In October 1975, OSHA proposed a new beryllium standard for all industries based on information that beryllium caused cancer in animal experiments (40 FR 48814 (October 17, 1975)). Adoption of this proposal would have lowered the 8-hour TWA exposure limit from 2 µg/m3 to 1 µg/m3. In addition, the proposal included ancillary provisions for such topics as exposure monitoring, hygiene facilities, medical surveillance, and training related to the health hazards from beryllium exposure. The rulemaking was never completed.

In 1977, NIOSH recommended an exposure limit of 0.5 µg/m3 and identified beryllium as a potential occupational carcinogen. In December 1998, ACGIH published a Notice of Intended Change for its beryllium exposure limit. The notice proposed a lower TLV of 0.2 µg/m3 over an 8-hour TWA based on evidence of CBD and sensitization in exposed workers.

In 1999, the Department of Energy (DOE) issued a Chronic Beryllium Disease Prevention Program (CBDPP) Final Rule for employees exposed to beryllium in its facilities (DOE, 1999). The DOE rule set an action level of 0.2 μg/m3, and adopted OSHA's PEL of 2 μg/m3 or any more stringent PEL OSHA might adopt in the future. The DOE action level triggers workplace precautions and control measures such as periodic monitoring, exposure reduction or minimization, regulated areas, hygiene facilities and practices, respiratory protection, protective clothing and equipment, and warning signs (DOE, 1999).

Also in 1999, OSHA was petitioned by the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE) (OSHA, 2002) and by Dr. Lee Newman and Ms. Margaret Mroz, from the National Jewish Medical Research Center (NJMRC) (OSHA, 2002), to promulgate an Emergency Temporary Standard (ETS) for beryllium in the workplace. In 2001, OSHA was petitioned for an ETS by Public Citizen Health Research Group and again by PACE (OSHA, 2002). In order to promulgate an ETS, the Secretary of Labor must prove (1) that employees are exposed to grave danger from exposure to a hazard, and (2) that such an emergency standard is necessary to protect employees from such danger (29 U.S.C. 655(c)). The burden of proof is on the Department and because of the difficulty of meeting this burden, the Department usually proceeds when appropriate with 6(b) rulemaking rather than a 6(c) ETS. Thus, instead of granting the ETS requests, OSHA instructed staff to further collect and analyze research regarding the harmful effects of beryllium.

On November 26, 2002, OSHA published a Request for Information (RFI) for “Occupational Exposure to Beryllium” (OSHA, 2002). The RFI contained questions on employee exposure, health effects, risk assessment, exposure assessment and monitoring methods, control measures and technological feasibility, training, medical surveillance, and impact on small business entities. In the RFI, OSHA expressed concerns about health effects such as CBD, lung cancer, and beryllium sensitization. OSHA pointed to studies indicating that even short-term exposures below OSHA's PEL of 2 µg/m3 could lead to CBD. The RFI also cited studies describing the relationship between beryllium sensitization and CBD (67 FR at 70708). In addition, OSHA stated that beryllium had been identified as a carcinogen by organizations such as NIOSH, the International Agency for Research on Cancer (IARC), and the Environmental Protection Agency (EPA); and cancer had been evidenced in animal studies (67 FR at 70709).

On November 15, 2007, OSHA convened a Small Business Advocacy Review Panel for a draft proposed standard for occupational exposure to beryllium. OSHA convened this panel under Section 609(b) of the Regulatory Flexibility Act (RFA), as amended by the Small Business Regulatory Enforcement Fairness Act of 1996 (SBREFA) (5 U.S.C. 601 et seq.).

The Panel included representatives from OSHA, the Solicitor's Office of the Department of Labor, the Office of Advocacy within the Small Business Administration, and the Office of Information and Regulatory Affairs of the Office of Management and Budget. Small Entity Representatives (SERs) made oral and written comments on the Start Printed Page 47579draft rule and submitted them to the panel.

The SBREFA Panel issued a report which included the SERs' comments on January 15, 2008. SERs expressed concerns about the impact of the ancillary requirements such as exposure monitoring and medical surveillance. Their comments addressed potential costs associated with compliance with the draft standard, and possible impacts of the standard on market conditions, among other issues. In addition, many SERs sought clarification of some of the ancillary requirements such as the meaning of “routine” contact or “contaminated surfaces.”

The SBREFA Panel issued a number of recommendations, which OSHA carefully considered. In section XVIII of this preamble, Summary and Explanation, OSHA has responded to the Panel's recommendations and clarified the requirements about which SERs expressed confusion. OSHA also examined the regulatory alternatives recommended by the SBREFA Panel. The regulatory alternatives examined by OSHA are listed in section I of this preamble, Issues and Alternatives. The alternatives are discussed in greater detail in section XVIII of this preamble, Summary and Explanation, and in the PEA (OSHA, 2014). In addition, the Agency intends to develop interpretive guidance documents following the publication of a final rule.

In 2010, OSHA hired a contractor to oversee an independent scientific peer review of a draft preliminary beryllium health effects evaluation (OSHA, 2010a) and a draft preliminary beryllium risk assessment (OSHA, 2010b). The contractor identified experts familiar with beryllium health effects research and ensured that these experts had no conflict of interest or apparent bias in performing the review. The contractor selected five experts with expertise in such areas as pulmonary and occupational medicine, CBD, beryllium sensitization, the BeLPT, beryllium toxicity and carcinogenicity, and medical surveillance. Other areas of expertise included animal modeling, occupational epidemiology, biostatistics, risk and exposure assessment, exposure-response modeling, beryllium exposure assessment, industrial hygiene, and occupational/environmental health engineering.

Regarding the health effects evaluation, the peer reviewers concluded that the health effect studies were described accurately and in sufficient detail, and OSHA's conclusions based on the studies were reasonable. The reviewers agreed that the OSHA document covered the significant health endpoints related to occupational beryllium exposure. Peer reviewers considered the preliminary conclusions regarding beryllium sensitization and CBD to be reasonable and well presented in the draft health evaluation section. All reviewers agreed that the scientific evidence supports sensitization as a necessary condition in the development of CBD. In response to reviewers' comments, OSHA made revisions to more clearly describe certain sections of the health effects evaluation. In addition, OSHA expanded its discussion regarding the BeLPT.

Regarding the preliminary risk assessment, the peer reviewers were highly supportive of the Agency's approach and major conclusions. The peer reviewers stated that the key studies were appropriate and their selection clearly explained in the document. They regarded the preliminary analysis of these studies to be reasonable and scientifically sound. The reviewers supported OSHA's conclusion that substantial risk of sensitization and CBD were observed in facilities where the highest exposure generating processes had median full-shift exposures around 0.2 µg/m3 or higher, and that the greatest reduction in risk was achieved when exposures for all processes were lowered to 0.1 µg/m3 or below.

In February 2012 the Agency received for consideration a draft recommended standard for beryllium (Materion and USW, 2012). This draft proposal was the product of a joint effort between two stakeholders: Materion Corporation, a leading producer of beryllium and beryllium products in the United States, and the United Steelworkers, an international labor union representing workers who manufacture beryllium alloys and beryllium-containing products in a number of industries. The United Steelworkers and Materion sought to craft an OSHA-like model beryllium standard that would have support from both labor and industry. OSHA has considered this proposal along with other information submitted during the development of the Notice of Proposed Rulemaking for beryllium.

IV. Chemical Properties and Industrial Uses

Chemical and Physical Properties

Beryllium (Be; CAS Number 7440-41-7) is a silver-grey to greyish-white, strong, lightweight, and brittle metal. It is a Group IIA element with an atomic weight of 9.01, atomic number of 4, melting point of 1,287 °C, boiling point of 2,970°C, and a density of 1.85 at 20 °C (NTP 2014). It occurs naturally in rocks, soil, coal, and volcanic dust (ATSDR, 2002). Beryllium is insoluble in water and soluble in acids and alkalis. It has two common oxidation states, Be(0) and Be(+2). There are several beryllium compounds with unique CAS numbers and chemical and physical properties. Table IV-1 describes the most common beryllium compounds.

Table IV—1, Properties of Beryllium and Beryllium Compounds

Chemical nameCAS No.Synonyms and trade namesMolecular weightMelting point (°C)DescriptionDensity (g/cm3)Solubility
Beryllium metal7440-41-7Beryllium; beryllium-9, beryllium element; beryllium metallic9.01221287Grey, close-packed, hexagonal, brittle metal1.85 (20 °C)Soluble in most dilute acids and alkali; decomposes in hot water; insoluble in mercury and cold water.
Beryllium chloride7787-47-5Beryllium dichloride79.92399.2Colorless to slightly yellow; orthorhombic, deliquescent crystal1.899 (25 °C)Soluble in water, ethanol, diethyl ether and pyridine; slightly soluble in benzene, carbon disulfide and chloroform; insoluble in acetone, ammonia, and toluene.
Start Printed Page 47580
Beryllium fluoride7787-49-7 (12323-05-6)Beryllium difluoride47.01555Colorless or white, amorphous, hygroscopic solid1.986Soluble in water, sulfuric acid, mixture of ethanol and diethyl ether; slightly soluble in ethanol; insoluble in hydrofluoric acid.
Beryllium hydroxide13327-32-7 (1304-49-0)Beryllium dihydroxide43.3138 (decomposes to beryllium oxide)White, amorphous, amphoteric powder1.92Soluble in hot concentrated acids and alkali; slightly soluble in dilute alkali; insoluble in water.
Beryllium sulfate13510-49-1Sulfuric acid, beryllium salt (1:1)105.07550-600 °C (decomposes to beryllium oxide)Colorless crystal2.443Forms soluble tetrahydrate in hot water; insoluble in cold water.
Beryllium sulfate tetrhydrate7787-56-6Sulfuric acid; beryllium salt (1:1), tetrahydrate177.14100 °CColorless, tetragonal crystal1.713Soluble in water; slightly soluble in concentrated sulfuric acid; insoluble in ethanol.
Beryllium Oxide1304-56-9Beryllia; beryllium monoxide thermalox TM25.012508-2547 °CColorless to white, hexagonal crystal or amorphous, amphoteric powder3.01 (20 °C)Soluble in concentrated acids and alkali; insoluble in water.
Beryllium carbonate1319-43-3Carbonic acid, beryllium salt, mixture with beryllium hydroxide112.05No dataWhite powderNo dataSoluble in acids and alkali; insoluble in cold water; decomposes in hot water.
Beryllium nitrate trihydrate7787-55-5Nitric acid, beryllium salt, trihydrate187.9760White to faintly yellowish, deliquescent mass1.56Very soluble in water and ethanol.
Beryllium phosphate13598-15-7Phosphoric acid, beryllium salt (1:1)104.99No dataNot reportedNot reportedSlightly soluble in water.
ATSDR, 2002.

The physical and chemical properties of beryllium were realized early in the 20th century, and it has since gained commercial importance in a wide range of industries. Beryllium is lightweight, hard, spark resistant, non-magnetic, and has a high melting point. It lends strength, electrical and thermal conductivity, and fatigue resistance to alloys (NTP, 2014). Beryllium also has a high affinity for oxygen in air and water, which can cause a thin surface film of beryllium oxide to form on the bare metal, making it extremely resistant to corrosion. These properties make beryllium alloys highly suitable for defense, nuclear, and aerospace applications (IARC, 1993).

There are approximately 45 mineralized forms of beryllium. In the United States, the predominant mineral form mined commercially and refined into pure beryllium and beryllium alloys is bertrandite. Bertrandite, while containing less than 1% beryllium compared to 4% in beryl, is easily and efficiently processed into beryllium hydroxide (IARC, 1993). Imported beryl is also converted into beryllium hydroxide as the United States has very little beryl that can be economically mined (USGS, 2013a).

Industrial Uses

Materion Corporation, formerly called Brush Wellman, is the only producer of primary beryllium in the United States. Beryllium is used in a variety of industries, including aerospace, defense, telecommunications, automotive, electronic, and medical specialty industries. Pure beryllium metal is used in a range of products such as X-ray transmission windows, nuclear reactor neutron reflectors, nuclear weapons, precision instruments, rocket propellants, mirrors, and computers (NTP, 2014). Beryllium oxide is used in components such as ceramics, electrical insulators, microwave oven components, military vehicle armor, laser structural components, and automotive ignition systems (ATSDR, 2002). Beryllium oxide ceramics are used to produce sensitive electronic items such as lasers and satellite heat sinks.

Beryllium alloys, typically beryllium/copper or beryllium/aluminum, are manufactured as high beryllium content or low beryllium content alloys. High content alloys contain greater than 30% beryllium. Low content alloys are typically less than 3% beryllium. Beryllium alloys are used in automotive electronics (e.g., electrical connectors and relays and audio components), computer components, home appliance parts, dental appliances (e.g., crowns), bicycle frames, golf clubs, and other articles (NTP, 2014; Ballance et al., 1978; Cunningham et al., 1998; Mroz, et al., 2001). Electrical components and conductors are stamped and formed from beryllium alloys. Beryllium-copper Start Printed Page 47581alloys are used to make switches in automobiles (Ballance et al., 1978, 2002; Cunningham et al., 1998) and connectors, relays, and switches in computers, radar, satellite, and telecommunications equipment (Mroz et al., 2001). Beryllium-aluminum alloys are used in the construction of aircraft, high resolution medical and industrial X-ray equipment, and mirrors to measure weather patterns (Mroz et al., 2001). High content and low content beryllium alloys are precision machined for military and aerospace applications. Some welding consumables are also manufactured using beryllium.

Beryllium is also found as a trace metal in materials such as aluminum ore, abrasive blasting grit, and coal fly ash. Abrasive blasting grits such as coal slag and copper slag contain varying concentrations of beryllium, usually less than 0.1% by weight. The burning of bituminous and sub-bituminous coal for power generation causes the naturally occurring beryllium in coal to accumulate in the coal fly ash byproduct. Scrap and waste metal for smelting and refining may also contain beryllium. A detailed discussion of the industries and job tasks using beryllium is included in the Preliminary Economic Analysis (OSHA, 2014).

Occupational exposure to beryllium can occur from inhalation of dusts, fume, and mist. Beryllium dusts are created during operations where beryllium is cut, machined, crushed, ground, or otherwise mechanically sheared. Mists can also form during operations that use machining fluids. Beryllium fume can form while welding with or on beryllium components, and from hot processes such as those found in metal foundries.

Occupational exposure to beryllium can also occur from skin, eye, and mucous membrane contact with beryllium particulate or solutions.

V. Health Effects

Beryllium-associated health effects, including acute beryllium disease (ABD), beryllium sensitization (also referred to in this preamble as “sensitization”), chronic beryllium disease (CBD), and lung cancer, can lead to a number of highly debilitating and life-altering conditions including pneumonitis, loss of lung capacity (reduction in pulmonary function leading to pulmonary dysfunction), loss of physical capacity associated with reduced lung capacity, systemic effects related to pulmonary dysfunction, and decreased life expectancy (NIOSH, 1972).

This Health Effects section presents information on beryllium and its compounds, the fate of beryllium in the body, research that relates to its toxic mechanisms of action, and the scientific literature on the adverse health effects associated with beryllium exposure, including ABD, sensitization, CBD, and lung cancer. OSHA considers CBD to be a progressive illness with a continuous spectrum of symptoms ranging from no symptomatology at its earliest stage following sensitization to mild symptoms such as a slight almost imperceptible shortness of breath, to loss of pulmonary function, debilitating lung disease, and, in many cases, death. This section also discusses the nature of these illnesses, the scientific evidence that they are causally associated with occupational exposure to beryllium, and the probable mechanisms of action with a more thorough review of the supporting studies.

A. Beryllium and Beryllium Compounds

1. Particle Physical/Chemical Properties

Beryllium (Be; CAS No. 7440-41-7) is a steel-grey, brittle metal with an atomic number of 4 and an atomic weight of 9.01 (Group IIA of the periodic table). Because of its high reactivity, beryllium is not found as a free metal in nature; however, there are approximately 45 mineralized forms of beryllium. Beryllium compounds and alloys include commercially valuable metals and gemstones.

Beryllium has two oxidative states: Be(0) and Be(2+) Agency for Toxic Substance and Disease Registry (ATSDR) 2002). It is likely that the Be(2+) state is the most biologically reactive and able to form a bond with peptides leading to it becoming antigenic (Snyder et al., 2003). This will be discussed in more detail in the Beryllium Sensitization section below. Beryllium has a high charge-to-radius ratio and in addition to forming various types of ionic bonds, beryllium has a strong tendency for covalent bond formation (e.g., it can form organometallic compounds such as Be(CH3)2 and many other complexes) (ATSDR, 2002; Greene et al., 1998). However, it appears that few, if any, toxicity studies exist for the organometallic compounds. Additional physical/chemical properties for beryllium compounds that may be important in their biological response are summarized in Table 1 below. This information was obtained from their International Chemical Safety Cards (ICSC) (beryllium metal (ICSC 0226), beryllium oxide (ICSC 1325), beryllium sulfate (ICSC 1351), beryllium nitrate (ICSC 1352), beryllium carbonate (ICSC 1353), beryllium chloride (ICSC 1354), beryllium fluoride (ICSC 1355)) and from the hazardous substance data bank (HSDB) for beryllium hydroxide (CASRN: 13327-32-7), and beryllium phosphate (CASRN: 13598-15-7). Additional information on chemical and physical properties as well as industrial uses for beryllium can be found in this preamble at Section IV, Chemical Properties and Industrial Uses.

Table 1—Physical/Chemical Properties of Beryllium and Compounds

Compound namePhysical appearanceChemical formulaMolecular massAcute physical hazardsSolubility in water at 20 °C
Beryllium MetalGrey to White PowderBe9.0Combustible; Finely dispersed particles—ExplosiveNone.
Beryllium OxideWhite Crystals or PowderBeO25.0Not combustible or explosiveVery sparingly soluble.
Beryllium CarbonateWhite PowderBe2 CO3 (OH)/Be2 CO5 H2181.07Not combustible or explosiveNone.
Beryllium SulfateColorless CrystalsBeSO4105.1Not combustible or explosiveSlightly soluble.
Beryllium NitrateWhite to Yellow SolidBeN2 O6/Be(NO3)2133.0Enhances combustion of other substancesVery soluble (1.66 × 106 mg/L).
Beryllium HydroxideWhite amorphous powder or crystalline solidBe(OH)243.0Not reportedSlightly soluble 0.8 × 10−4 mol/L (3.44 mg/L).
Beryllium ChlorideColorless to Yellow CrystalsBeCl279.9Not combustible or explosiveSoluble.
Beryllium FluorideColorless LumpsBeF247.0Not combustible or explosiveVery soluble.
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Beryllium PhosphateWhite solidBe3 (PO4)2271.0Not reportedSoluble.
Source: International Chemical Safety Cards (except beryllium phosphate and hydroxide—HSDB).

Beryllium shows a high affinity for oxygen in air and water, resulting in a thin surface film of beryllium oxide on the bare metal. If the surface film is disturbed, it may become airborne or dermal exposure may occur. The solubility, particle surface area, and particle size of some beryllium compounds are examined in more detail below. These properties have been evaluated in many toxicological studies. In particular, the properties related to the calcination (firing temperatures) and differences in crystal size and solubility are important aspects in their toxicological profile.

2. Factors Affecting Potency and Effect of Beryllium Exposure

The effect and potency of beryllium and its compounds, as for any toxicant, immunogen, or immunotoxicant, may be dependent upon the physical state in which they are presented to a host. For occupational airborne materials and surface contaminants, it is especially critical to understand those physical parameters in order to determine the extent of exposure to the respiratory tract and skin since these are generally the initial target organs for either route of exposure.

For example, large particles may have less of an effect in the lung than smaller particles due to reduced potential to stay airborne to be inhaled or be deposited along the respiratory tract. In addition, once inhalation occurs particle size is critical in determining where the particle will deposit along the respiratory tract. Solubility also has an important part in determining the toxicity and bioavailability of airborne materials as well. Respiratory tract retention and skin penetration are directly influenced by the solubility and reactivity of airborne material.

These factors may be responsible, at least in part, for the process by which beryllium sensitization progresses to CBD in exposed workers. Other factors influencing beryllium-induced toxicity include the surface area of beryllium particles and their persistence in the lung. With respect to dermal exposure, the physical characteristics of the particle are important as well since they can influence skin absorption and bioavailability. This section addresses certain physical characteristics (i.e., solubility, particle size, particle surface area) that are important in influencing the toxicity of beryllium materials in occupational settings.

a. Solubility

Solubility may be an important determinant of the toxicity of airborne materials, influencing the deposition and persistence of inhaled particles in the respiratory tract, their bioavailability, and the likelihood of presentation to the immune system. A number of chemical agents, including metals that contact and penetrate the skin, are able to induce an immune response, such as sensitization (Boeniger, 2003; Mandervelt et al., 1997). Similar to inhaled agents, the ability of materials to penetrate the skin is also influenced by solubility since dermal absorption may occur at a greater rate for soluble materials than insoluble materials (Kimber et al., 2011).

This section reviews the relevant information regarding solubility, its importance in a biological matrix and its relevance to sensitization and beryllium lung disease. The weight of evidence presented below suggests that both soluble and non-soluble forms of beryllium can induce a sensitization response and result in progression of lung disease.

Beryllium salts, including the chloride (BeCl2), fluoride (BeF2), nitrate (Be(NO3)2), phosphate (Be3 (PO4)2), and sulfate (tetrahydrate) (BeSO4 · 4H2 O) salts, are all water soluble. However, soluble beryllium salts can be converted to less soluble forms in the lung (Reeves and Vorwald, 1967). Aqueous solutions of the soluble beryllium salts are acidic as a result of the formation of Be(OH2)4 2+, the tetrahydrate, which will react to form insoluble hydroxides or hydrated complexes within the general physiological range of pH values (between 5 and 8) (EPA, 1998). This may be an important factor in the development of CBD since lower-solubility forms of beryllium have been shown to persist in the lung for longer periods of time and persistence in the lung may be needed in order for this disease to occur (NAS, 2008).

Beryllium oxide (BeO), hydroxide (Be(OH)2), carbonate (Be2 CO3 (OH)2), and sulfate (anhydrous) (BeSO4) are either insoluble, slightly soluble, or considered to be sparingly soluble (almost insoluble or having an extremely slow rate of dissolution). The solubility of beryllium oxide, which is prepared from beryllium hydroxide by calcining (heating to a high temperature without fusing in order to drive off volatile chemicals) at temperatures between 500 and 1,750 °C, has an inverse relationship with calcination temperature. Although the solubility of the low-fired crystals can be as much as 10 times that of the high-fired crystals, low-fired beryllium oxide is still only sparingly soluble (Delic, 1992). In a study that measured the dissolution kinetics (rate to dissolve) of beryllium compounds calcined at different temperatures, Hoover et al., compared beryllium metal to beryllium oxide particles and found them to have similar solubilities. This was attributed to a fine layer of beryllium oxide that coats the metal particles (Hoover et al., 1989). A study conducted by Deubner et al., (2011) determined ore materials to be more soluble than beryllium oxide at pH 7.2 but similar in solubility at pH 4.5. Beryllium hydroxide was more soluble than beryllium oxide at both pHs (Deubner et al., 2011).

Investigators have also attempted to determine how biological fluids can dissolve beryllium materials. In two studies, insoluble beryllium, taken up by activated phagocytes, was shown to be ionized by myeloperoxidases (Leonard and Lauwerys, 1987; Lansdown, 1995). The positive charge resulting from ionization enabled the beryllium to bind to receptors on the surface of cells such as lymphocytes or antigen-presenting cells which could make it more biologically active (NAS, 2008). In a study utilizing phagolysosomal-simulating fluid (PSF) with a pH of 4.5, both beryllium metal and beryllium oxide dissolved at a greater rate than that previously reported in water or SUF (simulant fluid) (Stefaniak et al., 2006), and the rate of dissolution of the multi-constituent (mixed) particles was greater than that of the single-constituent beryllium oxide powder. The authors speculated that copper in the particles rapidly dissolves, exposing the small inclusions of beryllium oxide, which have higher specific surface areas (SSA) Start Printed Page 47583and therefore dissolve at a higher rate. A follow-up study by the same investigational team (Duling et al., 2012) confirmed dissolution of beryllium oxide by PSF and determined the release rate was biphasic (initial rapid diffusion followed by a latter slower surface reaction-driven release). During the latter phase, dissolution half-times were 1,400 to 2,000 days. The authors speculated this indicated bertrandite was persistent in the lung (Duling et al., 2012).

In a recent study investigating the dissolution and release of beryllium ions for 17 beryllium-containing materials (ore, hydroxide, metal, oxide, alloys, and processing intermediates) using artificial human airway epithelial lining fluid, Stefaniak et al., (2011) found release of beryllium ions within 7 days (beryl ore melter dust). The authors calculated dissolution half-times ranging from 30 days (reduction furnace material) to 74,000 days (hydroxide). Stefaniak et al., (2011) speculated that despite the rapid mechanical clearance, billions of beryllium ions could be released in the respiratory tract via dissolution in airway lining fluid (ALF). Under this scenario beryllium-containing particles depositing in the respiratory tract dissolving in ALF could provide beryllium ions for absorption in the lung and interact with immune cells in the respiratory tract (Stefaniak et al., 2011).

Huang et al., (2011) investigated the effect of simulated lung fluid (SLF) on dissolution and nanoparticle generation and beryllium-containing materials. Bertrandite-containing ore, beryl-containing ore, frit (a processing intermediate), beryllium hydroxide (a processing intermediate) and silica (used as a control), were equilibrated in SLF at two pH values (4.5 and 7.2) to reflect inter- and intra-cellular environments in the lung tissue. Concentrations of beryllium, aluminum, and silica ions increased linearly during the first 20 days in SLF, rose slowly thereafter, reaching equilibrium over time. The study also found nanoparticle formation (in the size range of 10-100 nm) for all materials (Huang et al., 2011).

In an in vitro skin model, Sutton et al., (2003) demonstrated the dissolution of beryllium compounds (insoluble beryllium hydroxide, soluble beryllium phosphate) in a simulated sweat fluid. This model showed beryllium can be dissolved in biological fluids and be available for cellular uptake in the skin. Duling et al., (2012) confirmed dissolution and release of ions from bertrandite ore in an artificial sweat model (pH 5.3 and pH 6.5).

b. Particle Size

The toxicity of beryllium as exemplified by beryllium oxide also is dependent, in part, on the particle size, with smaller particles (<10 μm) able to penetrate beyond the larynx (Stefaniak et al., 2008). Most inhalation studies and occupational exposures involve quite small (<1-2 μm) beryllium oxide particles that can penetrate to the pulmonary regions of the lung (Stefaniak et al., 2008). In inhalation studies with beryllium ores, particle sizes are generally much larger, with deposition occurring in several areas throughout the respiratory tract for particles <10 μm.

The temperature at which beryllium oxide is calcined influences its particle size, surface area, solubility, and ultimately its toxicity (Delic, 1992). Low-fired (500 °C) beryllium oxide is predominantly made up of poorly crystallized small particles, while higher firing temperatures (1000—1750 °C) result in larger particle sizes (Delic, 1992).

In order to determine the extent to which particle size plays a role in the toxicity of beryllium in occupational settings, several key studies are reviewed and detailed below. The findings on particle size have been related, where possible, to work process and biologically relevant toxicity endpoints of either sensitization or CBD.

Numerous studies have been conducted evaluating the particle size generated during basic industrial and machining operations. In a study by Cohen et al., (1983), a multi-cyclone sampler was utilized to measure the size mass distribution of the beryllium aerosol at a beryllium-copper alloy casting operation. Briefly, Cohen et al., (1983) found variable particle size generation based on the operations being sampled with particle size ranging from 3 to 16 μm. Hoover et al., (1990) also found variable particle sizes being generated based on operations. In general, Hoover et al., (1990) found that milling operations generated smaller particle sizes than sawing operations. Hoover et al., (1990) also found that beryllium metal generated higher concentrations than metal alloys. Martyny et al., (2000) characterized generation of particle size during precision beryllium machining processes. The study found that more than 50 percent of the beryllium machining particles collected in the breathing zone of machinists were less than 10 μm in aerodynamic diameter with 30 percent of that fraction being particles of less than 0.6 μm. A study by Thorat et al., (2003) found similar results with ore mixing, crushing, powder production and machining ranging from 5.0 to 9.5 μm. Kent et al., (2001) measured airborne beryllium using size-selective samplers in five furnace areas at a beryllium processing facility. A statistically significant linear trend was reported between the above alveolar-deposited particle mass concentration and prevalence of CBD and sensitization in the furnace production areas. The study authors suggested that the concentration of alveolar-deposited particles (e.g., <3.5 μm) may be a better predictor of sensitization and CBD than the total mass concentration of airborne beryllium.

A recent study by Virji et al. (2011) evaluated particle size distribution, chemistry and solubility in areas with historically elevated risk of sensitization and CBD at a beryllium metal powder, beryllium oxide, and alloy production facility. The investigators observed that historically, exposure-response relationships have been inconsistent when using mass concentration to identify process-related risk, possibly due to incomplete particle characterization. Two separate exposure surveys were conducted in March 1999 and June-August 1999 using multi-stage personal impactor samplers (to determine particle size distribution) and personal 37 mm closed face cassette (CFC) samplers, both located in workers' breathing zones. One hundred and ninety eight time-weighted-average (TWA) personal impactor samples were analyzed for representative jobs and processes. A total of 4,026 CFC samples were collected over the 5-month collection period and analyzed for mass concentration, particle size, chemical content and solubility and compared to process areas with high risk of sensitization and CBD. The investigators found that total beryllium concentration varied greatly between workers and among process areas. Analysis of chemical form and solubility also revealed wide variability among process areas, but high risk process areas had exposures to both soluble and insoluble forms of beryllium. Analysis of particle size revealed most process areas had particles ranging from 5-14 µm mass median aerodynamic diameter (MMAD). Rank order correlating jobs to particle size showed high overall consistency (Spearman r=0.84) but moderate correlation (Pearson r=0.43). The investigators concluded that consideration of relevant aspects of exposure such as particle size Start Printed Page 47584distribution, chemical form, and solubility will likely improve exposure assessments (Virji et al., 2011)

c. Particle Surface Area.

Particle surface area has been postulated as an important metric for beryllium exposure. Several studies have demonstrated a relationship between the inflammatory and tumorigenic potential of ultrafine particles and their increased surface area (Driscoll, 1996; Miller, 1995; Oberdorster et al., 1996). While the exact mechanism explaining how particle surface area influences its biological activity is not known, a greater particle surface area has been shown to increase inflammation, cytokine production, anti-oxidant defenses and apoptosis (Elder et al., 2005; Carter et al., 2006; Refsne et al., 2006).

Finch et al., (1988) found that beryllium oxide calcined at 500 °C had 3.3 times greater specific surface area (SSA) than beryllium oxide calcined at 1000 °C, although there was no difference in size or structure of the particles as a function of calcining temperature. The beryllium-metal aerosol (airborne beryllium particles), although similar to the beryllium oxide aerosols in aerodynamic size, had an SSA about 30 percent that of the beryllium oxide calcined at 1000 °C. As discussed above, a later study by Delic (1992) found calcining temperatures had an effect on SSA as well as particle size.

Several studies have investigated the lung toxicity of beryllium oxide calcined at different temperatures and generally had found that those calcined at lower temperatures have greater toxicity and effect than materials calcined at higher temperatures. This may be because beryllium oxide fired at the lower temperature has a loosely formed crystalline structure with greater specific surface area than the fused crystal structure of beryllium oxide fired at the higher temperature. For example, beryllium oxide calcined at 500 °C has been found to have stronger pathogenic effects than material calcined at 1,000 °C, as shown in several of the beagle dog, rat, mouse and guinea pig studies discussed in the section on CBD pathogenesis that follows (Finch et al., 1988; Polak et al., 1968; Haley et al., 1989; Haley et al., 1992; Hall et al., 1950). Finch et al. have also observed higher toxicity of beryllium oxide calcined at 500 °C, an observation they attribute to the greater surface area of beryllium particles calcined at the lower temperature (Finch et al., 1988). These authors found that the in vitro cytotoxicity to Chinese hamster ovary (CHO) cells and cultured lung epithelial cells of 500 °C beryllium oxide was greater than that of 1,000 °C beryllium oxide, which in turn was greater than that of beryllium metal. However, when toxicity was expressed in terms of particle surface area, the cytotoxicity of all three forms was similar. Similar results were observed in a study comparing the cytotoxicity of beryllium metal particles of various sizes to cultured rat alveolar macrophages, although specific surface area did not entirely predict cytotoxicity (Finch et al., 1991).

Stefaniak et al., (2003b) investigated the particle structure and surface area of particles (powder and process-sampled) of beryllium metal, beryllium oxide, and copper-beryllium alloy. Each of these samples was separated by aerodynamic size, and their chemical compositions and structures were determined with x-ray diffraction and transmission electron microscopy, respectively. In summary, beryllium-metal powder varied remarkably from beryllium oxide powder and alloy particles. The metal powder consisted of compact particles, in which SSA decreases with increasing surface diameter. In contrast, the alloys and oxides consisted of small primary particles in clusters, in which the SSA remains fairly constant with particle size. SSA for the metal powders varied based on production and manufacturing process with variations among samples as high as a factor of 37. Stefaniak et al. (2003b) found lesser variation in SSA for the alloys or oxides. This is consistent with data from other studies summarized above showing that process may affect particle size and surface area. Particle size and/or surface area may explain differences in the rate of BeS and CBD observed in some epidemiological studies. However, these properties have not been consistently characterized in most studies.

B. Kinetics and Metabolism of Beryllium

Beryllium enters the body by inhalation, ingestion, or absorption through the skin. For occupational exposure, the airways and the skin are the primary routes of uptake.

1. Exposure via the Respiratory System

The respiratory tract, especially the lung, is the primary target of inhalation exposure in workers. Inhaled beryllium particles are deposited along the respiratory tract in a size dependent manner. In general, particles larger than 10 μm tend to deposit in the upper respiratory tract or nasal region and do not appreciably penetrate lower in the tracheobronchial or pulmonary regions (Figure 1). Particles less than 10 μm increasingly penetrate and deposit in the tracheobronchial and pulmonary regions with peak deposition in the pulmonary region occurring below 5 μm in particle diameter. The CBD pathology of concern is found in the pulmonary region. For particles below 1 μm, regional deposition changes dramatically. Ultrafine particles (generally considered to be 100 nm or lower) have a higher rate of deposition along the entire respiratory system (ICRP model, 1994). Those particles depositing in the lung and along the entire respiratory tract may encounter immunologic cells or may move into the vascular system where they are free to leave the lung and can contribute to systemic beryllium concentrations.

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Beryllium is removed from the respiratory tract by various clearance mechanisms. Soluble beryllium is removed from the respiratory tract via absorption. Sparingly soluble or insoluble beryllium may remain in the lungs for many years after exposure, as has been observed in workers (Schepers, 1962). Clearance mechanisms for sparingly soluble or insoluble beryllium particles include: In the nasal passage, sneezing, mucociliary transport to the throat, or dissolution; in the tracheobronchial region, mucociliary transport, coughing, phagocytosis, or dissolution; in the pulmonary or alveolar region, phagocytosis, movement through the interstitium (translocation), or dissolution (Schlesinger, 1997).

Clearance mechanisms may occur slowly in humans, which is consistent with some animal studies. For example, subjects in the Beryllium Case Registry (BCR), which identifies and tracks cases of acute and chronic beryllium diseases, had elevated concentrations of beryllium in lung tissue (e.g., 3.1 μg/g of dried lung tissue and 8.5 μg/g in a mediastinal node) more than 20 years after termination of short-term (generally between 2 and 5 years) occupational exposure to beryllium (Sprince et al., 1976).

Clearance rates may depend on the solubility, dose, and size of the beryllium particles inhaled as well as the sex and species of the animal tested. As reviewed in a WHO Report (2001), more soluble beryllium compounds generally tend to be cleared from the respiratory system and absorbed into the bloodstream more rapidly than less soluble compounds (Van Cleave and Kaylor, 1955; Hart et al., 1980; Finch et al., 1990). Animal inhalation or intratracheal instillation studies administering soluble beryllium salts demonstrated significant absorption of approximately 20 percent of the initial lung burden, while sparingly soluble compounds such as beryllium oxide demonstrated that absorption was slower and less significant (Delic, 1992). Additional animal studies have demonstrated that clearance of soluble and sparingly soluble beryllium compounds was biphasic: A more rapid initial mucociliary transport phase of particles from the tracheobronchial tree to the gastrointestinal tract, followed by a slower phase via translocation to tracheobronchial lymph nodes, alveolar macrophages uptake, and beryllium particles dissolution (Camner et al., 1977; Sanders et al., 1978; Delic, 1992; WHO, 2001). Confirmatory studies in rats have shown the half-time for the rapid phase between 1-60 days, while the slow phase ranged from 0.6-2.3 years. It was also shown that this process was influenced by the solubility of the beryllium compounds: Weeks/months for soluble compounds, months/years for sparingly soluble compounds (Reeves and Vorwald, 1967; Reeves et al., 1967; Zorn et al., 1977; Rhoads and Sanders, 1985). Studies in guinea-pigs and rats indicate that 40-50 percent of the inhaled soluble beryllium salts are retained in the respiratory tract. Similar data could not be found for the sparingly or less soluble beryllium compounds or metal administered by this exposure route. (WHO, 2001; ATSDR, 2002).

Evidence from animal studies suggests that greater amounts of beryllium deposited in the lung may result in slower clearance times. A comparative study of rats and mice using a single dose of inhaled aerosolized beryllium metal demonstrated that an acute inhalation exposure to beryllium metal can slow particle clearance and induce lung damage in rats (Haley et al., 1990) and mice (Finch et al., 1998a). In another study Finch et al. (1994) exposed male F344/N rats to beryllium metal at concentrations resulting in beryllium lung burdens of 1.8, 10, and 100 µg. These exposure levels resulted in an estimated clearance half-life ranging Start Printed Page 47586from 250-380 days for the three concentrations. For mice (Finch et al., 1998a), lung clearance half-lives were 91-150 days (for 1.7- and 2.6-μg lung burden groups) or 360-400 days (for 12- and 34-μg lung burden groups). While the lower exposure groups were quite different for rats and mice, the highest groups were similar in clearance half-lives for both species.

Beryllium absorbed from the respiratory system is mainly distributed to the tracheobronchial lymph nodes via the lymph system, bloodstream, and skeleton, which is the ultimate site of beryllium storage (Stokinger et al., 1953; Clary et al., 1975; Sanders et al., 1975; Finch et al., 1990). Trace amounts are distributed throughout the body (Zorn et al., 1977; WHO, 2001). Studies in rats have demonstrated accumulation of beryllium chloride in the skeletal system following intraperitoneal injection (Crowley et al., 1949; Scott et al., 1950) and accumulation of beryllium phosphate and beryllium sulfate in both nonparenchymal and parenchymal cells of the liver after intravenous administration in rats (Skilleter and Price, 1978). Studies have also demonstrated intracellular accumulation of beryllium oxide in bone marrow throughout the skeletal system after intravenous administration to rabbits (Fodor, 1977; WHO, 2001).

Systemic distribution of the more soluble compounds appears to be greater than that of the insoluble compounds (Stokinger et al., 1953). Distribution has also been shown to be dose dependent in research using intravenous administration of beryllium in rats; small doses were preferentially taken up in the skeleton, while higher doses were initially distributed preferentially to the liver. Beryllium was later mobilized from the liver and transferred to the skeleton (IARC, 1993). A half-life of 450 days has been estimated for beryllium in the human skeleton (ICRP, 1960). This indicates the skeleton may serve as a repository for beryllium that may later be reabsorbed by the circulatory system, making beryllium available to the immunological system.

2. Dermal Exposure

Beryllium compounds have been shown to cause skin irritation and sensitization in humans and certain animal models (Van Orstrand et al., 1945; de Nardi et al., 1953; Nishimura 1966; Epstein 1990; Belman, 1969; Tinkle et al., 2003; Delic, 1992). The Agency for Toxic Substances and Disease Registry (ATSDR) estimated that less than 0.1 percent of beryllium compounds are absorbed through the skin (ATSDR, 2002). However, even minute contact and absorption across the skin may directly elicit an immunological sensitization response (Deubner et al., 2001; Toledo et al., 2011). Recent studies by Tinkle et al. (2003) showed that penetration of beryllium oxide particles was possible ex vivo for human intact skin at particle sizes of ≤ 1μm, as confirmed by scanning electron microscopy. Using confocal microscopy, Tinkle et al. demonstrated that surrogate fluorescent particles up to 1 μm in size could penetrate the mouse epidermis and dermis layers in a model designed to mimic the flexing and stretching of human skin in motion. Other poorly soluble particles, such as titanium dioxide, have been shown to penetrate normal human skin (Tan et al., 1996) suggesting the flexing and stretching motion as a plausible mechanism for dermal penetration of beryllium as well. As earlier summarized, insoluble forms of beryllium can be solubilized in biological fluids (e.g., sweat) making them available for absorption through intact skin (Sutton et al., 2003; Stefaniak et al., 2011; Duling et al., 2012).

Although its precise role remains to be elucidated, there is evidence to indicate that dermal exposure can contribute to beryllium sensitization. As early as the 1940s it was recognized that dermatitis experienced by workers in primary beryllium production facilities was linked to exposures to the soluble beryllium salts. Except in cases of wound contamination, dermatitis was rare in workers whose exposures were restricted to exposure to poorly soluble beryllium-containing particles (Van Ordstrand et al., 1945). Further investigation by McCord in 1951 indicated that direct skin contact with soluble beryllium compounds, but not beryllium hydroxide or beryllium metal, caused dermal lesions (reddened, elevated, or fluid-filled lesions on exposed body surfaces) in susceptible persons. Curtis, in 1951, demonstrated skin sensitization to beryllium with patch testing using soluble and insoluble forms of beryllium in beryllium-naïve subjects. These subjects later developed granulomatous skin lesions with the classical delayed-type contact dermatitis following repeat challenge (Curtis, 1951). These lesions appeared after a latent period of 1-2 weeks, suggesting a delayed allergic reaction. The dermal reaction occurred more rapidly and in response to smaller amounts of beryllium in those individuals previously sensitized (Van Ordstrand et al., 1945). Contamination of cuts and scrapes with beryllium can result in the beryllium becoming embedded within the skin causing a granuloma to develop in the skin (Epstein, 1991). Introduction of soluble or insoluble beryllium compounds into or under the skin as a result of abrasions or cuts at work has been shown to result in chronic ulcerations with granuloma formation (Van Orstrand et al., 1945; Lederer and Savage, 1954). Beryllium absorption through bruises and cuts has been demonstrated as well (Rossman et al., 1991). In a study by Invannikov et al., (1982), beryllium chloride was applied directly to the skin of live animals with three types of wounds: abrasions (superficial skin trauma), cuts (skin and superficial muscle trauma), and penetration wounds (deep muscle trauma). The percentage of the applied dose absorbed into the systemic circulation during a 24-hour exposure was significant, ranging from 7.8 percent to 11.4 percent for abrasions, from 18.3 percent to 22.9 percent for cuts, and from 34 percent to 38.8 percent for penetration wounds (WHO, 2001).

A study by Deubner et al., (2001) concluded that exposure across damaged skin can contribute as much systemic loading of beryllium as inhalation (Deubner et al., 2001). Deubner et al., (2001) estimated dermal loading (amount of particles penetrating into the skin) in workers as compared to inhalation exposure. Deubner's calculations assumed a dermal loading rate for beryllium on skin of 0.43 μg/cm2, based on the studies of loading on skin after workers cleaned up (Sanderson et al., 1999), multiplied by a factor of 10 to approximate the workplace concentrations and the very low absorption rate of 0.001 percent (taken from EPA estimates). It should be noted that these calculations did not take into account absorption of soluble beryllium salts that might occur across nasal mucus membranes, which may result from contact between contaminated skin and the nose (EPA, 1998).

A study conducted by Day et al. (2007) evaluated the effectiveness of a dermal protection program implemented in a beryllium alloy facility in 2002. The investigators evaluated levels of beryllium in air, on workplace surfaces, on cotton gloves worn over nitrile gloves, and on the necks and faces of workers over a six day period. The investigators found a good correlation between air samples and work surface contamination at this facility. The investigators also found measurable levels of beryllium on the skin of workers as a result of work processes even from workplace areas Start Printed Page 47587promoted as “visually clean” by the company housekeeping policy. Importantly, the investigators found that the beryllium contamination could be transferred from body region to body region (e.g., hand to face, neck to face). The investigators demonstrated multiple pathways of exposure which could lead to sensitization, increasing risk for developing CBD (Day, et al., 2007).

The same group of investigators (Armstrong et al., 2014) extended their work on investigating multiple exposure pathways contributing to sensitization and CBD. The investigators evaluated four different beryllium manufacturing and processing facilities to assess the contribution of various exposure pathways on worker exposure. Airborne, work surface and cotton glove beryllium concentrations were evaluated. The investigators found strong correlations between air-surface concentrations, glove-surface concentrations, and air-glove concentrations at this facility. This work confirms findings from Day et al. (2007) demonstrating the importance of airborne beryllium concentrations to surface contamination and dermal exposure even at exposures below the current OSHA PEL (Armstrong et al., 2014).

3. Oral and Gastrointestinal Exposure

According to the WHO Report (2001), gastrointestinal absorption of beryllium can occur by both the inhalation and oral routes of exposure. Through inhalation exposure, a fraction of the inhaled material is transported to the gastrointestinal tract by the mucociliary escalator or by the swallowing of the insoluble material deposited in the upper respiratory tract (WHO, 2001). Gastrointestinal absorption of beryllium can occur by both the inhalation and oral routes of exposure. In the case of inhalation, a portion of the inhaled material is transported to the gastrointestinal tract by the mucociliary escalator or by the swallowing of the insoluble material deposited in the upper respiratory tract (Schlesinger, 1997). Animal studies have shown oral administration of beryllium compounds to result in very limited absorption and storage (as reviewed by U.S. EPA, 1998). In animal ingestion studies using radio-labeled beryllium chloride in rats, mice, dogs, and monkeys, the vast majority of the ingested dose passed through the gastrointestinal tract unabsorbed and was excreted in the feces. In most studies, <1 percent of the administered radioactivity was absorbed into the bloodstream and subsequently excreted in the urine (Crowley et al., 1949; Furchner et al., 1973; LeFevre and Joel, 1986). Research using soluble beryllium sulfate has shown that as the compound passes into the intestine, which has a higher pH than the stomach (approximate pH of 6 to 8 for the intestine, pH of 1 or 2 for the stomach), the beryllium is precipitated as the insoluble phosphate and thus is no longer available for absorption (Reeves, 1965; WHO, 2001).

Urinary excretion of beryllium has been shown to correlate with the amount of occupational exposure (Klemperer et al., 1951). Beryllium that is absorbed into the bloodstream is excreted primarily in the urine (Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973; Stiefel et al., 1980), whereas excretion of unabsorbed beryllium is primarily via the fecal route (Hart et al., 1980; Finch et al., 1990). A far higher percentage of the beryllium administered parenterally in various animal species was eliminated in the urine than in the feces (Crowley et al., 1949; Scott et al., 1950; Furchner et al., 1973), confirming that beryllium found in the feces following oral exposure is primarily unabsorbed material. A study using percutaneous incorporation of soluble beryllium nitrate in rats similarly demonstrated that more than 90 percent of the beryllium in the bloodstream was eliminated via urine (Zorn et al., 1977; WHO, 2001). More than 99 percent of ingested beryllium chloride was excreted in the feces (Mullen et al., 1972). Elimination half-times of 890-1,770 days (2.4-4.8 years) were calculated for mice, rats, monkeys, and dogs injected intravenously with beryllium chloride (Furchner et al., 1973). Mean daily excretion of beryllium metal was 4.6 × 10−5 percent of the dose administered by intratracheal instillation in baboons and 3.1 × 10−5 percent in rats (Andre et al., 1987).

4. Metabolism

Beryllium and its compounds are not metabolized or biotransformed, but soluble beryllium salts may be converted to less soluble forms in the lung (Reeves and Vorwald, 1967). As stated earlier, solubility is an important factor for persistence of beryllium in the lung. Insoluble beryllium, engulfed by activated phagocytes, can be ionized by an acidic environment and by myeloperoxidases (Leonard and Lauwerys, 1987; Lansdown, 1995; WHO, 2001), and this positive charge could potentially make it more biologically reactive because it may allow the beryllium to bind to a peptide or protein and be presented to the T cell receptor or antigen-presenting cell (Fontenot, 2000).

5. Preliminary Conclusion for Particle Characterization and Kinetics of Beryllium

The forms and concentrations of beryllium across the workplace vary substantially based upon location, process, production and work task. Many factors influence the potency of beryllium including concentration, composition, structure, size and surface area of the particle.

Studies have demonstrated that beryllium sensitization can occur via the skin or inhalation from soluble or poorly soluble beryllium particles. Beryllium must be presented to a cell in a soluble form for activation of the immune system (NAS, 2008), and this will be discussed in more detail in the section to follow. Poorly soluble beryllium can be solubilized via intracellular fluid, lung fluid and sweat (Sutton et al., 2003; Stefaniak et al., 2011). For beryllium to persist in the lung it needs to be insoluble. However, soluble beryllium has been shown to precipitate in the lung to form insoluble beryllium (Reeves and Vorwald, 1967).

Some animal and epidemiological studies suggest that the form of beryllium may affect the rate of development of BeS and CBD. Beryllium in an inhalable form (either as soluble or insoluble particles or mist) can deposit in the respiratory tract and interact with immune cells located along the entire respiratory tract (Scheslinger, 1997). However, more study is needed to precisely determine the physiochemical characteristics of beryllium that influence toxicity and immunogenicity.

C. Acute Beryllium Diseases

Acute beryllium disease (ABD) is a relatively rapid onset inflammatory reaction resulting from breathing high airborne concentrations of beryllium. It was first reported in workers extracting beryllium oxide (Van Ordstrand et al., 1943). Since the Atomic Energy Commission's adoption of occupational exposure limits for beryllium beginning in 1949, cases of ABD have been rare. According to the World Health Organization (2001), ABD is generally associated with exposure to beryllium levels at or above 100 μg/m3 and may be fatal in 10 percent of cases. However, cases have been reported with beryllium exposures below 100 µg/m3 (Cummings et al., 2009). The disease involves an inflammatory reaction that may include the entire respiratory tract, involving the nasal passages, pharynx, bronchial airways and alveoli. Other tissues including skin and conjunctivae may be affected as well. The clinical features of Start Printed Page 47588ABD include a nonproductive cough, chest pain, cyanosis, shortness of breath, low-grade fever and a sharp drop in functional parameters of the lungs. Pathological features of ABD include edematous distension, round cell infiltration of the septa, proteinaceous materials, and desquamated alveolar cells in the lung. Monocytes, lymphocytes and plasma cells within the alveoli are also characteristic of the acute disease process (Freiman and Hardy, 1970).

Two types of acute beryllium disease have been characterized in the literature: a rapid and severe course of acute fulminating pneumonitis generally developing within 48 to 72 hours of a massive exposure, and a second form that takes several days to develop from exposure to lower concentrations of beryllium (still above the levels set by regulatory and guidance agencies) (Hall, 1950; DeNardi et al., 1953; Newman and Kreiss, 1992). Evidence of a dose-response relationship to the concentration of beryllium is limited (Eisenbud et al., 1948; Stokinger, 1950; Sterner and Eisenbud, 1951). Recovery from either type of ABD is generally complete after a period of several weeks or months (DeNardi et al., 1953). However, deaths have been reported in more severe cases (Freiman and Hardy, 1970). There have been documented cases of progression to CBD (ACCP, 1965; Hall, 1950) suggesting the possibility of an immune component to this disease (Cummings et al., 2009) as well. According to the BCR, in the United States, approximately 17 percent of ABD patients developed CBD (BCR, 2010). The majority of ABD cases occurred between 1932 and 1970 (Eisenbud, 1983; Middleton, 1998). ABD is extremely rare in the workplace today due to more stringent exposure controls implemented following occupational and environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974).

D. Chronic Beryllium Disease

This section provides an overview of the immunology and pathogenesis of BeS and CBD, with particular attention to the role of skin sensitization, particle size, beryllium compound solubility, and genetic variability in individuals' susceptibility to beryllium sensitization and CBD.

Chronic beryllium disease (CBD), formerly known as “berylliosis” or “chronic berylliosis,” is a granulomatous disorder primarily affecting the lungs. CBD was first described in the literature by Hardy and Tabershaw (1946) as a chronic granulomatous pneumonitis. It was proposed as early as 1951 that CBD could be a chronic disease resulting from an immune sensitization to beryllium (Sterner and Eisenbud, 1951; Curtis, 1959; Nishimura, 1966). However, for a time, there remained some controversy as to whether CBD was a delayed-onset hypersensitivity disease or a toxicant-induced disease (NAS, 2008). Wide acceptance of CBD as a hypersensitivity lung disease did not occur until bronchoscopy studies and bronchoalveolar lavage (BAL) studies were performed demonstrating that BAL cells from CBD patients responded to beryllium challenge (Epstein et al., 1982; Rossman et al., 1988; Saltini et al., 1989).

CBD shares many clinical and histopathological features with pulmonary sarcoidosis, a granulomatous lung disease of unknown etiology. This includes such debilitating effects as airway obstruction, diminishment of physical capacity associated with reduced lung function, possible depression associated with decreased physical capacity, and decreased life expectancy. Without appropriate information, CBD may be difficult to distinguish from sarcoidosis. It is estimated that up to 6 percent of all patients diagnosed with sarcoidosis may actually have CBD (Fireman et al., 2003; Rossman and Kreiber, 2003). Among patients diagnosed with sarcoidosis in which beryllium exposure can be confirmed, as many as 40 percent may actually have CBD (Muller-Quernheim et al., 2006; Cherry et al., 2015).

Clinical signs and symptoms of CBD may include, but are not limited to, a simple cough, shortness of breath or dypsnea, fever, weight loss or anorexia, skin lesions, clubbing of fingers, cyanosis, night sweats, cor pulmonale, tachycardia, edema, chest pain and arthralgia. Changes or loss of pulmonary function also occur with CBD such as decrease in vital capacity, reduced diffusing capacity, and restrictive breathing patterns. The signs and symptoms of CBD constitute a continuum of symptoms that are progressive in nature with no clear demarcation between any stages in the disease (Rossman, 1996; NAS, 2008). Besides these listed symptoms from CBD patients, there have been reported cases of CBD that remained asymptomatic (Muller-Querheim, 2005; NAS, 2008).

Unlike ABD, CBD can result from inhalation exposure to beryllium at levels below the current OSHA PEL, can take months to years after initial beryllium exposure before signs and symptoms of CBD occur (Newman 1996, 2005 and 2007; Henneberger, 2001; Seidler et al., 2012; Schuler et al., 2012), and may continue to progress following removal from beryllium exposure (Newman, 2005; Sawyer et al., 2005; Seidler et al., 2012). Patients with CBD can progress to a chronic obstructive lung disorder resulting in loss of quality of life and the potential for decreased life expectancy (Rossman, et al., 1996; Newman et al., 2005). The NAS report (2008) noted the general lack of published studies on progression of CBD from an early asymptomatic stage to functionally significant lung disease (NAS, 2008). The report emphasized that risk factors and time course for clinical disease have not been fully delineated. However, for people now under surveillance, clinical progression from immunological sensitization and early pathological lesions (i.e., granulomatous inflammation) prior to onset of symptoms to symptomatic disease appears to be slow, although more follow-up is needed (NAS, 2008). A study by Newman (1996) emphasized the need for prospective studies to determine the natural history and time course from BeS and asymptomatic CBD to full-blown disease (Newman, 1996). Drawing from his own clinical experience, Newman was able to identify the sequence of events for those with symptomatic disease as follows: Initial determination of beryllium sensitization; gradual emergence of chronic inflammation of the lung; pathologic alterations with measurable physiologic changes (e.g., pulmonary function and gas exchange); progression to a more severe lung disease (with extrapulmonary effects such as clubbing and cor pulmonale in some cases); and finally death in some cases (reported between 5.8 to 38 percent) (NAS, 2008; Newman, 1996).

In contrast to some occupationally related lung diseases, the early detection of chronic beryllium disease may be useful since treatment of this condition can lead not only to regression of the signs and symptoms, but also may prevent further progression of the disease in certain individuals (Marchand-Adam, 2008; NAS, 2008). The management of CBD is based on the hypothesis that suppression of the hypersensitivity reaction (i.e., granulomatous process) will prevent the development of fibrosis. However, once fibrosis has developed, therapy cannot reverse the damage.

To date, there have been no controlled studies to determine the optimal treatment for CBD (Rossman, 1996; NAS 2008; Sood, 2009). Management of CBD is generally modeled after sarcoidosis treatment. Oral corticosteroid treatment can be initiated in patients with Start Printed Page 47589evidence of disease (either by bronchoscopy or other diagnostic measures before progression of disease or after clinical signs of pulmonary deterioration occur). This includes treatment with other anti-inflammatory agents (NAS, 2008; Maier et al., 2012; Salvator et al., 2013) as well. It should be noted, however, that treatment with corticosteroids has side-effects of their own that need to be measured against the possibility of progression of disease (Gibson et al., 1996; Zaki et al., 1987). Alternative treatments such as azathiopurine and infliximab, while successful at treating symptoms of CBD, have been demonstrated to have side-effects as well (Pallavicino et al., 2013; Freeman, 2012).

1. Development of Beryllium Sensitization

Sensitization to beryllium is an essential step for worker development of CBD. Sensitization to beryllium can result from inhalation exposure to beryllium (Newman et al., 2005; NAS, 2008), as well as from skin exposure to beryllium (Curtis, 1951; Newman et al., 1996; Tinkle et al., 2003). Sensitization is currently detected using a laboratory blood test described in Appendix A. Although there may be no clinical symptoms associated with BeS, a sensitized worker's immune system has been activated to react to beryllium exposures such that subsequent exposure to beryllium can progress to serious lung disease (Kreiss et al., 1996; Kreiss et al., 1997; Kelleher et al., 2001; and Rossman, 2001). Since the pathogenesis of CBD involves a beryllium-specific, cell-mediated immune response, CBD cannot occur in the absence of sensitization (NAS, 2008). Various factors, including genetic susceptibility, have been shown to influence risk of developing sensitization and CBD (NAS 2008) and will be discussed later in this section.

While various mechanisms or pathways may exist for beryllium sensitization, the most plausible mechanisms supported by the best available and most current science are discussed below. Sensitization occurs via the formation of a beryllium-protein complex (an antigen) that causes an immunological response. In some instances, onset of sensitization has been observed in individuals exposed to beryllium for only a few months (Kelleher et al., 2001; Henneberger et al., 2001). This suggests the possibility that relatively brief, short-term beryllium exposures may be sufficient to trigger the immune hypersensitivity reaction. Several studies (Newman et al., 2001; Henneberger et al., 2001; Rossman, 2001; Schuler et al., 2005; Donovan et al., 2007, Schuler et al., 2012) have detected a higher prevalence of sensitization among workers with less than one year of employment compared to some cross-sectional studies which, due to lack of information regarding initial exposure, cannot determine time of sensitization (Kreiss et al., 1996; Kreiss et al., 1997). While only very limited evidence has described humoral changes in certain patients with CBD (Cianciara et al., 1980), clear evidence exists for an immune cell-mediated response, specifically the T-cell (NAS, 2008). Figure 2 delineates the major steps required for progression from beryllium contact to sensitization to CBD.

Start Printed Page 47590

Beryllium presentation to the immune system is believed to occur either by direct presentation or by antigen processing. It has been postulated that beryllium must be presented to the immune system in an ionic form for cell-mediated immune activation to occur (Kreiss et al., 2007). Some soluble forms of beryllium are readily presented, since the soluble beryllium form disassociates into its ionic components. However, for insoluble forms, dissolution may need to occur. A study by Harmsen et al. (1986) suggested that a sufficient rate of dissolution of small amounts of poorly soluble beryllium compounds might occur in the lungs to allow persistent low-level beryllium presentation to the immune system. Stefaniak et al. (2005 and 2012) reported that insoluble beryllium particles phagocytized by macrophages were dissolved in phagolysomal fluid (Stefaniak et al., 2005; Stefaniak et al., 2012) and that the dissolution rate stimulated by phagolysomal fluid was different for various forms of beryllium (Stefaniak et al., 2006; Duling et al., 2012). Several studies have demonstrated that macrophage uptake of beryllium can induce aberrant apoptotic processes leading to the continued release of beryllium ions which will continually stimulate T-cell activation (Sawyer et al., 2000; Sawyer et al., 2004; Kittle et al., 2002). Antigen processing can be mediated by antigen-presenting cells (APC). These may include macrophages, dendritic cells, or other antigen-presenting cells, although this has not been well defined in most studies (NAS, 2008).

Because of their strong positive charge, beryllium ions have the ability to haptenate and alter the structure of peptides occupying the antigen-binding cleft of major histocompatibility complex (MHC) class II on antigen-presenting cells (APC). The MHC class II antigen-binding molecule for beryllium is the human leukocyte antigen (HLA) with specific alleles (e.g., Start Printed Page 47591HLA-DP, HLA-DR, HLA-DQ) associated with the progression to CBD (NAS, 2008; Yucesoy and Johnson, 2011). Several studies have also demonstrated that the electrostatic charge of HLA may be a factor in binding beryllium (Snyder et al., 2003; Bill et al., 2005; Dai et al., 2010). The strong positive ionic charge of the beryllium ion would have a strong attraction for the negatively charged patches of certain HLA alleles (Snyder et al., 2008; Dai et al., 2010). Alternatively, beryllium oxide has been demonstrated to bind to the MHC class II receptor in a neutral pH. The six carboxylates in the amino acid sequence of the binding pocket provide a stable bond with the Be-O-Be molecule when the pH of the substrate is neutral (Keizer et al., 2005). The direct binding of BeO may eliminate the biological requirement for antigen processing or dissolution of beryllium oxide to activate an immune response.

Next in sequence is the beryllium-MHC-APC complex binding to a T-cell receptor (TCR) on a naïve T-cell which stimulates the proliferation and accumulation of beryllium-specific CD4+ (cluster of differentiation 4+) T-cells (Saltini et al., 1989 and 1990; Martin et al., 2011) as depicted in Figure 3. Fontenot et al. (1999) demonstrated that diversely different variants of TCR were expressed by CD4+ T-cells in peripheral blood cells of CBD patients. However, the CD4+ T-cells from the lung were more homologous in expression of TCR variants in CBD patients, suggesting clonal expansion of a subset of T-cells in the lung (Fontenot et al., 1999). This may also indicate a pathogenic potential for subsets of T-cell clones expressing this homologous TCR (NAS, 2008). Fontenot et al. (2006) reported beryllium self-presentation by HLA-DP expressing BAL CD4+ T-cells. Self-presentation by BAL T-cells in the lung granuloma may result in activation-induced cell death, which may then lead to oligoclonality of the T-cell population characteristic of CBD (NAS, 2008).

As CD4+ T-cells proliferate, clonal expansion of various subsets of the CD4+ beryllium specific T-cells occurs (Figure 3). In the peripheral blood, the beryllium-specific CD4+ T cells require co-stimulation with a co-stimulant CD28 (cluster of differentiation 28). During the proliferation and differentiation process CD4+ T-cells secrete pro-inflammatory cytokines that may influence this process (Sawyer et al., 2004; Kimber et al., 2011).

2. Development of CBD

The continued persistence of residual beryllium in the lung leads to a T-cell maturation process. A large portion of beryllium-specific CD4+ T cells were shown to cease expression of CD28 mRNA and protein, indicating these cells no longer required co-stimulation with the CD28 ligand (Fontenot et al., 2003). This change in phenotype correlated with lung inflammation (Fontenot et al., 2003). The CD4+ independent cells continued to secrete cytokines necessary for additional recruitment of inflammatory and immunological cells; however, they were less proliferative and less susceptible to cell death compared to the CD28 dependent cells (Fontenot et al., 2005; Mack et al., 2008). These beryllium-specific CD4+ independent cells are considered to be mature memory effector cells (Ndejembi et al., 2006; Bian et al., 2005). Repeat exposure to beryllium in the lung resulting in a mature population of T cell development independent of co-stimulation by CD28 and development of a population of T effector memory cells (Tem cells) may be one of the mechanisms that lead to the more severe reactions observed specifically in the lung (Fontenot et al., 2005).

CD4+ T cells created in the sensitization process recognize the beryllium antigen, and respond by proliferating and secreting cytokines and inflammatory mediators, including IL-2, IFN-γ, and TNF-α (Tinkle et al., 1997a and b; Fontenot et al., 2002) and MIP-1α and GRO-1 (Hong-Geller, 2006). This also results in the accumulation of various types of inflammatory cells including mononuclear cells (mostly CD4+ T cells) in the bronchoalveolar lavage fluid (BAL fluid) (Saltini et al., 1989, 1990).

The development of granulomatous inflammation in the lung of CBD patients has been associated with the accumulation of beryllium responsive CD4+ Tem cells in BAL fluid (NAS, 2008). The subsequent release of pro-inflammatory cytokines, chemokines and reactive oxygen species by these cells may lead to migration of additional inflammatory/immune cells and the development of a microenvironment that contributes to the development of CBD (Sawyer et al., 2005; Tinkle et al., 1996; Hong-Geller et al., 2006; NAS, 2008).

The cascade of events described above results in the formation of a noncaseating granulomatous lesion. Start Printed Page 47592Release of cytokines by the accumulating T cells leads to the formation of granulomatous lesions that are characterized by an outer ring of histiocytes surrounding non-necrotic tissue with embedded multi-nucleated giant cells (Saltini et al., 1989, 1990).

Over time, the granulomas spread and can lead to lung fibrosis and abnormal pulmonary function, with symptoms including a persistent dry cough and shortness of breath (Saber and Dweik, 2000). Fatigue, night sweats, chest and joint pain, clubbing of fingers (due to impaired oxygen exchange), loss of appetite or unexplained weight loss, and cor pulmonale have been experienced in certain patients as the disease progresses (Conradi et al., 1971; ACCP, 1965; Kriebel et al., 1988a and b). While CBD primarily affects the lungs, it can also involve other organs such as the liver, skin, spleen, and kidneys (ATSDR, 2002).

As previously mentioned, the uptake of beryllium may lead to an aberrant apoptotic process with rerelease of beryllium ions and continual stimulation of beryllium-responsive CD4+ cells in the lung (Sawyer et al., 2000; Kittle et al., 2002; Sawyer et al., 2004). Several research studies suggest apoptosis may be one mechanism that enhances inflammatory cell recruitment, cytokine production and inflammation, thus creating a scenario for progressive granulomatous inflammation (Palmer et al., 2008; Rana, 2008). Macrophages and neutrophils can phagocytize beryllium particles in an attempt to remove the beryllium from the lung (Ding, et al., 2009). Multiple studies (Sawyer et al., 2004; Kittle et al., 2002) using BAL cells (mostly macrophages and neutrophils) from patients with CBD found that in vitro stimulation with beryllium sulfate induced the production of TNF-α (one of many cytokines produced in response to beryllium), and that production of TNF-α might induce apoptosis in CBD and sarcoidosis patients (Bost et al., 1994; Dai et al., 1999). The stimulation of CBD-derived macrophages by beryllium sulphate resulted in cells becoming apoptotic, as measured by propidium iodide. These results were confirmed in a mouse macrophage cell-line (p388D1) (Sawyer et al., 2000). However, other factors may influence the development of CBD and are outlined in the following section.

3. Genetic and Other Susceptibility Factors

Evidence from a variety of sources indicates genetic susceptibility may play an important role in the development of CBD in certain individuals, especially at levels low enough not to invoke a response in other individuals. Early occupational studies proposed that CBD was an immune reaction based on the high susceptibility of some individuals to become sensitized and progress to CBD and the lack of CBD in others who were exposed to levels several orders of magnitude higher (Sterner and Eisenbud, 1951). Additional in vitro human research has identified genes coding for specific protein molecules on the surface of their immune cells that place carriers at greater risk of becoming sensitized to beryllium and developing CBD (McCanlies et al., 2004). Recent studies have confirmed genetic susceptibility to CBD involves either HLA variants, T-cell receptor clonality, tumor necrosis factor (TNF-α) polymorphisms and/or transforming growth factor-beta (TGF-β) polymorphisms (Fontenot et al., 2000; Amicosante et al., 2005; Tinkle et al., 1996; Gaede et al., 2005; Van Dyke et al., 2011; Silveira et al., 2012).

Single Nucleotide Polymorphisms (SNPs) have been studied with regard to genetic variations associated with increased risk of developing CBD. SNPs are the most abundant type of human genetic variation. Polymorphisms in MHC class II and pro-inflammatory genes have been shown to contribute to variations in immune responses contributing to the susceptibility and resistance in many diseases including auto-immunity, and beryllium sensitization and CBD (McClesky et al., 2009). Specific SNPs have been evaluated as a factor in Glu69 variant from the HLA-DPB1 locus (Richeldi et al., 1993; Cai et al., 2000; Saltini et al., 2001; Silviera et al., 2012; Dai et al., 2013), HLA-DRPheβ47 (Amicosante et al., 2005).

HLA-DPB1 with a glutamic acid at amino position 69 (Glu 69) has been shown to confer increased risk of beryllium sensitization and CBD (Richeldi et al., 1993; Saltini et al., 2001; Amicosante et al., 2005; Van Dyke et al., 2011; Silveira et al., 2012). Fontenot et al. (2000) demonstrated that beryllium presentation by certain alleles of the class II human leukocyte antigen-DP (HLA-DP) to CD4+ T cells is the mechanism underlying the development of CBD. Richeldi et al. (1993) reported a strong association between the MHC class II allele HLA-DP 1 and the development of CBD in beryllium-exposed workers from a Tucson, AZ facility. This marker was found in 32 of the 33 workers who developed CBD, but in only 14 of 44 similarly exposed workers without CBD. The more common allele of the HLA-DP 1 variant is negatively charged at this site and could directly interact with the positively charged beryllium ion. The high percentage (~30 percent) of beryllium-exposed workers without CBD who had this allele indicates that other factors also contribute to the development of CBD (EPA, 1998). Additional studies by Amicosante et al. (2005) using blood lymphocytes derived from beryllium-exposed workers found a high frequency of this gene in those sensitized to beryllium. In a study of 82 CBD patients (beryllium-exposed workers), Stubbs et al. (1996) also found a relationship between the HLA-DP 1 allele and BeS. The glutamate-69 allele was present in 86 percent of sensitized subjects, but in only 48 percent of beryllium-exposed, non-sensitized subjects. Some variants of the HLA-DPB1 allele convey higher risk of BeS and CBD than others. For example, HLA-DPB1*0201 yielded an approximately 3-fold increase in disease outcome relative to controls; HLA-DPB1*1901 yielded an approximately 5-fold increase, and HLA-DPB1*1701 an approximately 10-fold increase (Weston et al., 2005; Snyder et al., 2008). By assigning odds ratios for specific alleles on the basis of previous studies discussed above, the researchers found a strong correlation (88 percent) between the reported risk of CBD and the predicted surface electrostatic potential and charge of the isotypes of the genes. They were able to conclude that the alleles associated with the most negatively charged proteins carry the greatest risk of developing beryllium sensitization and CBD. This confirms the importance of beryllium charge as a key factor in haptogenic potential.

In contrast, the HLA-DRB1 allele, which lacks Glu 69, has also been shown to increase the risk of developing sensitization and CBD (Amicosante et al., 2005; Maier et al., 2003). Bill et al. (2005) found that HLA-DR has a glutamic acid at position 71 of the β chain, functionally equivalent to the Glu 69 of HLA-DP (Bill et al., 2005). Associations with BeS and CBD have also been reported with the HLA-DQ markers (Amicosante et al., 2005; Maier et al., 2003). Stubbs et al. also found a biased distribution of the MHC class II HLA-DR gene between sensitized and non-sensitized subjects. Neither of these markers was completely specific for CBD, as each study found beryllium sensitization or CBD among individuals without the genetic risk factor. While there remains uncertainty as to which of the MHC class II genes interact directly with the beryllium ion, antibody inhibition data suggest that the HLA-DR gene product may be involved in the Start Printed Page 47593presentation of beryllium to T lymphocytes (Amicosante et al., 2002). In addition, antibody blocking experiments revealed that anti-HLA-DP strongly reduced proliferation responses and cytokine secretion by BAL CD4 T cells (Chou et al., 2005). In the study by Chou (2005), anti-HLA-DR ligand antibodies mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4 T cells may still contribute to inflammation leading to the progression of CBD (Chou et al., 2005).

TNF alpha (TNF-α) polymorphisms and TGF beta (TGF-β) polymorphisms have also been shown to confer a genetic susceptibility for developing CBD in certain individuals. TNF-α is a pro-inflammatory cytokine associated with a more severe pulmonary disease in CBD (NAS, 2008). Beryllium exposure has been shown to upregulate transcription factors AP-1 and NF-κB (Sawyer et al., 2007) inducing an inflammatory response by stimulating production of pro-inflammatory cytokines such as TNF-α by inflammatory cells. Polymorphisms in the 308 position of the TNF-α gene have been demonstrated to increase production of the cytokine and increase severity of disease (Maier et al., 2001; Saltini et al., 2001; Dotti et al., 2004). While a study by McCanlies et al. (2007) found no relationship between TNF-α polymorphism and BeS or CBD, the inconsistency may be due to misclassification, exposure differences or statistical power (NAS, 2008).

Other genetic variations have been shown to be associated with increased risk of beryllium sensitization and CBD (NAS, 2008). These include TGF-β (Gaede et al., 2005), angiotensin-1 converting enzyme (ACE) (Newman et al., 1992; Maier et al., 1999) and an enzyme involved in glutathione synthesis (glutamate cysteine ligase) (Bekris et al., 2006). McCanlies et al. (2010) evaluated the association between polymorphisms in a select group of interleukin genes (IL-1A; IL-1B, IL-1RN, IL-2, IL-9, IL-9R) due to their role in immune and inflammatory processes. The study evaluated SNPs in three groups of workers from large beryllium manufacturing facilities in OH and AZ. The investigators found a significant association between variants IL-1A-1142, IL-1A-3769 and IL-1A-4697 and CBD but not with beryllium sensitization. However, these still require confirmation in larger studies (NAS, 2008).

In addition to the genetic factors which may contribute to the susceptibility and severity of disease, other factors such as smoking and gender may play a role in the development of CBD (NAS, 2008). A recent longitudinal cohort study by Mroz et al. (2009) of 229 individuals identified with beryllium sensitization or CBD through workplace medical surveillance found that the prevalence of CBD among ever smokers was significantly lower than among never smokers (38.1 percent versus 49.4 percent, p=0.025). BeS subjects that never smoked were found to be more likely to develop CBD over the course of the study compared to current smokers (12.6 percent versus 6.4 percent, p=0.10). The authors suggested smoking may confer a protective effect against development of lung granulomas as has been demonstrated with hypersensitivity pneumonitis (Mroz et al., 2009).

4. Beryllium Sensitization and CBD in the Workforce

Sensitization to beryllium is currently detected in the workforce with the beryllium lymphocyte proliferation test (BeLPT), a laboratory blood test developed in the 1980s, also referred to as the LTT (Lymphocyte Transformation Test) or BeLT (Beryllium Lymphocyte Transformation Test). In this test, lymphocytes obtained from either bronchoalveolar lavage fluid (the BAL BeLPT) or from peripheral blood (the blood BeLPT) are cultured in vitro and exposed to beryllium sulfate to stimulate lymphocyte proliferation. The observation of beryllium-specific proliferation indicates beryllium sensitization. Hereafter, “BeLPT” generally refers to the blood BeLPT, which is typically used in screening for beryllium sensitization. This test is described in more detail in subsection D.5.b.

CBD can be detected at an asymptomatic stage by a number of techniques including bronchoalveolar lavage and biopsy (Cordeiro et al., 2007; Maier, 2001). Bronchoalveolar lavage is a method of “washing” the lungs with fluid inserted via a flexible fiberoptic instrument known as a bronchoscope, removing the fluid and analyzing the content for the inclusion of immune cells reactive to beryllium exposure, as described earlier in this section. Fiberoptic bronchoscopy can be used to detect granulomatous lung inflammation prior to the onset of CBD symptoms as well, and has been used in combination with the BeLPT to diagnose pre-symptomatic CBD in a number of recent screening studies of beryllium-exposed workers, which are discussed in the following section detailing diagnostic procedures. Of workers who were found to be sensitized and underwent clinical evaluation, 31-49 percent of them were diagnosed with CBD (Kreiss et al., 1993; Newman et al., 1996, 2005, 2007; Mroz, 2009), however some estimate that with increased surveillance the percent could be much higher (Newman, 2005; Mroz, 2009). It has been estimated from ongoing surveillance studies of sensitized individuals with an average follow-up time of 4.5 years that 31 percent of beryllium-sensitized employees were estimated to progress to CBD (Newman et al., 2005). A study of nuclear weapons facility employees enrolled in an ongoing medical surveillance program found that only 20 percent of sensitized workers employed less than 5 years eventually were diagnosed with CBD, while 40 percent of sensitized workers employed 10 years or more developed CBD (Stange et al., 2001). One limitation for all these studies is lack of long-term follow-up. It may be necessary to continue to monitor these workers in order to determine whether all BeS workers will develop CBD (Newman et al., 2005).

CBD has a clinical spectrum ranging from evidence of beryllium sensitization and granulomas in the lung with little symptomatology to loss of lung function and end stage disease which may result in the need for lung transplantation and decreased life expectancy. Unfortunately, there are very few published clinical studies describing the full range and progression of CBD from the beginning to the end stages and very few of the risk factors for progression of disease have been delineated (NAS, 2008). Clinical management of CBD is modeled after sarcoidosis where oral corticosteroid treatment is initiated in patients who have evidence of progressive lung disease, although progressive lung disease has not been well defined (NAS, 2008). In advanced cases of CBD, corticosteroids are the standard treatment (NAS, 2008). No comprehensive studies have been published measuring the overall effect of removal of workers from beryllium exposure on sensitization and CBD (NAS, 2008) although this has been suggested as part of an overall treatment regime for CBD (Mapel et al., 2002; Sood et al., 2004; Maier et al., 2006; Sood, 2009; Maier et al., 2012). Sood et al. reported that cessation of exposure can sometimes have beneficial effects on lung function (Sood et al., 2004). However, this was based on anecdotal evidence from six patients with CBD, so more research is needed to better determine the relationship between Start Printed Page 47594exposure duration and disease progression

5. Human Epidemiological Studies

This section describes the human epidemiological data supporting the mechanistic overview of beryllium-induced disease in workers. It has been divided into reviews of epidemiological studies performed prior to development and implementation of the BeLPT in the late 1980s and after wide use of the BeLPT for screening purposes. Use of the BeLPT has allowed investigators to screen for beryllium sensitization and CBD prior to the onset of clinical symptoms, providing a more sensitive and thorough analysis of the worker population. The discussion of the studies has been further divided by manufacturing processes that may have similar exposure profiles. Table A.1 in the Appendix summarizes the prevalence of beryllium sensitization and CBD, range of exposure measurements, and other salient information from the key epidemiological studies.

It has been well-established that beryllium exposure, either via inhalation or skin, may lead to beryllium sensitization, or, with inhalation exposure, may lead to the onset and progression of CBD. The available published epidemiological literature discussed below provides strong evidence of beryllium sensitization and CBD in workers exposed to airborne beryllium well below the current OSHA PEL of 2 μg/m3. Several studies demonstrate the prevalence of sensitization and CBD is related to the level of airborne exposure, including a cross-sectional survey of employees at a beryllium ceramics plant in Tucson, AZ (Henneberger et al., 2001), case-control studies of workers at the Rocky Flats nuclear weapons facility (Viet et al., 2000), and workers from a beryllium machining plant in Cullman, AL (Kelleher et al., 2001). The prevalence of beryllium sensitization also may be related to dermal exposure. An increased risk of CBD has been reported in workers with skin lesions, potentially increasing the uptake of beryllium (Curtis, 1951; Johnson et al., 2001; Schuler et al., 2005). Three studies describe comprehensive preventive programs, which included expanded respiratory protection, dermal protection, and improved control of beryllium dust migration, that substantially reduced the rate of beryllium sensitization among new hires (Cummings et al., 2007; Thomas et al., 2009; Bailey et al., 2010; Schuler et al., 2012).

Some of the epidemiological studies presented in this review suffer from challenges common to many published epidemiological studies: Limitations in study design (particularly cross-sectional); small sample size; lack of personal and/or short-term exposure data, particularly those published before the late 1990s; and incomplete information regarding specific chemical form and/or particle characterization. Challenges that are specific to beryllium epidemiological studies include: uncertainty regarding the contribution of dermal exposure; use of various BeLPT protocols; a variety of case definitions for determining CBD; and use of various exposure sampling/assessment methods (e.g., daily weighted average (DWA), lapel sampling). Even with these limitations, the epidemiological evidence presented in this section clearly demonstrates that beryllium sensitization and CBD are continuing to occur from present-day exposures below OSHA's PEL. The available literature also indicates that the rate of BeS can be substantially lowered by reducing inhalation exposure and minimizing dermal contact.

a. Studies Conducted Prior to the BeLPT

First reports of CBD came from studies performed by Hardy and Tabershaw (1946). Cases were observed in industrial plants that were refining and manufacturing beryllium metal and beryllium alloys and in plants manufacturing fluorescent light bulbs (NAS, 2008). From the late 1940s through the 1960s, clusters of non-occupational CBD cases were identified around beryllium refineries in Ohio and Pennsylvania, and outbreaks in family members of beryllium factory workers were assumed to be from exposure to contaminated clothes (Hardy, 1980). It had been established that the risk of disease among beryllium workers was variable and generally rose with the levels of airborne concentrations (Machle et al., 1948). And while there was a relationship between air concentrations of beryllium and risk of developing disease both in and surrounding these plants, the disease rates outside the plants were higher than expected and not very different from the rate of CBD within the plants (Eisenbud et al., 1949; Lieben and Metzner, 1959). There remained considerable uncertainty regarding diagnosis due to lack of well-defined cohorts, modern diagnostic methods, or inadequate follow-up. In fact, many patients with CBD may have been misdiagnosed with sarcoidosis (NAS, 2008).

The difficulties in distinguishing lung disease caused by beryllium from other lung diseases led to the establishment of the BCR in 1952 to identify and track cases of ABD and CBD. A uniform diagnostic criterion was introduced in 1959 as a way to delineate CBD from sarcoidosis. Patient entry into the BCR required either: documented past exposure to beryllium or the presence of beryllium in lung tissue as well as clinical evidence of beryllium disease (Hardy et al., 1967); or any three of the six criteria listed below (Hasan and Kazemi, 1974). Patients identified using the above criteria were registered and added to the BCR from 1952 through 1983 (Eisenbud and Lisson, 1983).

The BCR listed the following criteria for diagnosing CBD (Eisenbud and Lisson, 1983):

(1) Establishment of significant beryllium exposure based on sound epidemiologic history;

(2) Objective evidence of lower respiratory tract disease and clinical course consistent with beryllium disease;

(3) Chest X-ray films with radiologic evidence of interstitial fibronodular disease;

(4) Evidence of restrictive or obstructive defect with diminished carbon monoxide diffusing capacity (DLCO) by physiologic studies of lung function;

(5) Pathologic changes consistent with beryllium disease on examination of lung tissue; and

(6) Presence of beryllium in lung tissue or thoracic lymph nodes.

Prevalence of CBD in workers during the time period between the 1940s and 1950s was estimated to be between 1-10% (Eisenbud and Lisson, 1983). In a 1969 study, Stoeckle et al. presented 60 case histories with a selective literature review utilizing the above criteria except that urinary beryllium was substituted for lung beryllium to demonstrate beryllium exposure. Stoeckle et al. (1969) were able to demonstrate corticosteroids as a successful treatment option in one case of confirmed CBD. This study also presented a 28 percent mortality rate from complications of CBD at the time of publication. However, even with the improved methodology for determining CBD based on the BCR criteria, these studies suffered from lack of well-defined cohorts, modern diagnostic techniques or adequate follow-up.

b. Criteria for Beryllium Sensitization and CBD Case Definition Following the Development of the BeLPT

The criteria for diagnosis of CBD have evolved over time as more advanced Start Printed Page 47595diagnostic technology, such as the (blood) BeLPT and BAL BeLPT, has become available. More recent diagnostic criteria have both higher specificity than earlier methods and higher sensitivity, identifying subclinical effects. Recent studies typically use the following criteria (Newman et al., 1989; Pappas and Newman, 1993; Maier et al., 1999):

(1) History of beryllium exposure;

(2) Histopathological evidence of noncaseating granulomas or mononuclear cell infiltrates in the absence of infection; and

(3) Positive blood or BAL BeLPT (Newman et al., 1989).

The availability of transbronchial lung biopsy facilitates the evaluation of the second criterion, by making histopathological confirmation possible in almost all cases.

A significant component for the identification of CBD is the demonstration of a confirmed abnormal BeLPT result in a blood or BAL sample (Newman, 1996). Since the development of the BeLPT in the 1980s, it has been used to screen beryllium-exposed workers for sensitization in a number of studies to be discussed below. The BeLPT is a non-invasive in vitro blood test which measures the beryllium antigen-specific T-cell mediated immune response and is the most commonly available diagnostic tool for identifying beryllium sensitization. The BeLPT measures the degree to which beryllium stimulates lymphocyte proliferation under a specific set of conditions, and is interpreted based upon the number of stimulation indices that exceed the normal value. The `cut-off' is based on the mean value of the peak stimulation index among controls plus 2 or 3 standard deviations. This methodology was modeled into a statistical method known as the “least absolute values” or “statistical-biological positive” method and relies on natural log modeling of the median stimulation index values (DOE, 2001; Frome, 2003). In most applications, two or more stimulation indices that exceed the cut-off constitute an abnormal test.

Early versions of the BeLPT test had high variability, but the use of tritiated thymidine to identify proliferating cells has led to a more reliable test (Mroz et al., 1991; Rossman et al., 2001). In recent years, the peripheral blood test has been found to be as sensitive as the BAL assay, although larger abnormal responses have been observed with the BAL assay (Kreiss et al., 1993; Pappas and Newman, 1993). False negative results have also been observed with the BAL BeLPT in cigarette smokers who have marked excess of alveolar macrophages in lavage fluid (Kreiss et al., 1993). The BeLPT has also been a useful tool in animal studies to identify those species with a beryllium-specific immune response (Haley et al., 1994).

Screenings for beryllium sensitization have been conducted using the BeLPT in several occupational surveys and surveillance programs, including nuclear weapons facilities operated by the Department of Energy (Viet et al., 2000; Strange et al., 2001; DOE/HSS Report, 2006), a beryllium ceramics plant in Arizona (Kreiss et al., 1996; Henneberger et al., 2001; Cummings et al., 2007), a beryllium production plant in Ohio (Kreiss et al., 1997; Kent et al., 2001), a beryllium machining facility in Alabama (Kelleher et al., 2001; Madl et al., 2007), a beryllium alloy plant (Schuler et al., 2005, Thomas et al., 2009), and another beryllium processing plant (Rosenman et al., 2005) in Pennsylvania. In most of these studies, individuals with an abnormal BeLPT result were retested and were identified as sensitized (i.e., confirmed positive) if the abnormal result was repeated.

There has been criticism regarding the reliability and specificity of the BeLPT as a screening tool (Borak et al., 2006). Stange et al. (2004) studied the reliability and laboratory variability of the BeLPT by splitting blood samples and sending samples to two laboratories simultaneously for BeLPT analysis. Stange et al. found the range of agreement on abnormal (positive BeLPT) results was 26.2—61.8 percent depending upon the labs tested (Stange et al., 2004). Borak et al. (2006) contended that the positive predictive value (PPV) (PPV is the portion of patients with positive test result correctly diagnosed) is not high enough to meet the criteria of a good screening tool. Middleton et al. (2008) used the data from the Stange et al. (2004) study to estimate the PPV and determined that the PPV of the BeLPT could be improved from 0.383 to 0.968 when an abnormal BeLPT result is confirmed with a second abnormal result (Middleton et al., 2008). However, an apparent false positive can occur in people not occupationally exposed to beryllium (NAS, 2008). An analysis of survey data from the general workforce and new employees at a beryllium manufacturer was performed to assess the reliability of the BeLPT (Donovan et al. 2007). Donovan et al. analyzed more than 10,000 test results from nearly 2400 participants over a 12-year period. Donovan et al. found that approximately 2 percent of new employees had at least one positive BeLPT at the time of hire and 1 percent of new hires with no known occupational exposure were confirmed positive at the time of hire with two BeLPTs. Since there are currently no alternatives to the BeLPT in a screening program many programs rely on a second test to confirm a positive result (NAS, 2008).

The epidemiological studies presented in this section utilized the BeLPT as either a surveillance tool or a screening tool for determining sensitization status and/or sensitization/CBD prevalence in workers for inclusion in the published studies. Most epidemiological studies have reported rates of sensitization and disease based on a single screening of a working population (‘cross-sectional' or 'population prevalence' rates). Studies of workers in a beryllium machining plant and a nuclear weapons facility have included follow-up of the population originally screened, resulting in the detection of additional cases of sensitization over several years (Newman et al., 2001, Stange et al., 2001). OSHA regards the BeLPT as a reliable medical surveillance tool. The BeLPT is discussed in more detail in Non-Mandatory Appendix A to the proposed standard, Immunological Testing for the Determination of Beryllium Sensitization.

c. Beryllium Mining and Extraction

Mining and extraction of beryllium usually involves the two major beryllium minerals, beryl (an aluminosilicate containing up to 4 percent beryllium) and bertrandite (a beryllium silicate hydrate containing generally less than 1 percent beryllium) (WHO, 2001). The United States is the world leader in beryllium extraction and also leads the world in production and use of beryllium and its alloys (WHO, 2001). Most exposures from mining and extraction come in the form of beryllium ore, beryllium salts, beryllium hydroxide (NAS 2008) or beryllium oxide (Stefaniak et al., 2008).

Deubner et al. published a study of 75 workers employed at a beryllium mining and extraction facility in Delta, UT (Deubner et al., 2001b). Of the 75 workers surveyed for sensitization with the BeLPT, three were identified as sensitized by an abnormal BeLPT result. One of those found to be sensitized was diagnosed with CBD. Exposures at the facility included primarily beryllium ore and salts. General area (GA), breathing zone (BZ), and personal lapel (LP) exposure samples were collected from 1970 to 1999. Jobs involving beryllium hydrolysis and wet-grinding activities had the highest air concentrations, with an annual median GA concentration ranging from 0.1 to 0.4 μg/m3. Median BZ concentrations Start Printed Page 47596were higher than either LP or GA. The average duration of exposure for beryllium sensitized workers was 21.3 years (27.7 years for the worker with CBD), compared to an average duration for all workers of 14.9 years. However, these exposures were less than either the Elmore, OH, or Tucson, AZ, facilities described below, which also had higher reported rates of BeS and CBD. A study by Stefaniak et al. (2008) demonstrated that beryllium was present at the mill in three forms: mineral, poorly crystalline oxide, and hydroxide.

There was no sensitization or CBD among those who worked only at the mine where exposure to beryllium resulted solely from working with bertrandite ore. The authors concluded that the results of this study indicated that beryllium ore and salts may pose less of a hazard than beryllium metal and beryllium hydroxide. These results are consistent with the previously discussed animal studies examining solubility and particle size.

d. Beryllium Metal Processing and Alloy Production

Kreiss et al. (1997) conducted a study of workers at a beryllium production facility in Elmore, OH. The plant, which opened in 1953 and initially specialized in production of beryllium-copper alloy, later expanded its operations to include beryllium metal, beryllium oxide, and beryllium-aluminum alloy production; beryllium and beryllium alloy machining; and beryllium ceramics production, which was moved to a different factory in the early 1980s. Production operations included a wide variety of jobs and processes, such as work in arc furnaces and furnace rebuilding, alloy melting and casting, beryllium powder processing, and work in the pebble plant. Non-production work included jobs in the analytical laboratory, engineering research and development, maintenance, laundry, production-area management, and office-area administration. While the publication refers to the use of respiratory protection in some areas, such as the pebble plant, the extent of its use across all jobs or time periods was not reported. Use of dermal PPE was not reported.

The authors characterized exposures at the plant using industrial hygiene (IH) samples collected between 1980 and 1993. The exposure samples and the plant's formulas for estimating workers' DWA exposures were used, together with study participants' work histories, to estimate their cumulative and average beryllium exposure levels. Exposure concentrations reflected the high exposures found historically in beryllium production and processing. Short-term BZ measurements had a median of 1.4, with 18.5 percent of samples exceeding OSHA's STEL of 5.0 μg/m3. Particularly high beryllium concentrations were reported in the areas of beryllium powder production, laundry, alloy arc furnace (approximately 40 percent of DWA estimates over 2.0 μg/m3) and furnace rebuild (28.6 percent of short-term BZ samples over the OSHA STEL of 5 μg/m3). LP samples (n = 179), which were available from 1990 to 1992, had a median value of 1 μg/m3.

Of 655 workers employed at the time of the study, 627 underwent BeLPT screening. Blood samples were divided and split between two labs for analysis, with repeat testing for results that were abnormal or indeterminate. Thirty-one workers had an abnormal blood test upon initial testing and at least one of two subsequent tests was classified as sensitized. These workers, together with 19 workers who had an initial abnormal result and one subsequent indeterminate result, were offered clinical evaluation for CBD including the BAL-BeLPT and transbronchial lung biopsy. Nine with an initial abnormal test followed by two subsequent normal tests were not clinically evaluated, although four were found to be sensitized upon retesting in 1995. Of 47 workers who proceeded with evaluation for CBD (3 of the 50 initial workers with abnormal results declined to participate), 24 workers were diagnosed with CBD based on evidence of granulomas on lung biopsy (20 workers) or on other findings consistent with CBD (4 workers) (Kreiss et al., 1997). After including five workers who had been diagnosed prior to the study, a total of 29 (4.6 percent) current workers were found to have CBD. In addition, the plant medical department identified 24 former workers diagnosed with CBD before the study.

Kreiss et al. reported that the highest prevalence of sensitization and CBD occurred among workers employed in beryllium metal production, even though the highest airborne total mass concentrations of beryllium were generally among employees operating the beryllium alloy furnaces in a different area of the plant (Kreiss et al., 1997). Preliminary follow-up investigations of particle size-specific sampling at five furnace sites within the plant determined that the highest respirable (e.g., particles <10 μm in diameter as defined by the authors) and alveolar-deposited (e.g., particles <1 μm in diameter as defined by the authors) beryllium mass and particle number concentrations, as collected by a general area impactor device, were measured at the beryllium metal production furnaces rather than the beryllium alloy furnaces (Kent et al., 2001; McCawley et al., 2001). A statistically significant linear trend was reported between the above alveolar-deposited particle mass concentration and prevalence of CBD and sensitization in the furnace production areas. The authors concluded that alveolar-deposited particles may be a more relevant exposure metric for predicting the incidence of CBD or sensitization than the total mass concentration of airborne beryllium.

Bailey et al. (2010) evaluated the effectiveness of a workplace preventive program in lowering BeS at the beryllium metal, oxide, and alloy production plant studied by Kreiss et al. (1997). The preventive program included use of administrative and PPE controls (e.g., improved training, skin protection and other PPE, half-mask or air-purified respirators, medical surveillance, improved housekeeping standards, clean uniforms) as well as engineering controls (e.g., migration controls, physical separation of administrative offices from production facilities) implemented over the course of five years.

In a cross-sectional/longitudinal hybrid study, Bailey et al. compared rates of sensitization in pre-program workers to those hired after the preventive program began. Pre-program workers were surveyed cross-sectionally in 1993-1994, and again in 1999 using the BeLPT to determine sensitization and CBD prevalence rates. The 1999 cross-sectional survey was conducted to determine if improvements in engineering and administrative controls were successful, however, results indicated no improvement in reducing rates of sensitization or CBD.

An enhanced preventive program including particle migration control, respiratory and dermal protection, and process enclosure was implemented in 2000, with continuing improvements made to the program in 2001, 2002-2004, and 2005. Workers hired during this period were longitudinally surveyed for sensitization using the BeLPT. Both the pre-program and program survey of worker sensitization status utilized split-sample testing to verify positive test results using the BeLPT. Of the total 660 workers employed at the production plant, 258 workers participated from the pre-program group while 290 participated from the program group (206 partial program, 84 full program). Prevalence comparisons of the pre-program and Start Printed Page 47597program groups (partial and full) were performed by calculating prevalence ratios. A 95 percent confidence interval (95 percent CI) was derived using a cohort study method that accounted for the variance in survey techniques (cross-sectional versus longitudinal) (Bailey et al., 2010). The sensitization prevalence of the pre-program group was 3.8 times higher (95 percent CI, 1.5-9.3) than the program group, 4.0 times higher (95 percent CI, 1.4-11.6) than the partial program subgroup, and 3.3 times higher (95 percent CI, 0.8-13.7) than the full program subgroup indicating that a comprehensive preventive program can reduce, but not eliminate, occurrence of sensitization among non-sensitized workers (Bailey et al., 2010).

Rosenman et al. (2005) studied a group of several hundred workers who had been employed at a beryllium production and processing facility that operated in eastern Pennsylvania between 1957 and 1978. Of 715 former workers located, 577 were screened for BeS with the BLPT and 544 underwent chest radiography to identify cases of BeS and CBD. Workers were reported to have exposure to beryllium dust and fume in a variety of chemical forms including beryl ore, beryllium metal, beryllium fluoride, beryllium hydroxide, and beryllium oxide.

Rosenman et al. used the plant's DWA formulas to assess workers' full-shift exposure levels, based on IH data collected between 1957-1962 and 1971-1976, to calculate exposure metrics including cumulative, average, and peak for each worker in the study. The DWA was calculated based on air monitoring that consisted of GA and short-term task-based BZ samples. Workers' exposures to specific chemical and physical forms of beryllium were assessed, including insoluble beryllium (metal and oxide), soluble beryllium (fluoride and hydroxide), mixed soluble and insoluble beryllium, beryllium dust (metal, hydroxide, or oxide), fume (fluoride), and mixed dust and fume. Use of respiratory or dermal protection by workers was not reported. Exposures in the plant were high overall. Representative task-based IH samples ranged from 0.9 μ g/m3 to 84 μ g/m3 in the 1960s, falling to a range of 0.5-16.7 μ g/m3 in the 1970s. A large number of workers' mean DWA estimates (25 percent) were above the OSHA PEL of 2.0 μ g/m3, while most workers had mean DWA exposures between 0.2 and 2.0 μ g/m3 (74 percent) or below 0.02 μ g/m3 (1 percent) (Rosenman et al., Table 11; revised erratum April, 2006).

Blood samples for the BeLPT were collected from the former workers between 1996 and 2001 and were evaluated at a single laboratory. Individuals with an abnormal test result were offered repeat testing, and were classified as sensitized if the second test was also abnormal. Sixty workers with two positive BeLPTs and 50 additional workers with chest radiography suggestive of disease were offered clinical evaluation, including bronchoscopy with bronchial biopsy and BAL-BeLPT. Seven workers met both criteria. Only 56 (51 percent) of these workers proceeded with clinical evaluation, including 57 percent of those referred on the basis of confirmed abnormal BeLPT and 47 percent of those with abnormal radiographs.

Of those workers who underwent bronchoscopy, 32 (5.5 percent) with evidence of granulomas were classified as “definite” CBD cases. Twelve (2.1 percent) additional workers with positive BAL-BeLPT or confirmed positive BeLPT and radiographic evidence of upper lobe fibrosis were classified as “probable” CBD cases. Forty workers (6.9 percent) without upper lobe fibrosis who had confirmed abnormal BeLPT, but who were not biopsied or who underwent biopsy with no evidence of granuloma, were classified as sensitized without disease. It is not clear how many of the 40 workers underwent biopsy. Another 12 (2.1 percent) workers with upper lobe fibrosis and negative or unconfirmed positive BeLPT were classified as “possible” CBD cases. Nine additional workers who were diagnosed with CBD before the screening were included in some parts of the authors' analysis.

The authors reported a total prevalence of 14.5 percent for CBD (definite and probable) and sensitization. This rate, considerably higher than the overall prevalence of sensitization and disease in several other worker cohorts as described earlier in this section, reflects in part the very high exposures experienced by many workers during the plant's operation in the 1950s, 1960s and 1970s. A total of 115 workers had mean DWAs above the OSHA PEL of 2 μ g/m3. Of those, 7 (6.0 percent) had definite or probable CBD and another 13 (11 percent) were classified as sensitized without disease. The true prevalence of CBD in the group may be higher than reported, due to the low rate of clinical evaluation among sensitized workers.

Although most of the workers in this study had high exposures, sensitization and CBD also were observed within the small subgroup of participants believed to have relatively low beryllium exposures. Thirty-three cases of CBD and 24 additional cases of sensitization occurred among 339 workers with mean DWA exposures below OSHA's PEL of 2.0 μ g/m3 (Rosenman et al., Table 11, erratum 2006). Ten cases of sensitization and five cases of CBD were found among office and clerical workers, who were believed to have low exposures (levels not reported).

Follow-up time for sensitization screening of workers in this study who became sensitized during their employment had a minimum of 20 years to develop CBD prior to screening. In this sense the cohort is especially well suited to compare the exposure patterns of workers with CBD and those sensitized without disease, in contrast to several other studies of workers with only recent beryllium exposures. Rosenman et al. characterized and compared the exposures of workers with definite and probable CBD, sensitization only, and no disease or sensitization using chi-squared tests for discrete outcomes and analysis of variance (ANOVA) for continuous variables (cumulative, mean, and peak exposure levels). Exposure-response relationships were further examined with logistic regression analysis, adjusting for potential confounders including smoking, age, and beryllium exposure from outside of the plant. The authors found that cumulative, peak, and duration of exposure were significantly higher for workers with CBD than for sensitized workers without disease (p <0.05), suggesting that the risk of progressing from sensitization to CBD is related to the level or extent of exposure a worker experiences. The risk of developing CBD following sensitization appeared strongly related to exposure to insoluble forms of beryllium, which are cleared slowly from the lung and increase beryllium lung burden more rapidly than quickly mobilized soluble forms. Individuals with CBD had higher exposures to insoluble beryllium than those classified as sensitized without disease, while exposure to soluble beryllium was higher among sensitized individuals than those with CBD.

Cumulative, mean, peak, and duration of exposure were found to be comparable for workers with CBD and workers without sensitization or CBD (“normal” workers). Cumulative, peak, and duration of exposure were significantly lower for sensitized workers without disease than for normal workers. Rosenman et al. suggested that genetic predisposition to sensitization and CBD may have obscured an exposure-response relationship in this study, and plan to control for genetic risk factors in future studies. Exposure misclassification from the 1950s and 1960s may have been another limitation in this study, introducing bias that Start Printed Page 47598could have influenced the lack of exposure response. It is also unknown if the 25 percent who died from CBD-related conditions may have had higher exposures.

A follow-up was conducted of the cross-sectional study of a population of workers first evaluated by Kreiss et al. (1997) and Rosenman et al. (2005) at a beryllium production and processing facility in eastern Pennsylvania by Schuler et al. (2012), and in a companion study by Virji et al. (2012). Schuler et al. evaluated the worker population employed in 1999 with six years or less work tenure in a cross-sectional study. The investigators evaluated the worker population by administering a work history questionnaire with a follow-up examination for sensitization and CBD. A job-exposure matrix (JEM) was combined with work histories to create individual estimates of average, cumulative, and highest-job-related exposure for total, respirable, and sub-micron beryllium mass concentration. Of the 291 eligible workers, 90.7 percent (264) participated in the study. Sensitization prevalence was 9.8 percent (26/264) with CBD prevalence of 2.3 percent (6/264). The investigators found a general pattern of increasing sensitization prevalence as the exposure quartile increased indicating an exposure-response relationship. The investigators found positive associations with both total and respirable mass concentration with sensitization (average and highest job) and CBD (cumulative). Increased sensitization prevalence was observed with metal oxide production alloy melting and casting, and maintenance. CBD was associated with melting and casting. The investigators summarized that both total and respirable mass concentration were relevant predictors of risk (Schuler et al., 2012).

In the companion study by Virji et al. (2012), the investigators reconstructed historical exposure from 1994 to 1999 utilizing the personal sampling data collected in 1999 as baseline exposure estimates (BEE). The study evaluated techniques for reconstructing historical data to evaluate exposure-response relationships for epidemiological studies. The investigators constructed JEMs using the BEE and estimates of annual changes in exposure for 25 different process areas. The investigators concluded these reconstructed JEMs could be used to evaluate a range of exposure parameters from total, respirable and submicron mass concentration including cumulative, average, and highest exposure. These two studies demonstrate that high-quality exposure estimates can be developed both for total mass and respirable mass concentrations.

e. Beryllium Machining Operations

Newman et al. (2001) and Kelleher et al. (2001) studied a group of 235 workers at a beryllium metal machining plant. Since the plant opened in 1969, its primary operations have been machining and polishing beryllium metal and high-beryllium content composite materials, with occasional machining of beryllium oxide/metal matrix (‘E-metal'), and beryllium alloys. Other functions include machining of metals other than beryllium; receipt and inspection of materials; acid etching; final inspection, quality control, and shipping of finished materials; tool making; and engineering, maintenance, administrative and supervisory functions (Newman et al., 2001; Madl et al., 2007). Machining operations, including milling, grinding, lapping, deburring, lathing, and electrical discharge machining (EDM), were performed in an open-floor plan production area. Most non-machining jobs were located in a separate, adjacent area; however, non-production employees had access to the machining area.

Engineering and administrative measures, rather than PPE, were primarily used to control beryllium exposures at the plant (Madl et al., 2007). Based on interviews with long-standing employees of the plant, Kelleher et al. reported that work practices were relatively stable until 1994, when a worker was diagnosed with CBD and a new exposure control program was initiated. Between 1995 and 1999 new engineering and work practice controls were implemented, including removal of pressurized air hoses and discouragement of dry sweeping (1995), enclosure of deburring processes (1996), mandatory uniforms (1997), and installation or updating of local exhaust ventilation (LEV) in EDM, lapping, deburring, and grinding processes (1998) (Madl et al., 2007). Throughout the plant's history, respiratory protection was used mainly for “unusually large, anticipated exposures” to beryllium (Kelleher et al., 2001), and was not routinely used otherwise (Newman et al., 2001).

All workers at the plant participated in a beryllium disease surveillance program initiated in 1994, and were screened for beryllium sensitization with the BeLPT beginning in 1995. A BeLPT result was considered abnormal if two or more of six stimulation indices exceeded the normal range (see section on BeLPT testing above), and was considered borderline if one of the indices exceeded the normal range. A repeat BeLPT was conducted for workers with abnormal or borderline initial results. Workers were identified as beryllium sensitized and referred for a clinical evaluation, including bronchoalveolar lavage (BAL) and transbronchial lung biopsy, if the repeat test was abnormal. CBD was diagnosed upon evidence of sensititization with granulomas or mononuclear cell infiltrates in the lung tissue (Newman et al., 2001). Following the initial plant-wide screening, plant employees were offered BeLPT testing at two-year intervals. Workers hired after the initial screening were offered a BeLPT within 3 months of their hire date, and at 2-year intervals thereafter (Madl et al., 2007).

Kelleher et al. performed a nested case-control study of the 235 workers evaluated in Newman et al. (2001) to evaluate the relationship between beryllium exposure levels and risk of sensitization and CBD (Kelleher et al., 2001). The authors evaluated exposures at the plant using IH samples they had collected between 1996 and 1999, using personal cascade impactors designed to measure the mass of beryllium particles less than 6 μ m, particles less than 1 μm in diameter, and total mass. The great majority of workers' exposures were below the OSHA PEL of 2 μ g/m3. However, a few higher levels were observed in machining jobs including deburring, lathing, lapping, and grinding. Based on a statistical comparison between their samples and historical data provided by the plant, the authors concluded that worker beryllium exposures across all time periods could be approximated using the 1996-1999 data. They estimated workers' cumulative and `lifetime weighted' (LTW) beryllium exposure based on the exposure samples they collected for each job in 1996-1999 and company records of each worker's job history.

Twenty workers with beryllium sensitization or CBD (cases) were compared to 206 workers (controls) for the case-control analysis from the study evaluating workers originally conducted by Newman et al. Thirteen workers were diagnosed with CBD based on lung biopsy evidence of granulomas and/or mononuclear cell infiltrates (11) or positive BAL results with evidence of lymphocytosis (2). Seven were evaluated for CBD and found to be sensitized only, thus twenty composing the case group. Nine of the remaining 215 workers first identified in original study (Newman et al., 2001) were Start Printed Page 47599excluded due to incomplete job history information, leaving 206 workers in the control group.

Kelleher et al.' s analysis included comparisons of the case and control groups' median exposure levels; calculation of odds ratios for workers in high, medium, and low exposure groups; and logistic regression testing of the association of sensitization or CBD with exposure level and other variables. Median cumulative exposures for total mass, particles <6 μ m, and particles <1 μm were approximately three times higher among the cases than controls, although the relationships observed were not statistically significant (p values ~ 0.2). No clear difference between cases and controls was observed for the median LTW exposures. Odds ratios with sensitization and CBD as outcomes were elevated in high (upper third) and intermediate exposure groups relative to low (lowest third) exposure groups for both cumulative and LTW exposure, though the results were not statistically significant (p > 0.1). In the logistic regression analysis, only machinist work history was a significant predictor of case status in the final model. Quantitative exposure measures were not significant predictors of sensitization or disease risk.

Citing an 11.5 percent prevalence of beryllium sensitization or CBD among machinists as compared with 2.9 percent prevalence among workers with no machinist work history, the authors concluded that the risk of sensitization and CBD is increased among workers who machine beryllium. Although differences between cases and controls in median cumulative exposure did not achieve conventional thresholds for statistical significance, the authors noted that cumulative exposures were consistently higher among cases than controls for all categories of exposure estimates and for all particle sizes, suggesting an effect of cumulative exposure on risk. The levels at which workers developed CBD and sensitization were predominantly below OSHA's current PEL of 2 μ g/m3, and no cases of sensitization or CBD were observed among workers with LTW exposure <0.02 μg/m3. Twelve (60 percent) of the 20 sensitized workers had LTW exposures > 0.20 μ g/m3.

In 2007, Madl et a l. published an additional study of 27 workers at the machining plant who were found to be sensitized or diagnosed with CBD between the start of medical surveillance in 1995 and 2005. As previously described, workers were offered a BeLPT in the initial 1995 screening (or within 3 months of their hire date if hired after 1995) and at 2-year intervals after their first screening. Workers with two positive BeLPTs were identified as sensitized and offered clinical evaluation for CBD, including bronchoscopy with BAL and transbronchial lung biopsy. The criteria for CBD in this study were somewhat stricter than those used in the Newman et al. study, requiring evidence of granulomas on lung biopsy or detection of X-ray or pulmonary function changes associated with CBD, in combination with two positive BeLPTs or one positive BAL-BeLPT.

Based on the history of the plant's control efforts and their analysis of historical IH data, Madl et al. identified three “exposure control eras”: A relatively uncontrolled period from 1980-1995; a transitional period from 1996 to 1999; and a relatively well-controlled “modern” period from 2000-2005. They found that the engineering and work practice controls instituted in the mid-1990s reduced workers' exposures substantially, with nearly a 15-fold difference in reported exposure levels between the pre-control and the modern period (Madl et al., 2007). Madl et al. estimated workers' exposures using LP samples collected between 1980 and 2005, including those collected by Kelleher et al., and work histories provided by the plant. As described more fully in the study, they used a variety of approaches to describe individual workers' exposures, including approaches designed to characterize the highest exposures workers were likely to have experienced. Their exposure-response analysis was based primarily on an exposure metric they derived by identifying the year and job of each worker's pre-diagnosis work history with the highest reported exposures. They used the upper 95th percentile of the LP samples collected in that job and year (in some cases supplemented with data from other years) to characterize the worker's upper-level exposures.

Based on their estimates of workers' upper level exposures, Madl et al. concluded that workers with sensitization or CBD were likely to have been exposed to airborne beryllium levels greater than 0.2 μg/m3 as an 8-hour TWA at some point in their history of employment in the plant. They also concluded that most sensitization and CBD cases were likely to have been exposed to levels greater than 0.4 μg/m3 at some point in their work at the plant. Madl et al. did not reconstruct exposures for workers at the plant who did not have sensitization or CBD and therefore could not determine whether non-cases had upper-bound exposures lower than these levels. They found that upper-bound exposure estimates were generally higher for workers with CBD than for those who were sensitized but not diagnosed with CBD at the conclusion of the study (Madl et al., 2007). Because CBD is an immunological disease and beryllium sensitization has been shown to occur within a year of exposure for some workers, Madl et al. argued that their estimates of workers' short-term upper-bound exposures may better capture the exposure levels that led to sensitization and disease than estimates of long-term cumulative or average exposures such as the LTW exposure measure constructed by Kelleher et al. (Madl et al., 2007).

f. Beryllium Oxide Ceramics

Kreiss et al. (1993) conducted a screening of current and former workers at a plant that manufactured beryllium ceramics from beryllium oxide between 1958 and 1975, and then transitioned to metalizing circuitry onto beryllium ceramics produced elsewhere. Of the plant's 1,316 current and 350 retired workers, 505 participated who had not previously been diagnosed with CBD or sarcoidosis, including 377 current and 128 former workers. Although beryllium exposure was not estimated quantitatively in this survey, the authors conducted a questionnaire to assess study participants' exposures qualitatively. Results showed that 55 percent of participants reported working in jobs with exposure to beryllium dust. Close to 25 percent of participants did not know if they had exposure to beryllium, and just over 20 percent believed they had not been exposed.

BeLPT tests were administered to all 505 participants in the 1989-1990 screening period and evaluated at a single lab. Seven workers had confirmed abnormal BeLPT results and were identified as sensitized; these workers were also diagnosed with CBD based on findings of granulomas upon clinical evaluation. Radiograph screening led to clinical evaluation and diagnosis of two additional CBD cases, who were among three participants with initially abnormal BeLPT results that could not be confirmed on repeat testing. In addition, nine workers had been previously diagnosed with CBD, and another five were diagnosed shortly after the screening period, in 1991-1992.

Eight (3.7 percent of the screening population) of the nine CBD cases identified in the screening population were hired before the plant stopped producing beryllium ceramics in 1975, and were among the 216 participants who had reported having been near or Start Printed Page 47600exposed to beryllium dust. Particularly high CBD rates of 11.1-15.8 percent were found among screening participants who had worked in process development/engineering, dry pressing, and ventilation maintenance jobs believed to have high or uncontrolled dust exposure. One case (0.6 percent) of CBD was diagnosed among the 171 study participants who had been hired after the plant stopped producing beryllium ceramics. Although this worker was hired eight years after the end of ceramics production, he had worked in an area later found to be contaminated with beryllium dust. The authors concluded that the study results suggested an exposure-response relationship between beryllium exposure and CBD, and recommended beryllium exposure control to reduce workers' risk of CBD.

Kreiss et al. later published a study of workers at a second ceramics plant located in Tucson, AZ (Kreiss et al., 1996), which since 1980 had produced beryllium ceramics from beryllium oxide powder manufactured elsewhere. IH measurements collected between 1981 and 1992, primarily GA or short-term BZ samples and a few (<100) LP samples, were available from the plant. Airborne beryllium exposures were generally low. The majority of area samples were below the analytical detection limit of 0.1 μg/m3, while LP and short-term BZ samples had medians of 0.3 μg/m3. However, 3.6 percent of short-term BZ samples and 0.7 percent of GA samples exceeded 5.0 μg/mg3, while LP samples ranged from 0.1 to 1.8 μg/m3. Machining jobs had the highest beryllium exposure levels among job tasks, with short-term BZ samples significantly higher for machining jobs than for non-machining jobs (median 0.6 μg/m3 vs. 0.3 μg/mg3, p = 0.0001). The authors used DWA formulas provided by the plant to estimate workers' full-shift exposure levels, and to calculate cumulative and average beryllium exposures for each worker in the study. The median cumulative exposure was 591.7 mg-days/m3 and the median average exposure was 0.35 μg/m3.

One hundred thirty-six of the 139 workers employed at the plant at the time of the Kreiss et al. (1996) study underwent BeLPT screening and chest radiographs in 1992. Blood samples were split between two laboratories. If one or both test results were abnormal, an additional sample was collected and split between the labs. Seven workers with an abnormal result on two draws were initially identified as sensitized. Those with confirmed abnormal BeLPTs or abnormal chest X-rays were offered clinical evaluation for CBD, including transbronchial lung biopsy and BAL BeLPT. CBD was diagnosed based on observation of granulomas on lung biopsy, in five of the six sensitized workers who accepted evaluation. An eighth case of sensitization and sixth case of CBD were diagnosed in one worker hired in October 1991 whose initial BeLPT was normal, but who was confirmed as sensitized and found to have lung granulomas less than two years later, after sustaining a beryllium-contaminated skin wound. The plant medical department reported 11 additional cases of CBD among former workers (Kreiss et al., 1996). The overall prevalence of sensitization in the plant was 5.9 percent, with a 4.4 percent prevalence of CBD.

Kreiss et al. reported that six (75 percent) of the eight sensitized workers were exposed as machinists during or before the period October 1985-March 1988, when measurements were first available for machining jobs. The authors reported that 14.3 percent of machinists were sensitized, compared to 1.2 percent of workers who had never been machinists (p <0.01). Workers' estimated cumulative and average beryllium exposures did not differ significantly for machinists and non-machinists, or for cases and non-cases. As in the previous study of the same ceramics plant published by Kreiss et al. in 1993, one case of CBD was diagnosed in a worker who had never been employed in a production job. This worker was employed in administration, a job with a median DWA of 0.1 μg/m3 (range 0.1-0.3).

In 1998, Henneberger et al. conducted a follow-up cross-sectional survey of 151 employees employed at the beryllium ceramics plant studied by Kreiss et al. (1996) (Henneberger et al., 2001). Employees were eligible who either had not participated in the Kreiss et al. survey (“short-term workers”—74 of those studied by Henneberger et al.), or who had participated and were not found to have sensitization or disease (“long-term workers”—77 of those studied by Henneberger et al.).

The authors estimated workers' cumulative, average, and peak beryllium exposures based on the plant's formulas for estimating job-specific DWA exposures, participants' work histories, and area and short-term task-specific BZ samples collected from the start of full production at the plant in 1981 to 1998. The long-term workers, who were hired before the 1992 study was conducted, had generally higher estimated exposures (median of average exposures—0.39 μg/m3; mean—14.9 μg/m3) than the short-term workers, who were hired after 1992 (median 0.28 μg/m3, mean 6.1 μg/m3).

Fifteen cases of sensitization were found, including eight among short-term and seven among long-term workers. Eight of the 15 workers were found to have CBD. Of the workers diagnosed with CBD, seven (88 percent) were long-term workers. One non-sensitized long-term worker and one sensitized long-term worker declined clinical examination.

Henneberger et al. reported a higher prevalence of sensitization among long-term workers with “high” (greater than median) peak exposures compared to long-term workers with “low” exposures; however, this relationship was not statistically significant. No association was observed for average or cumulative exposures. The authors reported higher prevalence of sensitization (but not statistically significant) among short-term workers with “high” (greater than median) average, cumulative, and peak exposures compared to short-term workers with “low” exposures of each type.

The cumulative incidence of sensitization and CBD was investigated in a cohort of 136 workers at the beryllium ceramics plant previously studied by the Kreiss and Henneberger groups (Schuler et al., 2008). The study cohort consisted of those who participated in the plant-wide BeLPT screening in 1992. Both current and former workers from this group were invited to participate in follow-up BeLPT screenings in 1998, 2000, and 2002-03. A total of 106 of the 128 non-sensitized individuals in 1992 participated in the 11-year follow-up. Sensitization was defined as a confirmed abnormal BeLPT based on the split blood sample-dual laboratory protocol described earlier. CBD was diagnosed in sensitized individuals based on pathological findings from transbronchial biopsy and BAL fluid analysis. The 11-year crude cumulative incidence of sensitization and CBD was 13 percent (14 of 106) and 8 percent (9 of 106) respectively. The cumulative prevalence was about triple the point prevalences determined in the initial 1992 cross-sectional survey. The corrected cumulative prevalences for those that ever worked in machining were nearly twice that for non-machinists. The data illustrate the value of longitudinal medical screening over time to obtain a more accurate estimate of the occurrence of sensitization and CBD among an exposed working population.

Following the 1998 survey, the company continued efforts to reduce Start Printed Page 47601exposures and risk of sensitization and CBD by implementing additional engineering, administrative, and PPE measures (Cummings et al., 2007). Respirator use was required in production areas beginning in 1999, and latex gloves were required beginning in 2000. The lapping area was enclosed in 2000, and enclosures were installed for all mechanical presses in 2001. Between 2000 and 2003, water-resistant or water-proof garments, shoe covers, and taped gloves were incorporated to keep beryllium-containing fluids from wet machining processes off the skin. The new engineering measures did not appear to substantially reduce airborne beryllium levels in the plant. LP samples collected between 2000 and 2003 had a median of 0.18 μg/m3, similar to the 1994-1999 samples. However, respiratory protection requirements to control workers' airborne beryllium exposures were instituted prior to the 2000 sample collections.

To test the efficacy of the new measures instituted after 1998, in January 2000 the company began screening new workers for sensitization at the time of hire and at 3, 6, 12, 24, and 48 months of employment. These more stringent measures appear to have substantially reduced the risk of sensitization among new employees. Of 126 workers hired between 2000 and 2004, 93 completed BeLPT testing at hire and at least one additional test at 3 months of employment. One case of sensitization was identified at 24 months of employment (1 percent). This worker had experienced a rash after an incident of dermal exposure to lapping fluid through a gap between his glove and uniform sleeve, indicating that he may have become sensitized via the skin. He was tested again at 48 months of employment, with an abnormal result.

A second worker in the 2000-2004 group had two abnormal BeLPT tests at the time of hire, and a third had one abnormal test at hire and a second abnormal test at 3 months. Both had normal BeLPTs at 6 months, and were not tested thereafter. A fourth worker had one abnormal BeLPT result at the time of hire, a normal result at 3 months, an abnormal result at 6 months, and a normal result at 12 months. Four additional workers had one abnormal result during surveillance, which could not be confirmed upon repeat testing.

Cummings et al. calculated two sensitization rates based on these screening results: (1) a rate using only the sensitized worker identified at 24 months, and (2) a rate including all four workers who had repeated abnormal results. They reported a sensitization incidence rate (IR) of 0.7 per 1,000 person-months to 2.7 per 1,000 person-months for the workers hired between 2000 and 2004, using the sum of sensitization-free months of employment among all 93 workers as the denominator.

The authors also estimated an incidence rate (IR) of 5.6 per 1,000 person-months for workers hired between 1993 and the 1998 survey. This estimated IR was based on one BeLPT screening, rather than BeLPTs conducted throughout the workers' employment. The denominator in this case was the total months of employment until the 1998 screening. Because sensitized workers may have been sensitized prior to the screening, the denominator may overestimate sensitization-free time in the legacy group, and the actual sensitization IR for legacy workers may be somewhat higher than 5.6 per 1,000 person-months. Based on comparison of the IRs, the authors concluded that the addition of respirator use, dermal protection, and housekeeping improvements appeared to have reduced the risk of sensitization among workers at the plant, even though airborne beryllium levels in some areas of the plant had not changed significantly since the 1998 survey.

g. Copper-Beryllium Alloy Processing and Distribution

Schuler et al. (2005) studied a group of 152 workers at a facility processing copper-beryllium alloys and small quantities of nickel-beryllium alloys, and converting semi-finished alloy strip and wire into finished strip, wire and rod. Production activities included annealing, drawing, straightening, point and chamfer, rod and wire packing, die grinding, pickling, slitting, and degreasing. Periodically in the plant's history, they also did salt baths, cadmium plating, welding and deburring. Since the late 1980s, rod and wire production processes were physically segregated from strip metal production. Production support jobs included mechanical maintenance, quality assurance, shipping and receiving, inspection, and wastewater treatment. Administration was divided into staff primarily working within the plant and personnel who mostly worked in office areas (Schuler, et al., 2005). Workers' respirator use was limited, mostly to occasional tasks where high exposures were anticipated.

Following the 1999 diagnosis of a worker with CBD, the company surveyed the workforce, offering all current employees BeLPT testing in 2000 and offering sensitized workers clinical evaluation for CBD, including BAL and transbronchial biopsy. Of the facility's 185 employees, 152 participated in the BeLPT screening. Samples were split between two laboratories, with additional draws and testing for confirmation if conflicting tests resulted in the initial draw. Ten participants (7 percent) had at least two abnormal BeLPT results. The results of nine workers who had abnormal BeLPT results from only one laboratory were not included because the authors believed it was experiencing technical problems with the test (Schuler et al., 2005). CBD was diagnosed in six workers (4 percent) on evidence of pathogenic abnormalities (e.g., granulomas) or evidence of clinical abnormalities consistent with CBD based on pulmonary function testing, pulmonary exercise testing, and/or chest radiography. One worker diagnosed with CBD had been exposed to beryllium during previous work at another copper-beryllium processing facility.

Schuler et al. evaluated airborne beryllium levels at the plant using IH samples collected between 1969 and 2000, including 4,524 GA samples, 650 LP samples and 815 short-duration (3-5 min) high volume (SD-HV) BZ task-specific samples. Occupational exposures to airborne beryllium were generally low. Ninety-nine percent of all LP measurements were below the current OSHA PEL of 2.0 μg/m3 (8-hr TWA); 93 percent were below the DOE action level of 0.2 μg/m3; and the median value was 0.02 μg/m3. The SD-HV BZ samples had a median value of 0.44 μg/m3, with 90 percent below the OSHA Short-Term Exposure Limit (STEL) of 5.0 μg/m3. The highest levels of beryllium were found in rod and wire production, particularly in wire annealing and pickling, the only production job with a median personal sample measurement greater than 0.1 μg/m3 (median 0.12 μg/m3; range 0.01-7.8 μg/m3) (Schuler et al., Table 4). These concentrations were significantly higher than the exposure levels in the strip metal area (median 0.02, range 0.01-0.72 μg/m3), in production support jobs (median 0.02, range <0.01-0.33 μg/m3), plant administration (median 0.02, range <0.01-0.11 μg/m3), and office administration jobs (median 0.01, range <0.01-0.06 μg/m3).

The authors reported that eight of the ten sensitized employees, including all six CBD cases, had worked in both major production areas during their tenure with the plant. The 7 percent prevalence (6 of 81 workers) of CBD among employees who had ever worked in rod and wire was statistically Start Printed Page 47602significantly elevated compared with employees who had never worked in rod and wire (p <0.05), while the 6 percent prevalence (6 of 94 workers) among those who had worked in strip metal was not significantly elevated compared to non-strip metal workers (p > 0.1). Based on these results, together with the higher exposure levels reported for the rod and wire production area, Schuler et al. concluded that work in rod and wire was a key risk factor for CBD in this population. Schuler et al. also found a high prevalence (13 percent) of sensitization among workers who had been exposed to beryllium for less than a year at the time of the screening, a rate similar to that found by Henneberger et al. among beryllium ceramics workers exposed for one year or less (16 percent, Henneberger et al., 2001). All four workers who were sensitized without disease had been exposed 5 years or less; conversely, all six of the workers with CBD had first been exposed to beryllium at least five years prior to the screening (Schuler et al., Table 2).

As has been seen in other studies, beryllium sensitization and CBD were found among workers who were typically exposed to low time-weighted average airborne concentrations of beryllium. While jobs in the rod and wire area had the highest exposure levels in the plant, the median personal sample value was only 0.12 μg/m3. However, workers may have occasionally been exposed to higher beryllium levels for short periods during specific tasks. A small fraction of personal samples recorded in rod and wire were above the OSHA PEL of 2.0 μg/m3, and half of workers with sensitization or CBD reported that they had experienced a “high-exposure incident” at some point in their work history (Schuler et al., 2005). The only group of workers with no cases of sensitization or CBD, a group of 26 office administration workers, was the group with the lowest recorded exposures (median personal sample 0.01 μg/m3, range <0.01-0.06 μg/m3).

After the BeLPT screening was conducted in 2000, the company began implementing new measures to further reduce workers' exposure to beryllium (Thomas et al., 2009). Requirements designed to minimize dermal contact with beryllium, including long-sleeve facility uniforms and polymer gloves, were instituted in production areas in 2000. In 2001 the company installed LEV in die grinding and polishing. LP samples collected between June 2000 and December 2001 show reduced exposures plant-wide. Of 2,211 exposure samples collected, 98 percent were below 0.2 μg/m3, and 59 percent below the limit of detection (LOD), which was either 0.02 µg/m3 or 0.2 µg/m3 depending on the method of sample analysis (Thomas et al., 2009). Median values below 0.03 μg/m3 were reported for all processes except the wire annealing and pickling process. Samples for this process remained somewhat elevated, with a median of 0.1 μg/m3. In January 2002, the plant enclosed the wire annealing and pickling process in a restricted access zone (RAZ), requiring respiratory PPE in the RAZ and implementing stringent measures to minimize the potential for skin contact and beryllium transfer out of the zone. While exposure samples collected by the facility were sparse following the enclosure, they suggest exposure levels comparable to the 2000-01 samples in areas other than the RAZ. Within the RAZ, required use of powered air-purifying respirators indicates that respiratory exposure was negligible.

To test the efficacy of the new measures in preventing sensitization and CBD, in June 2000 the facility began an intensive BeLPT screening program for all new workers. The company screened workers at the time of hire; at intervals of 3, 6, 12, 24, and 48 months; and at 3-year intervals thereafter. Among 82 workers hired after 1999, three (3.7 percent) cases of sensitization were found. Two (5.4 percent) of 37 workers hired prior to enclosure of the wire annealing and pickling process were found to be sensitized within 3 and 6 months of beginning work at the plant. One (2.2 percent) of 45 workers hired after the enclosure was confirmed as sensitized.

Thomas et al. calculated a sensitization IR of 1.9 per 1,000 person-months for the workers hired after the exposure control program was initiated in 2000 (“program workers”), using the sum of sensitization-free months of employment among all 82 workers as the denominator (Thomas et al., 2009). They calculated an estimated IR of 3.8 per 1,000 person-months for 43 workers hired between 1993 and 2000 who had participated in the 2000 BeLPT screening (“legacy workers”). This estimated IR was based on one BeLPT screening, rather than BeLPTs conducted throughout the legacy workers' employment. The denominator in this case is the total months of employment until the 2000 screening. Because sensitized workers may have been sensitized prior to the screening, the denominator may overestimate sensitization-free time in the legacy group, and the actual sensitization IR for legacy workers may be somewhat higher than 3.8 per 1,000 person-months. Based on comparison of the IRs and the prevalence rates discussed previously, the authors concluded that the combination of dermal protection, respiratory protection, housekeeping improvements and engineering controls implemented beginning in 2000 appeared to have reduced the risk of sensitization among workers at the plant. However, they noted that the small size of the study population and the short follow-up time for the program workers suggested that further research is needed to confirm the program's efficacy (Thomas et al., 2009).

Stanton et al. (2006) conducted a study of workers in three different copper-beryllium alloy distribution centers in the United States. The distribution centers, including one bulk products center established in 1963 and strip metal centers established in 1968 and 1972, sell products received from beryllium production and finishing facilities and small quantities of copper-beryllium, aluminum-beryllium, and nickel-beryllium alloy materials. Work at distribution centers does not require large-scale heat treatment or manipulation of material typical of beryllium processing and machining plants, but involves final processing steps that can generate airborne beryllium. Slitting, the main production activity at the two strip product distribution centers, generates low levels of airborne beryllium particles, while operations such as tensioning and welding used more frequently at the bulk products center can generate somewhat higher levels. Non-production jobs at all three centers included shipping and receiving, palletizing and wrapping, production-area administrative work, and office-area administrative work.

The authors estimated workers' beryllium exposures using IH data from company records and job history information collected through interviews conducted by a company occupational health nurse. Stanton et al. evaluated airborne beryllium levels in various jobs based on 393 full-shift LP samples collected from 1996 to 2004. Airborne beryllium levels at the plant were generally very low, with 54 percent of all samples at or below the LOD, which ranged from 0.02 to 0.1 μg/m3. The authors reported a median of 0.03 μg/m3 and an arithmetic mean of 0.05 μg/m3 for the 393 full-shift LP samples, where samples below the LOD were assigned a value of half the applicable LOD. Median and geometric mean values for specific jobs ranged from 0.01-0.07 and 0.02-0.07 µg/m3, respectively. All measurements were Start Printed Page 47603below the OSHA PEL of 2.0 μg/m3 and 97 percent were below the DOE action level of 0.2 μg/m3. The paper does not report use of respiratory or skin protection. Exposure conditions may have changed somewhat over the history of the plant due to changes in exposure control measures, including improvements to product and container cleaning practices instituted during the 1990s.

Eighty-eight of the 100 workers (88 percent) employed at the three centers at the time of the study participated in screening for beryllium sensitization. Blood samples were collected between November 2000 and March 2001 by the company's medical staff. Samples collected from employees of the strip metal centers were split and evaluated at two laboratories, while samples from the bulk product center workers were evaluated at a single laboratory. Participants were considered to be “sensitized” to beryllium if two or more BeLPT results, from two laboratories or from repeat testing at the same laboratory, were found to be abnormal. One individual was found to be sensitized and was offered clinical evaluation, including BAL and fiberoptic bronchoscopy. He was found to have lung granulomas and was diagnosed with CBD.

The worker diagnosed with CBD had been employed at a strip metal distribution center from 1978 to 2000 as a shipper and receiver, loading and unloading trucks delivering materials from a beryllium production facility and to the distribution center's customers. Although the LP samples collected for his job between 1996 and 2000 were generally low (n = 35, median 0.01, range < 0.02-0.13 µg/m3), it is not clear whether these samples adequately characterize his exposure conditions over the course of his work history. He reported that early in his work history, containers of beryllium oxide powder were transported on the trucks he entered. While he did not recall seeing any breaks or leaks in the beryllium oxide containers, some containers were known to have been punctured by forklifts on trailers used by the company during the period of his employment, and could have contaminated trucks he entered. With 22 years of employment at the facility, this worker had begun beryllium-related work earlier and performed it longer than about 90 percent of the study population (Stanton et al., 2006).

h. Nuclear Weapons Production Facilities & Cleanup of Former Facilities

Primary exposure from nuclear weapons production facilities comes from beryllium metal and beryllium alloys. A study conducted by Kreiss et al. (1989) documented sensitization and CBD among beryllium-exposed workers in the nuclear industry. A company medical department identified 58 workers with beryllium exposure among a work force of 500, of whom 51 (88 percent) participated in the study. Twenty-four workers were involved in research and development (R&D), while the remaining 27 were production workers. The R&D workers had a longer tenure with a mean time from first exposure of 21.2 years, compared to a mean time since first exposure of 5 years among the production workers. The number of workers with abnormal BeLPT readings was 6, with 4 being diagnosed with CBD. This resulted in an estimated 11.8 percent prevalence of sensitization.

Kreiss et al. (1993) expanded the work of Kreiss et al. (1989) by performing a cross-sectional study of 895 (current and former) beryllium workers in the same nuclear weapons plant. Participants were placed in qualitative exposure groups (“no exposure,” “minimal exposure,” “intermittent exposure,” and “consistent exposure”) based on questionnaire responses. The number of workers with abnormal BeLPT totaled 18 with 12 being diagnosed with CBD. Three additional workers with sensitization developed CBD over the next 2 years. Sensitization occurred in all of the qualitatively defined exposure groups. Individuals who had worked as machinists were statistically overrepresented among beryllium-sensitized cases, compared with non-cases. Cases were more likely than non-cases to report having had a measured overexposure to beryllium (p = 0.009), a factor which proved to be a significant predictor of sensitization in logistic regression analyses, as was exposure to beryllium prior to 1970. Beryllium sensitized cases were also significantly more likely to report having had cuts that were delayed in healing (p = 0.02). The authors concluded that individual variability and susceptibility along with exposure circumstances are important factors in developing beryllium sensitization and CBD.

In 1991, the Beryllium Health Surveillance Program (BHSP) was established at the Rocky Flats Nuclear Weapons Facility to offer BLPT screening to current and former employees who may have been exposed to beryllium (Stange et al., 1996). Participants received an initial BeLPT and follow-ups at one and three years. Based on histologic evidence of pulmonary granulomas and a positive BAL-BeLPT, Stange et al. published a study of 4,397 BHSP participants tested from June 1991 to March 1995, including current employees (42.8 percent) and former employees (57.2 percent). Twenty-nine cases of CBD and 76 cases of sensitization were identified. The sensitization rate for the population was 2.43 percent. Available exposure data included fixed airhead (FAH) exposure samples collected between 1970 and 1988 (mean concentration 0.016 µg/m3) and personal samples collected between 1984 and 1987 (mean concentration 1.04 µg/m3). Cases of CBD and sensitization were noted in individuals in all jobs classifications, including those believed to involve minimal exposure to beryllium. The authors recommended ongoing surveillance for workers in all jobs with potential for beryllium exposure.

Stange et al. (2001) extended the previous study, evaluating 5,173 participants in the Rocky Flats BHSP who were tested between June 1991 and December 1997. Three-year serial testing was offered to employees who had not been tested for three years or more and did not show beryllium sensitization during the previous study. This resulted in 2,891 employees being tested. Of the 5,173 workers participating in the study, 172 were found to have abnormal BeLPT. Ninety-eight (3.33 percent) of the workers were found to be sensitized (confirmed abnormal BeLPT results) in the initial screening, conducted in 1991. Of these workers 74 were diagnosed with CBD (history of beryllium exposure, evidence of non-caseating granulomas or mononuclear cell infiltrates on lung biopsy, and a positive BeLPT or BAL-BeLPT). A follow-up survey of 2,891 workers three years later identified an additional 56 sensitized workers and an additional seven cases of CBD. Sensitization and CBD rates were analyzed with respect to gender, building work locations, and length of employment. Historical employee data included hire date, termination date, leave of absences, and job title changes. Exposure to beryllium was determined by job categories and building or work area codes. Personal beryllium air monitoring results were used, when available, from employees with the same job title or similar job. However, no quantitative information was presented in the study. The authors conclude that for some individuals, exposure to beryllium at levels less that the OSHA PEL could cause sensitization and CBD.

Viet et al. (2001) conducted a case-control study of the Rocky Flats worker population studied by Stange et al. (1996 and 2001) to examine the relationship between estimated Start Printed Page 47604beryllium exposure level and risk of sensitization or CBD. The worker population included 74 beryllium-sensitized workers and 50 workers diagnosed with CBD. Beryllium exposure levels were estimated based on FAH airhead samples from one building, the beryllium machine shop. These were collected away from the BZ of the machine operator and likely underestimated exposure. To estimate levels in other locations, these air sample concentrations were used to construct a job exposure matrix that included the determination of the Building 444 exposure estimates for a 30-year period; each subject's work history by job location, task, and time period; and assignment of exposure estimates to each combination of job location, task, and time period as compared to Building 444 machinists. The authors adjusted the levels observed in the machine shop by factors based on interviews with former workers. Workers' estimated mean exposure concentrations ranged from 0.083 µg/m3 to 0.622 µg/m3. Estimated maximum air concentrations ranged from 0.54 µg/m3 to 36.8 µg/m3. Cases were matched to controls of the same age, race, gender, and smoking status (Viet et al., 2001).

Estimated mean and cumulative exposure levels and duration of employment were found to be significantly higher for CBD cases than for controls. Estimated mean exposure levels were significantly higher for sensitization cases than for controls. No significant difference was observed for estimated cumulative exposure or duration of exposure. Similar results were found using logistic regression analysis, which identified statistically significant relationships between CBD and both cumulative and mean estimated exposure, but did not find significant relationships between estimated exposure levels and sensitization without CBD. Comparing CBD with sensitization cases, Viet et al. found that workers with CBD had significantly higher estimated cumulative and mean beryllium exposure levels than workers who were sensitized, but did not have CBD.

Johnson et al. (2001) conducted a review of personal sampling records and medical surveillance reports at an atomic weapons establishment in Cardiff, United Kingdom. The study evaluated airborne samples collected over the 36-year period of operation for the plant. Data included 367,757 area samples and 217,681 personal lapel samples from 194 workers over the time period from 1981-1997. Data was available prior to this time period but was not analyzed since this data was not available electronically. The authors estimated that over the 17 years of measurement data analyzed, airborne beryllium concentrations did exceed 2.0 µg/m3, however, due to the limitations with regard to collection times it is difficult to assess the full reliability of this estimate. The authors noted that in the entire plant's history, only one case of CBD had been diagnosed. It was also noted that BeLPT has not been routinely conducted among any of the workers at this facility.

Armojandi et al. (2010) conducted a cross-sectional study of workers at a nuclear weapons research and development (R&D) facility to determine the risk of developing CBD in sensitized workers at facilities with exposures much lower than production plants. Of the 1875 current or former workers at the R&D facility, 59 were determined to be sensitized based on at least two positive BeLPTs (i.e., samples drawn on two separate occasions or on split samples tested in two separate DOE-approved laboratories) for a sensitization rate of 3.1 percent. Workers found to have positive BeLPTs were further evaluated in an Occupational Medicine Clinic between 1999 through 2005. Armojandi et al. (2010) evaluated 50 of the sensitized workers who also had medical and occupational histories, physical examination, chest imaging with high-resolution computed tomography (HRCT) (N = 49), and pulmonary function testing (nine of the 59 workers refused physical examinations so were not included in this study). Forty of the 50 workers chosen for this study underwent bronchoscopy for bronchoalveolar lavage and transbronchial biopsies in additional to the other testing. Five of the 49 workers had CBD at the time of evaluation (based on histology or high-resolution computed tomography); three others had evidence of probable CBD; however, none of these cases were classified as severe at the time of evaluation. The rate of CBD at the time of study among sensitized individuals was 12.5 percent (5/40) for those using pathologic review of lung tissue, and 10.2 percent (5/49) for those using HRCT as a criteria for diagnosis. The rate of CBD among the entire population (5/1875) was 0.3 percent.

The mean duration of employment at the facility was 18 years, and the mean latency period (from first possible exposure) to time of evaluation and diagnosis was 32 years. There was no available exposure monitoring in the breathing zone of workers at the facility but the beryllium levels were believed to be relatively low (possibly less than 0.1 μg/m3 for most jobs). There was not an apparent exposure-response relationship for sensitization or CBD. The sensitization prevalence was similar and the CBD prevalence higher among workers with the lower-exposure jobs. The authors concluded that these sensitized workers, who were subjected to an extended duration of low potential beryllium exposures over a long latency period, had a low prevalence of CBD (Armojandi et al., 2010).

i. Aluminum Smelting

Bauxite ore, the primary source of aluminum, contains naturally occurring beryllium. Worker exposure to beryllium can occur at aluminum smelting facilities where aluminum extraction occurs via electrolytic reduction of aluminum oxide into aluminum metal. Characterization of beryllium exposures and sensitization prevalence rates were examined by Taiwo et al. (2010) in a study of nine aluminum smelting facilities from four different companies in the U.S., Canada, Italy and Norway.

Of the 3,185 workers determined to be potentially exposed to beryllium, 1,932 agreed to participate in a medical surveillance program between 2000 and 2006 (60 percent participation rate). The medical surveillance program included serum BeLPT analysis, confirmation of an abnormal BeLPT with a second BeLPT, and follow-up of all confirmed positive responses by a pulmonary physician to evaluate for progression to CBD.

Eight-hour TWAs were assessed utilizing 1,345 personal samples collected from the 9 smelters. The personal beryllium samples obtained showed a range of 0.01-13.00 μg/m3 time-weighted average with an arithmetic mean of 0.25 μg/m3 and geometric mean of 0.06 μg/m3. Exposure levels to beryllium observed in aluminum smelters are similar to those seen in other industries that utilize beryllium. Of the 1,932 workers surveyed by BeLPT, nine workers were diagnosed with sensitization (prevalence rate of 0.47 percent, 95% confidence interval = 0.21-0.88 percent) with 2 of these workers diagnosed with probable CBD after additional medical evaluations.

The authors concluded that compared with beryllium-exposed workers in other industries, the rate of sensitization among aluminum smelter workers appears lower. The authors speculated that this lower observed rate could be related to a more soluble form of beryllium found in the aluminum smelting work environment as well as Start Printed Page 47605the consistent use of respiratory protection. However, the authors also speculated that the 60 percent participation rate may have underestimated the sensitization rate in this worker population.

A study by Nilsen et al. (2010) also found a low rate of sensitization among aluminum workers in Norway. Three-hundred sixty-two workers and thirty-one control individuals were tested for beryllium sensitization based on the BeLPT. The results found that one (0.28%) of the smelter workers had been sensitized. No borderline results were reported. The exposure estimated in this plant was 0.1 µg/m3 to 0.31 µg/m3 (Nilsen et al., 2010).

6. Animal Models of CBD

This section reviews the relevant animal studies supporting the mechanisms outlined above. Researchers have attempted to identify animal models with which to further investigate the mechanisms underlying the development of CBD. A suitable animal model should exhibit major characteristics of CBD, including the demonstration of a beryllium-specific immune response, the formation of immune granulomas following inhalation exposure to beryllium, and mimicking the progressive nature of the human disease. While exposure to beryllium has been shown to cause chronic granulomatous inflammation of the lung in animal studies using a variety of species, most of the granulomatous lesions were formed by foreign-body reactions, which result from persistent irritation and consist predominantly of macrophages and monocytes, and small numbers of lymphocytes. Foreign-body granulomas are distinct from the immune granulomas of CBD, which are caused by antigenic stimulation of the immune system and contain large numbers of lymphocytes. Animal studies have been useful in providing biological plausibility for the role of immunological alterations and lung inflammation and in clarifying certain specific mechanistic aspects of beryllium disease. However, the lack of a dependable animal model that mimics all facets of the human response combined with study limitations in terms of single dose experiments, few animals, or abbreviated observation periods have limited the utility of the data. Currently, no single model has completely mimicked the disease process as it progresses in humans. The following is a discussion of the most relevant animal studies regarding the mechanisms of sensitization and CBD development in humans. Table A.2 in the Appendix summarizes species, route, chemical form of beryllium, dose levels, and pathological findings of the key studies.

Harmsen et al. performed a study to assess whether the beagle dog could provide an adequate model for the study of beryllium-induced lung diseases (Harmsen et al., 1986). One group of dogs served as a control group (air inhalation only) and four other groups received high (approximately 50 μg/kg) and low (approximately 20 μg/kg) doses of beryllium oxide calcined at 500 °C or 1,000° C, administered as aerosols in a single exposure. As discussed above, calcining temperature controls the solubility and SSA of beryllium particles. Those particles calcined at higher temperatures (e.g., 1,000° C) are less soluble and have lower SSA than particles calcined at lower temperatures (e.g., 500 °C). Solubility and SSA are factors in determining the toxic potential of beryllium compounds or materials.

Cells were collected from the dogs by BAL at 30, 60, 90, 180, and 210 days after exposure, and the percentages of neutrophils and lymphocytes were determined. In addition, the mitogenic responses of blood lymphocytes and lavage cells collected at 210 days were determined with either phytohemagglutinin or beryllium sulfate as mitogen. The percentage of neutrophils in the lavage fluid was significantly elevated only at 30 days with exposure to either dose of 500 °C beryllium oxide. The percentage of lymphocytes in the fluid was significantly elevated in samples across all times with exposure to the high dose of this beryllium oxide form. Beryllium oxide calcined at 1,000° C elevated lavage lymphocytes only in high dose at 30 days. No significant effect of 1,000° C beryllium oxide exposure on mitogenic response of any lymphocytes was seen. In contrast, peripheral blood lymphocytes from the 500 °C beryllium oxide exposed groups were significantly stimulated by beryllium sulfate compared with the phytohemagglutinin exposed cells. The investigators in this study were able to replicate some of the same findings as those observed in human studies—specifically, that beryllium in soluble and insoluble forms can be mitogenic to immune cells, an important finding for progression of sensitization and proliferation of immune cells to developing full-blown CBD.

In another beagle study Haley et al. also found that the beagle dog appears to model some aspects of human CBD (Haley et al., 1989). The authors monitored lung pathologic effects, particle clearance, and immune sensitization of peripheral blood leukocytes following a single exposure to beryllium oxide aerosol generated from beryllium oxide calcined at 500 °C or 1,000° C. The aerosol was administered to the dogs perinasally to attain initial lung burdens of 6 or 18 μg beryllium/kg body weight. Granulomatous lesions and lung lymphocyte responses consistent with those observed in humans with CBD were observed, including perivascular and peribronchiolar infiltrates of lymphocytes and macrophages, progressing to microgranulomas with areas of granulomatous pneumonia and interstitial fibrosis. Beryllium specificity of the immune response was demonstrated by positive results in the BeLPT, although there was considerable inter-animal variation. The lesions declined in severity after 64 days post-exposure. Thus, while this model was able to mimic the formation of Be-specific immune granulomas, it was not able to mimic the progressive nature of disease.

This study also provided an opportunity to compare the effects of beryllium oxide calcination temperature on granulomatous disease in the beagle respiratory system. Haley et al. found an increase in the percentage and numbers of lymphocytes in BAL fluid at 3 months post-exposure in dogs exposed to either dose of beryllium oxide calcined at 500 °C, but not in dogs exposed to the material calcined at the higher temperature. Although there was considerable inter-animal variation, lesions were generally more severe in the dogs exposed to material calcined at 500 °C. Positive BeLPT results were observed with BAL lymphocytes only in the group with a high initial lung burden of the material calcined at 500 °C, but positive results with peripheral blood lymphocytes were observed at both doses with material calcined at both temperatures.

The histologic and immunologic responses of canine lungs to aerosolized beryllium oxide were investigated in another Haley et al. (1989) study. Beagle-dogs were exposed in a single exposure to high dose (50 µg/kg of body weight) or low dose (l7 µg/kg) levels of beryllium oxide calcined at either 500° or 1000° C. One group of dogs was examined up to 365 days after exposure for lung histology and biochemical assay to determine the fate of inhaled beryllium oxide. A second group underwent BAL for lung lymphocyte analysis for up to 22 months after exposure. Histopathologic examination revealed peribronchiolar and perivascular lymphocytic histiocytic Start Printed Page 47606inflammation, peaking at 64 days after beryllium oxide exposure. Lymphocytes were initially well differentiated, but progressed to lymphoblastic cells and aggregated in lymphofollicular nodules or microgranulomas over time. Alveolar macrophages were large, and filled with intracytoplasmic material. Cortical and paracortical lymphoid hyperplasia of the tracheobronchial nodes was found. Lung lymphocyte concentrations were increased at 3 months and returned to normal in both dose groups given 500 °C treated beryllium chloride. No significant elevations in lymphocyte concentrations were found in dogs given 1,000° C treated beryllium oxide. Lung retention was higher in the 500 °C treated beryllium oxide group. The lesions found in dog lungs closely resembled those found in humans with CBD: severe granulomas, lymphoblast transformation, increased pulmonary lymphocyte concentrations and variation in beryllium sensitivity. It was concluded that the canine model for berylliosis may provide insight into this disease.

In a follow-up experiment, control dogs and those exposed to beryllium oxide calcined at 500 °C were allowed to rest for 2.5 years, and then re-exposed to filtered air (controls) or beryllium oxide calcined at 500 °C for an initial lung burden (ILB) target of 50 μg beryllium oxide/kg body weight (Haley et al., 1992). Immune responses of blood and BAL lymphocytes, and lung lesions in dogs sacrificed 210 days post-exposure, were compared with results following the initial exposure. The severity of lung lesions was comparable under both conditions, suggesting that a 2.5-year interval was sufficient to prevent cumulative pathologic effects. Conradi et al. (1971) found no exposure-related histological alterations in the lungs of six beagle dogs exposed to a range of 3,300-4,380 μg Be/m3 as beryllium oxide calcined at 1,400° C for 30 min, once per month for 3 months. Because the dogs were sacrificed 2 years post-exposure, the long time period between exposure and response may have allowed for the reversal of any beryllium-induced changes (EPA, 1998).

A 1994 study by Haley et al. showed that intra-bronchiolar instillation of beryllium induced immune granulomas and sensitization in monkeys. Haley et al. (1994) exposed male cynomolgus monkeys to either beryllium metal or beryllium oxide calcined at 500 °C by intrabronchiolar instillation as a saline suspension. Lymphocyte counts in BAL fluid were observed, and were found to be significantly increased in monkeys exposed to beryllium metal on post-exposure days 14 to 90, and on post-exposure day 60 in monkeys exposed to beryllium oxide. The lungs of monkeys exposed to beryllium metal had lesions characterized by interstitial fibrosis, Type II cell hyperplasia, and lymphocyte infiltration. Some monkeys also exhibited immune granulomas. Similar lesions were observed in monkeys exposed to beryllium oxide, but the incidence and severity were much less. BAL lymphocytes from monkeys exposed to beryllium metal, but not from monkeys exposed to beryllium oxide, proliferated in response to beryllium sulfate in the BeLPT (EPA, 1998).

In an experiment similar to the one conducted with dogs, Conradi et al. (1971) found no effect in monkeys (Macaca irus) exposed via whole-body inhalation for three 30-minute monthly exposures to a range of 3,300-4,380 μg Be/m3 as beryllium oxide calcined at 1,400° C. The lack of effect may have been related to the long period (2 years) between exposure and sacrifice, or to low toxicity of beryllium oxide calcined at such a high temperature.

As discussed earlier in this Health Effects section, at the cellular level, beryllium dissolution must occur for either a dendritic cell or a macrophage to present beryllium as an antigen to induce the cell-mediated CBD immune reactions (Stefaniak et al., 2006). Several studies have shown that low-fired beryllium oxide, which is predominantly made up of poorly crystallized small particles, is more immunologically reactive than beryllium oxide calcined at higher firing temperatures that result in less reactivity due to increasing crystal size. As discussed previously, Haley et al. (1989a) found more severe lung lesions and a stronger immune response in beagle dogs receiving a single inhalation exposure to beryllium oxide calcined at 500 °C than in dogs receiving an equivalent initial lung burden of beryllium oxide calcined at 1,000° C. Haley et al. found that beryllium oxide calcined at 1,000° C elicited little local pulmonary immune response, whereas the much more soluble beryllium oxide calcined at 500 °C produced a beryllium-specific, cell-mediated immune response in dogs (Haley et al., 1991).

In a later study, beryllium metal appeared to induce a greater toxic response than beryllium oxide following intrabronchiolar instillation in cynomolgus monkeys, as evidenced by more severe lung lesions, a larger effect on BAL lymphocyte counts, and a positive response in the BeLPT with BAL lymphocytes only after exposure to beryllium metal (Haley et al., 1994). Because an oxide layer may form on beryllium-metal surfaces after exposure to air (Mueller and Adolphson, 1979; Harmsen et al., 1986) dissolution of small amounts of poorly soluble beryllium compounds in the lungs might be sufficient to allow persistent low-level beryllium presentation to the immune system (NAS, 2008).

Genetic studies in humans led to the creation of an animal model containing different human HLA-DP alleles inserted into FVB/N mice for mechanistic studies of CBD. Three strains of genetically engineered mice (transgenic mice) were created that conferred different risks for developing CBD based on human studies (Weston et al., 2005; Snyder et al., 2008): (1) the HLDPB1*401 transgenic strain, where the transgene codes for lysine residue at the 69th position of the B-chain conferred low risk of CBD; (2) the HLA-DPB1*201 mice, where the transgene codes for glutamic acid residue at the 69th position of the B-chain and glycine residues at positions 84 and 85 conferred medium risk of CBD; and (3) the HLA-DPB1*1701 mice, where the transgene codes for glutamic acid at the 69th position of the B-chain and aspartic acid and glutamic acid residues at positions 84 and 85, respectively, conferred high risk of CBD (Tarantino-Hutchinson et al., 2009).

In order to validate the transgenic model, Tarantino-Hutchison et al. challenged the transgenic mice along with seven different inbred mouse strains to determine the susceptibility and sensitivity to beryllium exposure. Mice were dermally exposed with either saline or beryllium, then challenged with either saline or beryllium (as beryllium sulfate) using the MEST protocol (mouse ear-swelling test). The authors determined that the high risk HLA-DPB1*1701 transgenic strain responded 4 times greater (as measured via ear swelling) than control mice and at least 2 times greater than other strains of mice. The findings correspond to epidemiological study results reporting an enhanced CBD odds ratio for the HLA-DPB1*1701 in humans (Weston et al., 2005; Snyder et al., 2008). Transgenic mice with the genes corresponding to the low and medium odds ratio study did not respond significantly over the control group. The authors concluded that while HLA-DPB1*1701 is important to beryllium sensitization and progression to CBD, other genetic and environmental factors contribute to the disease process as well.Start Printed Page 47607

7. Preliminary Beryllium Sensitization and CBD Conclusions

It is well-established that skin and inhalation exposure to beryllium may lead to sensitization and that inhalation exposure, or skin exposure coupled with inhalation exposure, may lead to the onset and progression of CBD. This is supported by extensive human studies. While all facets of the biological mechanism for this complex disease have yet to be fully elucidated, many of the key events in the disease sequence have been identified and described in the previous sections. Sensitization is a necessary first step to the onset of CBD (NAS, 2008). Sensitization is the process by which the immune system recognizes beryllium as a foreign substance and responds in a manner that may lead to development of CBD. It has been documented that a substantial proportion of sensitized workers exposed to airborne beryllium progress to CBD (Rosenman et al., 2005; NAS, 2008; Mroz et al., 2009). Animal studies, particularly in dogs and monkeys, have provided supporting evidence for T-cell lymphocyte proliferation in the development of granulomatous lung lesions after exposure to beryllium (Harmsen et al., 1986; Haley et al., 1989, 1992, 1994). The animal studies have also provided important insights into the roles of chemical form, genetic susceptibility, and residual lung burden in the development of beryllium lung disease (Harmsen et al., 1986; Haley et al., 1992; Tarantino-Hutchison et al., 2009). OSHA has made a preliminary determination to consider sensitization and CBD to be adverse events along the pathological continuum in the disease process, with sensitization being the necessary first step in the progression to CBD.

The epidemiological evidence presented in this section demonstrates that sensitization and CBD are continuing to occur from present-day exposures below OSHA's PEL (Rosenman, 2005 with erratum published 2006). The available literature discussed above shows that disease prevalence can be reduced by reducing inhalation exposure (Thomas et al., 2009). However, the available epidemiological studies also indicate that it may be necessary to minimize skin exposure to further reduce the incidence of sensitization (Bailey et al., 2010). The preliminary risk assessment further discusses the effectiveness of interventions to reduce beryllium exposures and the risk of sensitization and CBD (see section VI, Preliminary Risk Assessment).

Studies have demonstrated there remains a prevalence of sensitization and CBD in facilities with exposure levels below the current OSHA PEL (Rosenman et al., 2005; Thomas et al., 2009), that risk of sensitization and CBD appears to vary across industries and processes (Deubner et al., 2001; Kreiss et al., 1997; Newman et al., 2001; Henneberger et al., 2001; Schuler et al., 2005; Stange et al., 2001; Taiwo et al., 2010), and that efforts to reduce exposure have succeeded in reducing the frequency of beryllium sensitization and CBD (Bailey et al., 2010) (See Table A-1 in the Appendix).

Of workers who were found to be sensitized and underwent clinical evaluation, 20-49 percent were diagnosed with CBD (Kreiss et al., 1993; Newman, 1996, 2005 and 2007; Stange et al., 2001). Overall prevalence of CBD in cross-sectional screenings ranges from 0.6 to 8 percent (Kreiss et al., 2007). A study by Newman (2005) estimated from ongoing surveillance of sensitized individuals, with an average follow-up time of 6 years, that 31 percent of beryllium-exposed employees progressed to CBD (Newman, 2005). However, Newman (2005) went on to suggest that if follow-up times were increased the rate of progression from sensitization to CBD could be much higher. A study of nuclear weapons facility employees enrolled in an ongoing medical surveillance program found that only about 20 percent of sensitized individuals employed less than five years eventually were diagnosed with CBD, while 40 percent of sensitized employees employed ten years or more developed CBD (Stange et al., 2001) indicating length of exposure may play a role in further development of the disease. In addition, Mroz et al. (2009) conducted a longitudinal study of individuals clinically evaluated at National Jewish Health (between 1982 and 2002) who were identified as having sensitization and CBD through workforce medical surveillance. The authors identified 171 cases of CBD and 229 cases of sensitization; all individuals were identified through workplace screening using the BeLPT (Mroz et al., 2009). Over the 20-year study period, 8.8 percent (i.e., 22 cases out 251 sensitized) of individuals with sensitization went on to develop CBD. The findings from this study indicated that on the average span of time from initial beryllium exposure to CBD diagnosis was 24 years (Mroz et al., 2009).

E. Beryllium Lung Cancer Section

Beryllium exposure has been associated with a variety of adverse health effects including lung cancer. The potential for beryllium and its compounds to cause cancer has been previously assessed by various other agencies (EPA, ATSDR, NAS, NIEHS, and NIOSH) with each agency identifying beryllium as a potential carcinogen. In addition, the International Agency for Research on Cancer (IARC) did an extensive evaluation in 1993 and reevaluation in April 2009 (IARC, 2012). In brief, IARC determined beryllium and its compounds to be carcinogenic to humans (Group 1 category), while EPA considers beryllium to be a probable human carcinogen (EPA, 1998), and the National Toxicology Program (NTP) has determined beryllium and its compounds to be known carcinogens (NTP, 2014). OSHA has conducted an independent evaluation of the carcinogenic potential of beryllium and these compounds as well. The following is a summary of the studies used to support the Agency findings that beryllium and its compounds are human carcinogens.

1. Genotoxicity Studies

Genotoxicity can be an important indicator for screening the potential of a material to induce cancer and an important mechanism leading to tumor formation and carcinogenesis. In a review conducted by the National Academy of Science, beryllium and its compounds have tested positively in nearly 50 percent of the genotoxicity studies conducted without exogenous metabolic activity. However, they were found to be non-genotoxic in most bacterial assays (NAS, 2008).

Gene mutations have been observed in mammalian cells cultured with beryllium chloride in a limited number of studies (EPA, 1998; ATSDR, 2002; Gordon and Bowser, 2003). Culturing mammalian cells with beryllium chloride, beryllium sulfate, or beryllium nitrate has resulted in clastogenic alterations. However, most studies have found that beryllium chloride, beryllium nitrate, beryllium sulfate, and beryllium oxide did not induce gene mutations in bacterial assays with or without metabolic activation. In the case of beryllium sulfate, all mutagenicity studies (Ames (Simmon, 1979; Dunkel et al., 1984; Arlauskas et al., 1985; Ashby et al., 1990); E. coli pol A (Rosenkranz and Poirer, 1979); E. coli WP2 uvr A (Dunkel et al., 1984) and Saccharomyces cerevisiae (Simmon, 1979)) were negative with the exception of results reported for Bacillus subtilis rec assay (Kada et al., 1980; Kanematsu et al., 1980; EPA, 1998). Beryllium sulfate did not induce unscheduled Start Printed Page 47608DNA synthesis in primary rat hepatocytes and was not mutagenic when injected intraperitoneally in adult mice in a host-mediated assay using Salmonella typhimurium (Williams et al., 1982).

Beryllium nitrate was negative in the Ames assay (Tso and Fung, 1981; Kuroda et al., 1991) but positive in a Bacillus subtilis rec assay (Kuroda et al., 1991). Beryllium chloride was negative in a variety of studies (Ames (Ogawa et al., 1987; Kuroda et al., 1991); E. coli WP2 uvr A (Rossman and Molina, 1984); and Bacillus subtilis rec assay (Nishioka, 1975)). In addition, beryllium chloride failed to induce SOS DNA repair in E. coli (Rossman et al., 1984). However, positive results were reported for Bacillus subtilis rec assay using spores (Kuroda et al., 1991), E. coli KMBL 3835; lacI gene (Zakour and Glickman, 1984), and hprt locus in Chinese hamster lung V79 cells (Miyaki et al., 1979). Beryllium oxide was negative in the Ames assay and Bacillus subtilis rec assays (Kuroda et al., 1991; EPA, 1998).

Gene mutations have been observed in mammalian cells (V79 and CHO) cultured with beryllium chloride (Miyaki et al., 1979; Hsie et al., 1979a, b), and culturing of mammalian cells with beryllium chloride (Vegni-Talluri and Guiggiani, 1967), and beryllium sulfate (Brooks et al., 1989; Larramendy et al., 1981) has resulted in clastogenic alterations—producing breakage or disrupting chromosomes (EPA, 1998). Beryllium chloride evaluated in a mouse model indicated increased DNA strand breaks and the formation of micronuclei in bone marrow (Attia et al., 2013).

Data on the in vivo genotoxicity of beryllium are limited to a single study that found beryllium sulfate (1.4 and 2.3 g/kg, 50 percent and 80 percent of median lethal dose) administered by gavage did not induce micronuclei in the bone marrow of CBA mice. However, a marked depression of erythropoiesis (red blood cell production) was suggestive of bone marrow toxicity which was evident 24 hours after dosing. No mutations were seen in p53 or c-raf-1 and only weak mutations were detected in K-ras in lung carcinomas from F344/N rats given a single nose-only exposure to beryllium metal (Nickell-Brady et al., 1994). The authors concluded that the mechanisms for the development of lung carcinomas from inhaled beryllium in the rat do not involve gene dysfunctions commonly associated with human non-small-cell lung cancer (EPA, 1998).

2. Human Epidemiological Studies

This section reviews in greater detail the studies used to support the mechanistic findings for beryllium-induced cancer. Table A.3 in the Appendix summarizes the important features and characteristics of each study.

a. Beryllium Case Registry (BCR).

Two studies evaluated participants in the BCR (Infante et al., 1980; Steenland and Ward, 1991). Infante et al. (1980) evaluated the mortality patterns of white male participants in the BCR diagnosed with non-neoplastic respiratory symptoms of beryllium disease. Of the 421 cases evaluated, 7 of the participants had died of lung cancer. Six of the deaths occurred more than 15 years after initial beryllium exposure. The duration of exposure for 5 of the 7 participants with lung cancer was less than 1 year, with the time since initial exposure ranging from 12 to 29 years. One of the participants was exposed for 4 years with a 26-year interval since the initial exposure. Exposure duration for one participant diagnosed with pulmonary fibrosis could not be determined; however, it had been 32 years since the initial exposure. Based on BCR records, the participants were classified as being in the acute respiratory group (i.e., those diagnosed with acute respiratory illness at the time of entry in the registry) or the chronic respiratory group (i.e., those diagnosed with pulmonary fibrosis or some other chronic lung condition at the time of entry into the BCR). The 7 participants with lung cancer were in the BCR because of diagnoses of acute respiratory illness. For only one of those individuals was initial beryllium exposure less than 15 years prior. Only 1 of the 6 (with greater than 15 years since initial exposure to beryllium) had been diagnosed with chronic respiratory disease. The study did not report exposure concentrations or smoking habits. The authors concluded that the results of this cohort agreed with previous animal studies and with epidemiological studies demonstrating an increased risk of lung cancer in workers exposed to beryllium.

Steenland and Ward (1991) extended the work of Infante et al. (1980) to include females and to include 13 additional years of follow-up. At the time of entry in the BCR, 93 percent of the women in the study, but only 50 percent of the men, had been diagnosed with CBD. In addition, 61 percent of the women had worked in the fluorescent tube industry and 50 percent of the men had worked in the basic manufacturing industry. A total of 22 males and 6 females died of lung cancer. Of the 28 total deaths from lung cancer, 17 had been exposed to beryllium for less than 4 years and 11 had been exposed for greater than 4 years. The study did not report exposure concentrations. Survey data collected in 1965 provided information on smoking habits for 223 cohort members (32 percent), on the basis of which the authors suggested that the rate of smoking among workers in the cohort may have been lower than U.S. rates. The authors concluded that there was evidence of increased risk of lung cancer in workers exposed to beryllium and diagnosed with beryllium disease.

b. Beryllium Manufacturing and/or Processing Plants (Extraction, Fabrication, and Processing)

Several epidemiological cohort studies have reported excess lung cancer mortality among workers employed in U.S. beryllium production and processing plants during the 1930s to 1960s. The largest and most comprehensive study investigated the mortality experience of 9,225 workers employed in seven different beryllium processing plants over a 30-year period (Ward et al., 1992). The workers at the two oldest facilities (i.e., Lorain, OH, and Reading, PA) were found to have significant excess lung cancer mortality relative to the U.S. population. Of the seven plants in the study, these two plants were believed to have the highest exposure levels to beryllium. A different analysis of the lung cancer mortality in this cohort using various local reference populations and alternate adjustments for smoking generally found smaller, non-significant rates of excess mortality among the beryllium employees (Levy et al., 2002). Both cohort studies are limited by a lack of job history and air monitoring data that would allow investigation of mortality trends with beryllium exposure. The majority of employees at the Lorain, OH, and Reading, PA, facilities were employed for a relatively short period of less than one year.

Bayliss et al. (1971) performed a nested cohort study of more than 7,000 former workers from the beryllium processing industry employed from 1942-1967. Information for the workers was collected from the personnel files of participating companies. Of the more than 7,000 employees, a cause of death was known for 753 male workers. The number of observed lung cancer deaths was 36 compared to 34.06 expected for a standardized mortality ratio (SMR) of 1.06. When evaluated by the number of years of employment, 24 of the 36 men were employed for less than 1 year in Start Printed Page 47609the industry (SMR = 1.24), 8 were employed for 1 to 5 years (SMR 1.40), and 4 were employed for more than 5 years (SMR = 0.54). Half of the workers who died from lung cancer began employment in the beryllium production industry prior to 1947. When grouped by job classification, over two thirds of the workers with lung cancer were in production-related jobs while the rest were classified as office workers. The authors concluded that while the lung cancer mortality rates were the highest of all other mortality rates, the SMR for lung cancer was still within range of the expected based on death rates in the United States. The limitations of this study included the lack of information regarding exposure concentrations, smoking habits, and the age and race of the participants.

Mancuso (1970, 1979, 1980) and Mancuso and El-Attar (1969) performed a series of occupational cohort studies on a group of over 3,685 workers (primarily white males) employed in the beryllium manufacturing industry during 1937-1948.[3] The beryllium production facilities were located in Ohio and Pennsylvania and the records for the employees, including periods of employment, were obtained from the Social Security Administration. These studies did not include analyses of mortality by job title or exposure category. In addition, there were no exposure concentrations estimated or adjustments for smoking. The estimated duration of employment ranged from less than 1 year to greater than 5 years. In the most recent study (Mancuso, 1980), employees from the viscose rayon industry served as a comparison population. There was a significant excess of lung cancer deaths based on the total number of 80 observed lung cancer mortalities at the end of 1976 compared to an expected number of 57.06 based on the comparison population resulting in an SMR of 1.40 (p < 0.01) (Mancuso, 1980). There was a statistically significant excess in lung cancer deaths for the shortest duration of employment (< 12 months, p < 0.05) and the longest duration of employment (> 49 months, p < 0.01). Based on the results of this study, the author concluded that the ability of beryllium to induce cancer in workers does not require continuous exposure and that it is reasonable to assume that the amount of exposure required to produce lung cancer can occur within a few months of exposure regardless of the length of employment.

Wagoner et al. (1980) expanded the work of Mancuso (1970; 1979; 1980) using a cohort of 3,055 white males from the beryllium extraction, processing, and fabrication facility located in Reading, Pennsylvania. The men included in the study worked at the facility sometime between 1942 and 1968, and were followed through 1976. The study accounted for length of employment. Other factors accounted for included age, smoking history, and regional lung cancer mortality. Forty-seven members of the cohort died of lung cancer compared to an expected 34.29 based on U.S. white male lung cancer mortality rates (p < .05). The results of this cohort showed an excess risk of lung cancer in beryllium-exposed workers at each duration of employment (< 5 years and ≥ 5 years), with a statistically significant excess noted at < 5 years durations of employment and a ≥ 25-year interval since the beginning of employment (p < 0.05). The study was criticized by several epidemiologists (MacMahon, 1978, 1979; Roth, 1983), by a CDC Review Committee appointed to evaluate the study, and by one of the study's coauthors (Bayliss, 1980) for inadequate discussion of possible alternative explanations of excess lung cancer in the cohort. The specific issues identified include the use of 1965-1967 U.S. white male lung cancer mortality rates to generate expected numbers of lung cancers in the period 1968-1975 and inadequate adjustment for smoking.

Ward et al. (1992) performed a retrospective mortality cohort study of 9,225 male workers employed at seven beryllium processing facilities, including the Ohio and Pennsylvania facilities studied by Mancuso and El-Attar (1969), Mancuso (1970; 1979; 1980), and Wagoner et al. (1980). The men were employed for no less than 2 days between January 1940 and December 1988. At the end of the study 61.1 percent of the cohort was known to be living and 35.1 percent was known to be deceased. The duration of employment ranged from 1 year or less to greater than 10 years with the largest percentage of the cohort (49.7 percent) employed for less than one year, followed by 1 to 5 years of employment (23.4 percent), greater than 10 years (19.1 percent), and 5 to 10 years (7.9 percent). Of the 3,240 deaths, 280 observed deaths were caused by lung cancer compared to 221.5 expected deaths, yielding a statistically significant SMR of 1.26 (p < 0.01). Information on the smoking habits of 15.9 percent of the cohort members, obtained from a 1968 Public Health Service survey conducted at four of the plants, was used to calculate a smoking-adjusted SMR of 1.12, which was not statistically significant. The number of deaths from lung cancer was also examined by decade of hire. The authors reported a relationship between earlier decades of hire and increased lung cancer risk.

The EPA Integrated Risk Information System (IRIS), IARC, and California EPA Office of Environmental Health Hazard Assessment (OEHHA) have all based their cancer assessment on the Ward et al. 1992 study, with supporting data concerning exposure concentrations from Eisenbud and Lisson (1983) and NIOSH (1972), who estimated that the lower-bound estimate of the median exposure concentration exceeded 100 µg/m3 and found that concentrations in excess of 1,000 µg/m3 were common. The IRIS cancer risk assessment recalculated expected lung cancers based on U.S. white male lung cancer rates (including the period 1968-1975) and used an alternative adjustment for smoking. In addition, one individual with lung cancer, who had not worked at the plant, was removed from the cohort. After these adjustments were made, an elevated rate of lung cancer was still observed in the overall cohort (46 cases vs. 41.9 expected cases). However, based on duration of employment or interval since beginning of employment, neither the total cohort nor any of the subgroups had a statistically significant excess in lung cancer (EPA, 1987). Based on their evaluation of this and other epidemiological studies, the EPA characterized the human carcinogenicity data then available as “limited” but “suggestive of a causal relationship between beryllium exposure and an increased risk of lung cancer” (IRIS database). This report includes quantitative estimates of risk that were derived using the information presented in Wagoner et al. (1980), the expected lung cancers recalculated by the EPA, and bounds on presumed exposure levels.

Levy et al. (2002) questioned the results of Ward et al. (1992) and performed a reanalysis of the Ward et al. data. The Levy et al. reanalysis differed from the Ward et al. analysis in the following significant ways. First, Levy et al. (2002) examined two alternative adjustments for smoking, which were based on (1) a different analysis of the American Cancer Society (ACS) data used by Ward et al. (1992) for their smoking adjustment, or (2) results from a smoking/lung cancer study of veterans (Levy and Marimont, 1998). Second, Levy et al. (2002) also examined the Start Printed Page 47610impact of computing different reference rates derived from information about the lung cancer rates in the cities in which most of the workers at two of the plants lived. Finally, Levy et al. (2002) considered a meta-analytical approach to combining the results across beryllium facilities. For all of the alternatives Levy et al. (2002) considered, except the meta-analysis, the facility-specific and combined SMRs derived were lower than those reported by Ward et al. (1992). Only the SMR for the Lorain, OH, facility remained statistically significantly elevated in some reanalyses. The SMR obtained when combining over the plants was not statistically significant in eight of the nine approaches they examined, leading Levy et al. (2002) to conclude that there was little evidence of statistically significant elevated SMRs in those plants.

One occupational nested case-control study evaluated lung cancer mortality in a cohort of 3,569 male workers employed at a beryllium alloy production plant in Reading, PA, from 1940 to 1969 and followed through 1992 (Sanderson et al., 2001). There were a total of 142 known lung cancer cases and 710 controls. For each lung cancer death, 5 age- and race-matched controls were selected by incidence density sampling. Confounding effects of smoking were evaluated. Job history and historical air measurements at the plant were used to estimate job-specific beryllium exposures from the 1930s to 1990s. Calendar-time-specific beryllium exposure estimates were made for every job and used to estimate workers' cumulative, average, and maximum exposure. Because of the long period of time required for the onset of lung cancer, an “exposure lag” was employed to discount recent exposures less likely to contribute to the disease.

The cumulative, average, and maximum beryllium exposure concentration estimates for the 142 known lung cancer cases were 46.06 ± 9.3µg/m3-days, 22.8 ± 3.4 µg/m3, and 32.4 ± 13.8 µg/m3, respectively. The lung cancer mortality rate was 1.22 (95 percent CI = 1.03 − 1.43). Exposure estimates were lagged by 10 and 20 years in order to account for exposures that did not contribute to lung cancer because they occurred after the induction of cancer. In the 10- and 20-year lagged exposures the geometric mean tenures and cumulative exposures of the lung cancer mortality cases were higher than the controls. In addition, the geometric mean and maximum exposures of the workers were significantly higher than controls when the exposure estimates were lagged 10 and 20 years (p < 0.01).

Results of a conditional logistic regression analysis indicated that there was an increased risk of lung cancer in workers with higher exposures when dose estimates were lagged by 10 and 20 years. There was also a lack of evidence that confounding factors such as smoking affected the results of the regression analysis. The authors noted that there was considerable uncertainty in the estimation of exposure in the 1940's and 1950's and the shape of the dose-response curve for lung cancer. Another analysis of the study data using a different statistical method did not find a significantly greater relative risk of lung cancer with increasing beryllium exposures (Levy et al., 2007). The average beryllium air levels for the lung cancer cases were estimated to be an order of magnitude above the current 8-hour OSHA TWA PEL (2 μg/m3) and roughly two orders of magnitude higher than the typical air levels in workplaces where beryllium sensitization and pathological evidence of CBD have been observed. IARC evaluated this reanalysis in 2012 and found the study introduced a downward bias into risk estimates (IARC, 2012).

Schubauer-Berigan et al. reanalyzed data from the nested case-control study of 142 lung cancer cases in the Reading, PA, beryllium processing plant (Schubauer-Berigan et al., 2008). This dataset was reanalyzed using conditional (stratified by case age) logistic regression. Independent adjustments were made for potential confounders of birth year and hire age. Average and cumulative exposures were analyzed using the values reported in the original study. The objective of the reanalysis was to correct for the known differences in smoking rates by birth year. In addition, the authors evaluated the effects of age at hire to determine differences observed by Sanderson et al. in 2001. The effect of birth cohort adjustment on lung cancer rates in beryllium-exposed workers was evaluated by adjusting in a multivariable model for indicator variables for the birth cohort quartiles.

Unadjusted analyses showed little evidence of lung cancer risk associated with beryllium occupational exposure using cumulative exposure until a 20-year lag was used. Adjusting for either birth cohort or hire age attenuated the risk for lung cancer associated with cumulative exposure. Using a 10- or 20-year lag in workers born after 1900 also showed little evidence of lung cancer risk, while those born prior to 1900 did show a slight elevation in risk. Unlagged and lagged analysis for average exposure showed an increase in lung cancer risk associated with occupational exposure to beryllium. The finding was consistent for either workers adjusted or unadjusted for birth cohort or hire age. Using a 10-year lag for average exposure showed a significant effect by birth cohort.

The authors stated that the reanalysis indicated that differences in the hire ages among cases and controls, first noted by Deubner et al. (2001) and Levy et al. (2007), were primarily due to the fact that birth years were earlier among controls than among cases, resulting from much lower baseline risk of lung cancer for men born prior to 1900 (Schubauer-Berigan et al., 2008). The authors went on to state that the reanalysis of the previous NIOSH case-control study suggested the relationship observed previously between cumulative beryllium exposure and lung cancer was greatly attenuated by birth cohort adjustment.

Hollins et al. (2009) re-examined the weight of evidence of beryllium as a lung carcinogen in a recent publication (Hollins et al., 2009). Citing more than 50 relevant papers, the authors noted the methodological shortcomings examined above, including lack of well-characterized historical occupational exposures and inadequacy of the availability of smoking history for workers. They concluded that the increase in potential risk of lung cancer was observed among those exposed to very high levels of beryllium and that beryllium's carcinogenic potential in humans at these very high exposure levels were not relevant to today's industrial settings. IARC performed a similar re-evaluation in 2009 (IARC, 2012) and found that the weight of evidence for beryllium lung carcinogenicity, including the animal studies described below, still warranted a Group I classification, and that beryllium should be considered carcinogenic to humans.

Schubauer-Berigan et al. (2010) extended their analysis from a previous study estimating associations between mortality risk and beryllium exposure to include workers at 7 beryllium processing plants. The study (Schubauer-Berigan et al., 2010) followed the mortality incidences of 9,199 workers from 1940 through 2005 at the 7 beryllium plants. JEMs were developed for three plants in the cohort: The Reading plant, the Hazleton plant, and the Elmore plant. The last is described in Couch et al. 2010. Including these JEMs substantially improved the evidence base for evaluating the carcinogenicity of beryllium and, and this change Start Printed Page 47611represents more than an update of the beryllium cohort. Standardized mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers.

Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was ≥ 10 μg/m3 had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. These studies showed strong associations for cumulative exposure (when short-term workers were excluded), maximum exposure or both. Significant positive trends with cumulative exposure were observed for nervous system cancers (p = 0.0006) and, when short-term workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p = 0.003) and COPD (p < 0.0001).

The authors concluded the findings from this reanalysis reaffirmed that lung cancer and CBD are related to beryllium exposure. The authors went on to suggest that beryllium exposures may be associated with nervous system and urinary tract cancers and that cigarette smoking and other lung carcinogens were unlikely to explain the increased incidences in these cancers. The study corrected an error that was discovered in the indirect smoking adjustment initially conducted by Ward et al., concluding that cigarette smoking rates did not differ between the cohort and the general U.S. population. No association was found between cigarette smoking and either cumulative or maximum beryllium exposure, making it very unlikely that smoking was a substantial confounder in this study (Schubauer-Berigan et al., 2010).

3. Animal Cancer Studies

This section reviews the animal literature used to support the findings for beryllium-induced lung cancer. Lung tumors have been induced via inhalation and intratracheal administration of beryllium to rats and monkeys, and osteosarcomas have been induced via intravenous and intramedullary (inside the bone) injection of beryllium in rabbits and possibly in mice. The chronic oral studies did not report increased incidences of tumors in rodents, but these were conducted at doses below the maximum tolerated dose (MTD) (EPA, 1998).

Early animal studies revealed that some beryllium compounds are carcinogenic when inhaled (ATSDR, 2002). Animal experiments have shown consistent increases in lung cancers in rats, mice and rabbits chronically exposed to beryllium and beryllium compounds by inhalation or intratracheal instillation. In addition to lung cancer, osteosarcomas have been produced in mice and rabbits exposed to various beryllium salts by intravenous injection or implantation into the bone (NTP, 1999).

In an inhalation study assessing the potential tumorigenicity of beryllium, Schepers et al. (1957) exposed 115 albino Sherman and Wistar rats (male and female) via inhalation to 0.0357 mg beryllium/m[3] (1 γ beryllium/ft[3] ) [4] as an aqueous aerosol of beryllium sulfate for 44 hours/week for 6 months, and observed the rats for 18 months after exposure. Three to four control rats were killed every two months for comparison purposes. Seventy-six lung neoplasms, [5] including adenomas, squamous-cell carcinomas, acinous adenocarcinomas, papillary adenocarcinomas, and alveolar-cell adenocarcinomas, were observed in 52 rats exposed to beryllium sulfate aerosol. Adenocarcinomata were the most numerous. Pulmonary metastases tended to localize in areas with foam cell clustering and granulomatosis. No neoplasia was observed in any of the control rats. The incidence of lung tumors in exposed rats is presented in the following Table 2:

Table 2—Neoplasm Analysis

NeoplasmNumberMetastases
Adenoma18
Squamous carcinoma51
Acinous adenocarcinoma242
Papillary adenocarcinoma111
Alveolar-cell adenocarcinoma7
Mucigenous tumor71
Endothelioma1
Retesarcoma33
Total768

Schepers (1962) reviewed 38 existing beryllium studies that evaluated seven beryllium compounds and seven mammalian species. Beryllium sulfate, beryllium fluoride, beryllium phosphate, beryllium alloy (BeZnMnSiO4), and beryllium oxide were proven to be carcinogenic and have remarkable pleomorphic neoplasiogenic proclivities. Ten varieties of tumors were observed, with adenocarcinoma being the most common variety.

In another study, Vorwald and Reeves (1959) exposed Sherman albino rats via the inhalation route to aerosols of 0.006 mg beryllium/m3 as beryllium oxide and 0.0547 mg beryllium/m3 as beryllium sulfate for 6 hours/day, 5 days/week for an unspecified duration. Lung tumors (single or multifocal) were observed in the animals sacrificed following 9 months of daily inhalation exposure. The histologic pattern of the cancer was primarily adenomatous; however, epidermoid and squamous cell cancers were also observed. Infiltrative, vascular, and lymphogenous extensions often developed with secondary metastatic growth in the tracheobronchial lymph nodes, the mediastinal connective tissue, the parietal pleura, and the diaphragm.

In the first of two articles, Reeves et al. (1967a) investigated the carcinogenic process in lungs resulting from chronic (up to 72 weeks) beryllium sulfate inhalation. One hundred fifty male and female Sprague Dawley C.D. strain rats were exposed to beryllium sulfate aerosol at a mean atmospheric concentration of 34.25 μg beryllium/m3 (with an average particle diameter of 0.12 µm). Prior to initial exposure and again during the 67-68 and 75-76 weeks of life, the animals received prophylactic treatments of tetracycline-HCl to combat recurrent pulmonary infections.

The animals entered the exposure chamber at 6 weeks of age and were Start Printed Page 47612exposed 7 hours per day/5 days per week for up to 2,400 hours of total exposure time. An equal number of unexposed controls were held in a separate chamber. Three male and three female rats were sacrificed monthly during the 72-week exposure period. Mortality due to respiratory or other infections did not appear until 55 weeks of age, and 87 percent of all animals survived until their scheduled sacrifices.

Average lung weight towards the end of exposure was 4.25 times normal with progressively increasing differences between control and exposed animals. The increase in lung weight was accompanied by notable changes in tissue texture with two distinct pathological processes—inflammatory and proliferative. The inflammatory response was characterized by marked accumulation of histiocytic elements forming clusters of macrophages in the alveolar spaces. The proliferative response progressed from early epithelial hyperplasia of the alveolar surfaces, through metaplasia (after 20-22 weeks of exposure), anaplasia (cellular dedifferentiation) (after 32-40 weeks of exposure), and finally to lung tumors.

Although the initial proliferative response occurred early in the exposure period, tumor development required considerable time. Tumors were first identified after nine months of beryllium sulfate exposure, with rapidly increasing rates of incidence until tumors were observed in 100 percent of exposed animals by 13 months. The 9-to-13-month interval is consistent with earlier studies. The tumors showed a high degree of local invasiveness. No tumors were observed in control rats. All 56 tumors studied appeared to be alveolar adenocarcinomas and 3 “fast-growing” tumors that reached a very large size comparatively early. About one-third of the tumors showed small foci where the histologic pattern differed. Most of the early tumor foci appeared to be alveolar rather than bronchiolar, which is consistent with the expected pathogenesis, since permanent deposition of beryllium was more likely on the alveolar epithelium rather than on the bronchiolar epithelium. Female rats appeared to have an increased susceptibility to beryllium exposure. Not only did they have a higher mortality (control males [n = 8], exposed males [n = 9] versus control females [n = 4], exposed females [n = 17]) and body weight loss than male rats, but the three “fast-growing” tumors only occurred in females.

In the second article, Reeves et al. (1967b) described the rate of accumulation and clearance of beryllium sulfate aerosol from the same experiment (Reeves et al., 1967a). At the time of the monthly sacrifice, beryllium assays were performed on the lungs, tracheobronchial lymph nodes, and blood of the exposed rats. The pulmonary beryllium levels of rats showed a rate of accumulation which decreased during continuing exposure and reached a plateau (defined as equilibrium between deposition and clearance) of about 13.5 μg beryllium for males and 9 μg beryllium for females in whole lungs after approximately 36 weeks. Females were notably less efficient than males in utilizing the lymphatic route as a method of clearance, resulting in slower removal of pulmonary beryllium deposits, lower accumulation of the inhaled material in the tracheobronchial lymph nodes, and higher morbidity and mortality.

There was no apparent correlation between the extent and severity of pulmonary pathology and total lung load. However, when the beryllium content of the excised tumors was compared with that of surrounding nonmalignant pulmonary tissues, the former showed a notable decrease (0.50 ± 0.35 μg beryllium/gram versus 1.50 ± 0.55 μg beryllium/gram). This was believed to be largely a result of the dilution factor operating in the rapidly growing tumor tissue. However, other factors, such as lack of continued local deposition due to impaired respiratory function and enhanced clearance due to high vascularity of the tumor, may also have played a role. The portion of inhaled beryllium retained in the lungs for a longer duration, which is in the range of one-half of the original pulmonary load, may have significance for pulmonary carcinogenesis. This pulmonary beryllium burden becomes localized in the cell nuclei and may be an important factor in eliciting the carcinogenic response associated with beryllium inhalation.

Groth et al. (1980) conducted a series of experiments to assess the carcinogenic effects of beryllium, beryllium hydroxide, and various beryllium alloys. For the beryllium metal/alloys experiment, 12 groups of 3-month-old female Wistar rats (35 rats/group) were used. All rats in each group received a single intratracheal injection of either 2.5 or 0.5 mg of one of the beryllium metals or beryllium alloys as described in Table 3 below. These materials were suspended in 0.4 cc of isotonic saline followed by 0.2 cc of saline. Forty control rats were injected with 0.6 cc of saline. The geometric mean particle sizes varied from 1 to 2 µm. Rats were sacrificed and autopsied at various intervals ranging from 1 to 18 months post-injection.

Table 3—Summary of Beryllium Dose From Groth et al. (1980)

Form of BePercent BePercent other compoundsTotal No. rats autopsiedCompound dose (mg)Be dose (mg)
Be metal100None162.52.5
210.50.5
Passivated Be metal990.26% Chromium262.52.5
200.50.5
BeAl alloy6238% Aluminum242.51.55
210.50.3
BeCu alloy496% Copper282.50.1
240.50.02
BeCuCo alloy2.40.4% Cobalt332.50.06
96% Copper300.50.012
BeNi alloy2.297.8% Nickel282.50.056
270.50.011

Lung tumors were observed only in rats exposed to beryllium metal, passivated beryllium metal, and beryllium-aluminum alloy. Passivation refers to the process of removing iron contamination from the surface of Start Printed Page 47613beryllium metal. As discussed, metal alloys may have a different toxicity than beryllium alone. Rats exposed to 100 percent beryllium exhibited relatively high mortality rates, especially in the groups where lung tumors were observed. Nodules varying from 1 to 10 mm in diameter were also observed in the lungs of rats exposed to beryllium metal, passivated beryllium metal, and beryllium-aluminum alloy. These nodules were suspected of being malignant.

To test this hypothesis, transplantation experiments involving the suspicious nodules were conducted in nine rats. Seven of the nine suspected tumors grew upon transplantation. All transplanted tumor types metastasized to the lungs of their hosts. Lung tumors were observed in rats injected with both the high and low doses of beryllium metal, passivated beryllium metal, and beryllium-aluminum alloy. No lung tumors were observed in rats injected with the other compounds. From a total of 32 lung tumors detected, most were adenocarcinomas and adenomas; however, two epidermoid carcinomas and at least one poorly differentiated carcinoma were observed. Bronchiolar alveolar cell tumors were frequently observed in rats injected with beryllium metal, passivated beryllium metal, and beryllium-aluminum alloy. All stages of cuboidal, columnar, and squamous cell metaplasia were observed on the alveolar walls in the lungs of rats injected with beryllium metal, passivated beryllium metal, and beryllium-aluminum alloy. These lesions were generally reduced in size and number or absent from the lungs of animals injected with the other alloys (BeCu, BeCuCo, BeNi).

The extent of alveolar metaplasia could be correlated with the incidence of lung cancer. The incidences of lung tumors in the rats that received 2.5 mg of beryllium metal, and 2.5 and 0.5 mg of passivated beryllium metal, were significantly different (p ≤ 0.008) from controls. When autopsies were performed at the 16-to-19-month interval, the incidence (2/6) of lung tumors in rats exposed to 2.5 mg of beryllium-aluminum alloy was statistically significant (p = 0.004) when compared to the lung tumor incidence (0/84) in rats exposed to BeCu, BeNi, and BeCuCo alloys, which contained much lower concentrations of Be (Groth et al., 1980).

Finch et al. (1998b) investigated the carcinogenic effects of inhaled beryllium on heterozygous TSG-p53 knockout mice (p53+/−) and wild-type (p53+/+) mice. Knockout mice can be valuable tools in determining the role of specific genes on the toxicity of a material of interest, in this case, beryllium. Equal numbers of approximately 10-week-old male and female mice were used for this study. Two exposure groups were used to provide dose-response information on lung carcinogenicity. The maximum initial lung burden (ILB) target of 60 μg beryllium was based on previous acute inhalation exposure studies in mice. The lower exposure target level of 15 μg was selected to provide a lung burden significantly less than the high-level group, but high enough to yield carcinogenic responses. Mice were exposed in groups to beryllium metal or to filtered air (controls) via nose-only inhalation. The specific exposure parameters are presented in Table 4 below. Mice were sacrificed 7 days post exposure for ILB analysis, and either at 6 months post exposure (n = 4-5 mice per group per gender) or when 10 percent or less of the original population remained (19 months post exposure for p53+/− knockout and 22.5 months post exposure for p53+/+ wild-type mice). The sacrifice time was extended in the study because a significant number of lung tumors were not observed at 6 months post exposure.

Table 4—Summary of Animal Data From Finch Et Al., 1998 b

Mouse strainMean exposure concentration (μg Be/L)Target be lung burden (μg)Number of miceMean daily exposure duration (minutes)Mean ILB (μg)Number of mice with 1 or more lung tumors/total number examined
Knockout (p53+/−)341530112 (single)NA0/29
366030139‡NA4/28
Wild-type (p53+/+)34156*112 (single)12 ± 4NA
366036†139‡54 ± 60/28
Knockout (p53+/−)NA (air)Control3060-180 (single)NA0/30
ILB = initial lung burden; NA = not applicable
Median aerodynamic diameter of Be aerosol = 1.4 μm (σg = 1.8)
* Wild-type mice in the low exposure group were not evaluated for carcinogenic effects; however ILB was analyzed in six wild-type mice.
† Thirty wild-type mice were analyzed for carcinogenic effects; six wild-type mice were analyzed for ILB.
‡ Mice were exposed for 2.3 hours/day for three consecutive days.

Lung burdens of beryllium measured in wild-type mice at 7 days post exposure were approximately 70-90 percent of target levels. No exposure-related effects on body weight were observed in mice; however, lung weights and lung-to-body-weight ratios were somewhat elevated in 60 μg target ILB p53+/− knockout mice compared to controls (0.05 < p < 0.10). In general, p53+/+ wild-type mice survived longer than p53+/− knockout mice and beryllium exposure tended to decrease survival time in both groups. The incidence of beryllium-induced lung tumors was marginally higher in the 60 μg target ILB p53+/− knockout mice compared to 60 μg target ILB p53+/+ wild-type mice (p = 0.056). The incidence of lung tumors in the 60 μg target ILB p53+/− knockout mice was also significantly higher than controls (p = 0.048). No tumors developed in the control mice, 15 μg target ILB p53+/− knockout mice, or 60 μg target ILB p53+/+ wild-type mice throughout the length of the study. Most lung tumors in beryllium-exposed mice were squamous cell carcinomas, three of four of which were poorly circumscribed and all were associated with at least some degree of granulomatous pneumonia. The study results suggest that having an inactivated p53 allele is associated with lung tumor progression in p53+/− knockout mice. This is based on the significant difference seen in the incidence of beryllium-induced lung neoplasms for the p53+/− knockout mice compared with the p53+/+ wild-type mice. The authors conclude that since there was a relatively late onset of tumors in the beryllium-exposed p53+/− knockout mice, a 6-month bioassay in this mouse strain might not be an appropriate model for lung carcinogenesis (Finch et al., 1998b).Start Printed Page 47614

Nickell-Brady et al. (1994) investigated the development of lung tumors in 12-week-old F344/N rats after a single nose-only inhalation exposure to beryllium aerosol, and evaluated whether beryllium lung tumor induction involves alterations in the K-ras, p53, and c-raf−1 genes. Four groups of rats (30 males and 30 females per group) were exposed to different mass concentrations of beryllium (Group 1: 500 mg/m3 for 8 min; Group 2: 410 mg/m3 for 30 min; Group 3: 830 mg/m3 for 48 min; Group 4: 980 mg/m3 for 39 min). The beryllium mass median aerodynamic diameter was 1.4 μm (σg = 1.9). The mean beryllium lung burdens for each exposure group were 40, 110, 360, and 430 μg, respectively.

To examine genetic alterations, DNA isolation and sequencing techniques (PCR amplification and direct DNA sequence analysis) were performed on wild-type rat lung tissue (i.e., control samples) along with two mouse lung tumor cell lines containing known K-ras mutations, 12 carcinomas induced by beryllium (i.e., experimental samples), and 12 other formalin-fixed specimens. Tumors appeared in beryllium-exposed rats by 14 months, and 64 percent of exposed rats developed lung tumors during their lifetime. Lungs frequently contained multiple tumor sites, with some of the tumors greater than 1 cm. A total of 24 tumors were observed. Most of the tumors (n = 22) were adenocarcinomas exhibiting a papillary pattern characterized by cuboidal or columnar cells, although a few had a tubular or solid pattern. Fewer than 10 percent of the tumors were adenosquamous (n = 1) or squamous cell (n = 1) carcinomas.

No transforming mutations of the K-ras gene (codons 12, 13, or 61) were detected by direct sequence analysis in any of the lung tumors induced by beryllium. However, using a more sensitive sequencing technique (PCR enrichment restriction fragment length polymorphism (RFLP) analysis) resulted in the detection of K-ras codon 12 GGT to GTT transversions in 2 of 12 beryllium-induced adenocarcinomas. No p53 and c-raf-1 alterations were observed in any of the tumors induced by beryllium exposure (i.e., no differences observed between beryllium-exposed and control rat tissues). The authors note that the results suggest that activation of the K-ras proto-oncogene is both a rare and late event, possibly caused by genomic instability during the progression of beryllium-induced rat pulmonary adenocarcinomas. It is unlikely that the K-ras gene plays a role in the carcinogenicity of beryllium. The results also indicate that p53 mutation is unlikely to play a role in tumor development in rats exposed to beryllium.

Belinsky et al. (1997) reviewed the findings by Nickell-Brady et al. (1994) to further examine the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by non-mutagenic (non-genotoxic) exposures to beryllium. Their findings are discussed along with the results of other genomic studies that look at carcinogenic agents that are either similarly non-mutagenic or, in other cases, mutagenic. The authors conclude that the identification of non-ras transforming genes in rat lung tumors induced by non-mutagenic exposures, such as beryllium, as well as mutagenic exposures will help define some of the mechanisms underlying cancer induction by different types of DNA damage.

The inactivation of the p16INK4a (p16) gene is a contributing factor in disrupting control of the normal cell cycle and may be an important mechanism of action in beryllium-induced lung tumors. Swafford et al. (1997) investigated the aberrant methylation and subsequent inactivation of the p16 gene in primary lung tumors induced in F344/N rats exposed to known carcinogens via inhalation. The research involved a total of 18 primary lung tumors that developed after exposing rats to five agents, one of which was beryllium. In this study, only one of the 18 lung tumors was induced by beryllium exposure; the majority of the other tumors were induced by radiation (x-rays or plutonium-239 oxide). The authors hypothesized that if p16 inactivation plays a central role in development of non-small-cell lung cancer, then the frequency of gene inactivation in primary tumors should parallel that observed in the corresponding cell lines. To test the hypothesis, a rat model for lung cancer was used to determine the frequency and mechanism for inactivation of p16 in matched primary lung tumors and derived cell lines. The methylation-specific PCR (MSP) method was used to detect methylation of p16 alleles. The results showed that the presence of aberrant p16 methylation in cell lines was strongly correlated with absent or low expression of the gene. The findings also demonstrated that aberrant p16 CpG island methylation, an important mechanism in gene silencing leading to the loss of p16 expression, originates in primary tumors.

Building on the rat model for lung cancer and associated findings from Swafford et al. (1997), Belinsky et al. (2002) conducted experiments in 12-week-old F344/N rats (male and female) to determine whether beryllium-induced lung tumors involve inactivation of the p16 gene and estrogen receptor α (ER) gene. Rats received a single nose-only inhalation exposure to beryllium aerosol at four different exposure levels. The mean lung burdens measured in each exposure group were 40, 110, 360, and 430 μg. The methylation status of the p16 and ER genes was determined by MSP. A total of 20 tumors detected in beryllium-exposed rats were available for analysis of gene-specific promoter methylation. Three tumors were classified as squamous cell carcinomas and the others were determined to be adenocarcinomas. Methylated p16 was present in 80 percent (16/20), and methylated ER was present in one-half (10/20), of the lung tumors induced by exposure to beryllium. Additionally, both genes were methylated in 40 percent of the tumors. The authors noted that four tumors from beryllium-exposed rats appeared to be partially methylated at the p16 locus. Bisulfite sequencing of exon 1 of the ER gene was conducted on normal lung DNA and DNA from three methylated, beryllium-induced tumors to determine the density of methylation within amplified regions of exon 1 (referred to as CpG sites). Two of the three methylated, beryllium-induced lung tumors showed extensive methylation, with more than 80 percent of all CpG sites methylated.

The overall findings of this study suggest that inactivation of the p16 and ER genes by promoter hypermethylation are likely to contribute to the development of lung tumors in beryllium-exposed rats. The results showed a correlation between changes in p16 methylation and loss of gene transcription. The authors hypothesize that the mechanism of action for beryllium-induced p16 gene inactivation in lung tumors may be inflammatory mediators that result in oxidative stress. The oxidative stress damages DNA directly through free radicals or indirectly through the formation of 8-hydroxyguanosine DNA adducts, resulting primarily in a single-strand DNA break.

Wagner et al. (1969) studied the development of pulmonary tumors after intermittent daily chronic inhalation exposure to beryllium ores in three groups of male squirrel monkeys. One group was exposed to bertrandite ore, a second to beryl ore, and the third served as unexposed controls. Each of these three exposure groups contained 12 monkeys. Monkeys from each group were sacrificed after 6, 12, or 23 months of exposure. The 12-month sacrificed Start Printed Page 47615monkeys (n = 4 for bertrandite and control groups; n = 2 for beryl group) were replaced by a separate replacement group to maintain a total animal population approximating the original numbers and to provide a source of confirming data for biologic responses that might arise following the ore exposures. Animals were exposed to bertrandite and beryl ore concentrations of 15 mg/m3, corresponding to 210 μg beryllium/m3 and 620 μg beryllium/m3 in each exposure chamber, respectively. The parent ores were reduced to particles with geometric mean diameters of 0.27 μm (± 2.4) for bertrandite and 0.64 μm (± 2.5) for beryl. Animals were exposed for approximately 6 hours/day, 5 days/week. The histological changes in the lungs of monkeys exposed to bertrandite and beryl ore exhibited a similar pattern. The changes generally consisted of aggregates of dust-laden macrophages, lymphocytes, and plasma cells near respiratory bronchioles and small blood vessels. There were, however, no consistent or significant pulmonary lesions or tumors observed in monkeys exposed to either of the beryllium ores. This is in contrast to the findings in rats exposed to beryl ore and to a lesser extent bertrandite, where atypical cell proliferation and tumors were frequently observed in the lungs. The authors hypothesized that the rats' greater susceptibility may be attributed to the spontaneous lung disease characteristic of rats, which might have interfered with lung clearance.

As previously described, Conradi et al. (1971) investigated changes in the lungs of monkeys and dogs two years after intermittent inhalation exposure to beryllium oxide calcined at 1,400 °C. Five adult male and female monkeys (Macaca irus) weighing between 3 and 5.75 kg were used in the study. The study included two control monkeys. Beryllium concentrations in the atmosphere of whole-body exposed monkeys varied between 3.30 and 4.38 mg/m3. Thirty-minute exposures occurred once a month for three months, with beryllium oxide concentrations increasing at each exposure interval. Lung tissue was investigated using electron microscopy and morphometric methods. Beryllium content in portions of the lungs of five monkeys was measured two years following exposure by emission spectrography. The reported concentrations in monkeys (82.5, 143.0, and 112.7 μg beryllium per 100 gm of wet tissue in the upper lobe, lower lobe, and combined lobes, respectively) were higher than those in dogs. No neoplastic or granulomatous lesions were observed in the lungs of any exposed animals and there was no evidence of chronic proliferative lung changes after two years.

4. In vitro Studies

The exact mechanism by which beryllium induces pulmonary neoplasms in animals remains unknown (NAS 2008). Keshava et al. (2001) performed studies to determine the carcinogenic potential of beryllium sulfate in cultured mammalian cells. Joseph et al. (2001) investigated differential gene expression to understand the possible mechanisms of beryllium-induced cell transformation and tumorigenesis. Both investigations used cell transformation assays to study the cellular/molecular mechanisms of beryllium carcinogenesis and assess carcinogenicity. Cell lines were derived from tumors developed in nude mice injected subcutaneously with non-transformed BALB/c-3T3 cells that were morphologically transformed in vitro with 50-200 μg beryllium sulfate/ml for 72 hours. The non-transformed cells were used as controls.

Keshava et al. (2001) found that beryllium sulfate is capable of inducing morphological cell transformation in mammalian cells and that transformed cells are potentially tumorigenic. A dose-dependent increase (9-41 fold) in transformation frequency was noted. Using differential polymerase chain reaction (PCR), gene amplification was investigated in six proto-oncogenes (K-ras, c-myc, c-fos, c-jun, c-sis, erb-B2) and one tumor suppressor gene (p53). Gene amplification was found in c-jun and K-ras. None of the other genes tested showed amplification. Additionally, Western blot analysis showed no change in gene expression or protein level in any of the genes examined. Genomic instability in both the non-transformed and transformed cell lines was evaluated using random amplified polymorphic DNA fingerprinting (RAPD analysis). Using different primers, 5 of the 10 transformed cell lines showed genomic instability when compared to the non-transformed BALB/c-3T3 cells. The results indicate that beryllium sulfate-induced cell transformation might, in part, involve gene amplification of K-ras and c-jun and that some transformed cells possess neoplastic potential resulting from genomic instability.

Using the Atlas mouse 1.2 cDNA expression microarrays, Joseph et al. (2001) studied the expression profiles of 1,176 genes belonging to several different functional categories. Compared to the control cells, expression of 18 genes belonging to two functional groups (nine cancer-related genes and nine DNA synthesis, repair, and recombination genes) was found to be consistently and reproducibly different (at least 2-fold) in the tumor cells. Differential gene expression profile was confirmed using reverse transcription-PCR with primers specific to the differentially expressed genes. Two of the differentially expressed genes (c-fos and c-jun) were used as model genes to demonstrate that the beryllium-induced transcriptional activation of these genes was dependent on pathways of protein kinase C and mitogen-activated protein kinase and independent of reactive oxygen species in the control cells. These results indicate that beryllium-induced cell transformation and tumorigenesis are associated with up-regulated expression of the cancer-related genes (such as c-fos, c-jun, c-myc, and R-ras) and down-regulated expression of genes involved in DNA synthesis, repair, and recombination (such as MCM4, MCM5, PMS2, Rad23, and DNA ligase I).

5. Preliminary Lung Cancer Conclusions

OSHA has preliminarily determined that the weight of evidence indicates that beryllium compounds should be regarded as potential occupational lung carcinogens. Other scientific organizations, including the International Agency for Research on Cancer (IARC), the National Toxicology Program (NTP), the U.S. Environmental Protection Agency (EPA), the National Institute for Occupational Safety and Health (NIOSH), and the American Conference of Governmental Industrial Hygienists (ACGIH) have reached similar conclusions with respect to the carcinogenicity of beryllium.

While some evidence exists for direct-acting genotoxicity as a possible mechanism for beryllium carcinogenesis, the weight of evidence suggests a possible indirect mechanism may be responsible for most tumorigenic activity of beryllium in animal models and possibly humans (EPA, 1998). Inflammation has been postulated to be a key contributor to many different forms of cancer (Jackson et al., 2006; Pikarsky et al., 2004; Greten et al., 2004; Leek, 2002). In fact, chronic inflammation may be a primary factor in the development of up to one-third of all cancers (Ames et al., 1990; NCI, 2010).

In addition to a T-cell mediated response beryllium has been demonstrated to produce an inflammatory response in animal models similar to other particles (Reeves et al., 1967; Swafford et al., 1997; Wagner et al., 1969) possibly Start Printed Page 47616contributing to its carcinogenic potential. Animal studies, as summarized above, have demonstrated a consistent scenario of beryllium exposure resulting in chronic pulmonary inflammation. Studies conducted in rats have demonstrated that chronic inhalation of materials similar in solubility to beryllium result in increased pulmonary inflammation, fibrosis, epithelial hyperplasia, and, in some cases, pulmonary adenomas and carcinomas (Heinrich et al., 1995; Nikula et al., 1995; NTP, 1993; Lee et al., 1985; Warheit et al., 1996). This response is generally referred to as an “overload” response or threshold effect. Substantial data indicate that tumor formation in the rat after exposure to some sparingly soluble particles at doses causing marked, chronic inflammation is due to a secondary mechanism unrelated to the genotoxicity (or lack thereof) of the particle itself.

It has been hypothesized that the recruitment of neutrophils during the inflammatory response and subsequent release of oxidants from these cells have been demonstrated to play an important role in the pathogenesis of rat lung tumors (Borm et al., 2004; Carter and Driscoll, 2001; Carter et al., 2006; Johnston et al., 2000; Knaapen et al., 2004; Mossman, 2000). Inflammatory mediators, as characterized in many of the studies summarized above, have been shown to play a significant role in the recruitment of cells responsible for the release of reactive oxygen and hydrogen species. These species have been determined to be highly mutagenic themselves as well as mitogenic, inducing a proliferative response (Feriola and Nettesheim, 1994; Jetten et al., 1990; Moss et al., 1994; Coussens and Werb, 2002). The resultant effect is an environment rich for neoplastic transformations and the progression of fibrosis and tumor formation. This finding does not imply no risk at levels below an inflammatory response; rather, the overall weight of evidence is suggestive of a mechanism of an indirect carcinogen at levels where inflammation is seen. While tumorigenesis secondary to inflammation is one reasonable mode of action, other plausible modes of action independent of inflammation (e.g., epigenetic, mitogenic, reactive oxygen mediated, indirect genotoxicity, etc.) may also contribute to the lung cancer associated with beryllium exposure.

Epidemiological studies indicate excess risk of lung cancer mortality from occupational beryllium exposure levels at or below the current OSHA PEL (Schubauer-Berigan et al., 2010; Table 4).

F. Other Health Effects

Past studies on other health effects have been thoroughly reviewed by several scientific organizations (NTP, 1999; EPA, 1998; ATSDR, 2002; WHO, 2001; HSDB, 2010). These studies include summaries of animal studies, in vitro studies, and human epidemiological studies associated with cardiovascular, hematological, hepatic, renal, endocrine, reproductive, ocular and mucosal, and developmental effects. High-dose exposures to beryllium have been shown to have an adverse effect upon a variety of organs and tissues in the body, particularly the liver. The adverse systemic effects from human exposures mostly occurred prior to the introduction of occupational and environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974) and therefore are less relevant today than in the past. The available data is fairly limited. The hepatic, cardiovascular, renal, and ocular and mucosal effects are briefly summarized below. Health effects in other organ systems listed above were only observed in animal studies at very high exposure levels and are, therefore, not discussed here.

1. Hepatic Effects

Beryllium has been shown to accumulate in the liver and a correlation has been demonstrated between beryllium content and hepatic damage. Different compounds have been shown to distribute differently within the hepatic tissues. For example, beryllium phosphate had accumulated almost exclusively within sinusoidal (Kupffer) cells of the liver, while the beryllium derived from beryllium sulfate was found mainly in parenchymal cells. Conversely, beryllium sulphosalicylic acid complexes were rapidly excreted (Skillteter and Paine, 1979).

According to a few autopsies, beryllium-laden liver had central necrosis, mild focal necrosis as well as congestion, and occasionally beryllium granuloma.

Residents near a beryllium plant may have been exposed by inhaling trace amounts of beryllium powder, and different beryllium compounds may have induced different toxicant reactions (Yian and Yin, 1982).

2. Cardiovascular Effects

There is very limited evidence of cardiovascular effects of beryllium and its compounds in humans. Severe cases of chronic beryllium disease can result in cor pulmonale, which is hypertrophy of the right heart ventricle. In a case history study of 17 individuals exposed to beryllium in a plant that manufactured fluorescent lamps, autopsies revealed right atrial and ventricular hypertrophy (Hardy and Tabershaw, 1946). It is not likely that these cardiac effects were due to direct toxicity to the heart, but rather were a response to impaired lung function. However, an increase in deaths due to heart disease or ischemic heart disease was found in workers at a beryllium manufacturing facility (Ward et al., 1992).

Animal studies performed in monkeys indicate heart enlargement after acute inhalation exposure to 13 mg beryllium/m3 as beryllium hydrogen phosphate, 0.184 mg beryllium/m3 as beryllium fluoride, or 0.198 mg beryllium/m3 as beryllium sulfate (Schepers 1964). Decreased arterial oxygen tension was observed in dogs exposed to 30 mg beryllium/m3 as beryllium oxide for 15 days (HSDB, 2010), 3.6 mg beryllium/m3 as beryllium oxide for 40 days (Hall et al., 1950), or 0.04 mg beryllium/m3 as beryllium sulfate for 100 days (Stokinger et al., 1950). These are expected to be indirect effects on the heart due to pulmonary fibrosis and toxicity which can increase arterial pressure and restrict blood flow.

3. Renal Effects

Renal calculi (stones) were unusually prevalent in severe cases that resulted from high levels of beryllium exposure. Renal stones containing beryllium occurred in about 10 percent of patients affected by high exposures (Barnett, et al., 1961). Kidney stones were observed in 10 percent of the CBD cases collected by the BCR up to 1959 (Hall et al., 1959). In addition, an excess of calcium in the blood and urine has been seen frequently in patients with chronic beryllium disease (ATSDR, 2002).

4. Ocular and Mucosal Effects

Both the soluble, sparingly soluble, and insoluble beryllium compounds have been shown to cause ocular irritation in humans (Van Orstrand et al., 1945; De Nardi et al., 1953; Nishimura, 1966; Epstein, 1990; NIOSH, 1994). In addition, beryllium compounds (soluble, sparingly soluble, or insoluble) have been demonstrated to induce acute conjunctivitis with corneal maculae and diffuse erythema (HSDB, 2010).

The mucosa (mucosal membrane) is the moist lining of certain tissues/organs including the eyes, nose, mouth, lungs, and the urinary and digestive tracts. Soluble beryllium salts have been Start Printed Page 47617shown to be directly irritating to mucous membranes (HSDB, 2010).

G. Summary of Preliminary Conclusions Regarding Health Effects

Through careful analysis of the current best available scientific information outlined in this Health Effects Section V, OSHA has preliminarily determined that beryllium and beryllium-containing compounds are able to cause sensitization, chronic beryllium disease (CBD) and lung cancer below the current OSHA PEL of 2 μg/m3. The Agency has preliminarily determined through the studies outlined in section V.A.2 of this health effects section that skin and inhalation exposure to beryllium can lead to sensitization; and inhalation exposure, or skin exposure coupled with inhalation, can cause onset and progression of CBD. In addition, the Agency has preliminarily determined through studies outlined in section V.E. of this health effects section that inhalation exposure to beryllium and beryllium containing materials causes lung cancer.

1. Beryllium Causes Sensitization Below the Current PEL and Sensitization is a Precursor to CBD

Through the biological and immunological processes outlined in section V.B. of the Health Effects, the Agency believes that the scientific evidence supports the following mechanism for the development of sensitization and CBD.

  • Inhaled beryllium and beryllium-containing materials able to be retained and solubilized in the lungs initiate sensitization and facilitate CBD development (Section V.B.5).
  • Beryllium compounds that dissolve in biological fluids, such as sweat, can penetrate intact skin and initiate sensitization (section V.A.2; V.B). Phagosomal fluid and lung fluid have been demonstrated to dissolve beryllium compounds in the lung (section V.A.2a).
  • Sensitization occurs through a CD4+ T-cell mediated process with both soluble and insoluble beryllium and beryllium-containing compounds through direct antigen presentation or through further antigen processing (section V.D.1) in the skin or lung. T-cell mediated responses, such as sensitization, are generally regarded as long-lasting (e.g., not transient or readily reversible) immune conditions.
  • Beryllium sensitization and CBD are adverse events along a pathological continuum in the disease process with sensitization being the necessary first step in the progression to CBD (section V.D).

○ Animal studies have provided supporting evidence for T-cell proliferation in the development of granulomatous lung lesions after beryllium exposure (section V.D.2; V.D.6).

○ Since the pathogenesis of CBD involves a beryllium-specific, cell-mediated immune response, CBD cannot occur in the absence of beryllium sensitization (V.D.1). While no clinical symptoms are associated with sensitization, a sensitized worker is at risk of developing CBD upon subsequent inhalation exposure to beryllium.

○ Epidemiological evidence that covers a wide variety of different beryllium compounds and industrial processes demonstrates that sensitization and CBD are continuing to occur at present-day exposures below OSHA's PEL (section V.D.4; V.D.5).

  • OSHA considers CBD to be a progressive illness with a continuous spectrum of symptoms ranging from its earliest asymptomatic stage following sensitization through to full-blown CBD and death (section V.D.7).
  • Genetic variabilities may enhance risk for developing sensitization and CBD in some groups (section V.D.3).

In addition, epidemiological studies outlined in section V.D.5 have demonstrated that efforts to reduce exposures have succeeded in reducing the frequency of sensitization and CBD.

2. Evidence Indicates Beryllium is a Human Carcinogen

OSHA has conducted an evaluation of the current available scientific information of the carcinogenic potential of beryllium and beryllium-containing compounds (section V.E). Based on weight of evidence and plausible mechanistic information obtained from in vitro and in vivo animal studies as well as clinical and epidemiological investigations, the Agency has preliminarily determined that beryllium and beryllium-containing materials should be regarded as human carcinogens. This information is in accordance with findings from IARC, NTP, EPA, NIOSH, and ACGIH (section V.E).

  • Lung cancer is an irreversible and frequently fatal disease with an extremely poor 5-year survival rate (NCI, 2009).
  • Epidemiological cohort studies have reported statistically significant excess lung cancer mortality among workers employed in U.S. beryllium production and processing plants during the 1930s to 1970s (Section V.E.2).
  • Significant positive associations were found between lung cancer mortality and both average and cumulative beryllium exposures when appropriately adjusted for birth cohort and short-term work status (Section V.E.2).
  • Studies in which large amounts of different beryllium compounds were inhaled or instilled in the respiratory tracts of experimental animals resulted in an increased incidence of lung tumors (Section V.E.3).
  • Authoritative scientific organizations, such as the IARC, NTP, and EPA, have classified beryllium as a known or probable human carcinogen.

While OSHA has preliminarily determined there is sufficient evidence of beryllium carcinogenicity, the exact tumorigenic mechanism for beryllium is unclear and a number of mechanisms are plausibly involved, including chronic inflammation, genotoxicity, mitogenicity oxidative stress, and epigenetic changes (section V.E.3).

  • Studies of beryllium exposed animals have consistently demonstrated chronic pulmonary inflammation after exposure (section V.E.3).

○ Substantial data indicate that tumor formation in certain animal models after inhalation exposure to sparingly soluble particles at doses causing marked, chronic inflammation is due to a secondary mechanism unrelated to the genotoxicty of the particle (section V.E.5).

  • A review conducted by the NAS (2008) found that beryllium and beryllium-containing compounds tested positive for genotoxicity in nearly 50 percent of studies without exogenous metabolic activity, suggesting a possible direct-acting mechanism may exist (section V.E.1) as well as the potential for epigenetic changes (section V.E.4).

Other health effects have been summarized in sections F of the Health Effects Section and include hepatic, cardiovascular, renal, ocular, and mucosal effects. The adverse systemic effects from human exposures mostly occurred prior to the introduction of occupational and environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974) and therefore are less relevant today than in the past.

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APPENDIX

Table A.1—Summary of Beryllium Sensitization and Chronic Beryllium Disease Epidemiological Studies

ReferenceStudy type(%) PrevalenceRange of exposure measurementsExposure-response relationshipStudy limitationsAdditional comments
SensitizationCBD
Studies Conducted Prior to BeLPT
Hardy and Tabershaw, 1946Case-seriesN/AN/AN/AN/ASelection biasSmall sample size.
Hardy, 1980Case-seriesN/AN/AN/AN/ASelection biasSmall sample size.
Machle et al., 1948Case-seriesN/AN/ASemi-quantitativeYesSelection biasSmall sample size; unreliable exposure data.
Eisenbud et al., 1949Case-seriesN/AN/AAverage concentration: 350-750 ft from plant—0.05-0.15 μg/m3; <350 ft from plant—2.1 μg/m3Non-occupational; ambient air sampling.
Lieben and Metzner, 1959N/AN/ANo quantitative exposure dataFamily member contact with contaminated clothes.
Hardy et al., 1967Case Registry ReviewN/AN/AN/AN/AIncomplete exposure concentration data
Hasan and Kazemi, 1974N/A
Eisenbud and Lisson, 1983N/A1-10
Stoeckle et al., 1969Case-series (60 cases)N/ANoSelection biasProvided information regarding progression and identifying sarcoidosis from CBD.
Studies Conducted Following the Development of the BeLPT
Beryllium Mining and Extraction
Deubner et al., 2001bCross-sectional (75 workers)4.0 (3 cases)1.3 (1 case)Mining, milling—range 0.05-0.8 μg/m3; Annual maximum 0.04-165.7 μg/m3NoSmall sample sizePersonal sampling.
Beryllium Metal Processing and Alloy Production
Kreiss et al., 1997Cross-sectional study of 627 workers6.9 (43 cases)4.6 (29 cases)Median—1.4 μg/m3NoInconsistent BeLPT results between labsShort-term Breathing Zone sampling.
Rosenman et al., 2005Cross-sectional study of 577 workers14.5 (83 cases)5.5 (32 cases)Mean average range—7.1-8.7 μg/m3; Mean peak range—53-87 μg/m3; Mean cumulative range—100-209 μg/m3NoDaily weighted average: High exposures compared to other studies.
Beryllium Machining Operations
Newman et al., 2001Longitudinal study of 235 workers9.4 (22 cases)8.5 (20 cases)NoEngineering and administrative controls primarily used to control exposures.
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Kelleher et al., 2001Case-control study of 20 cases and 206 controls11.5 (machinists) 2.9 (non-machinists)11.5 (machinists) 2.9 (non-machinists)0.08-0.6 μg/m3—lifetime weighted exposuresYesIdentified 20 workers with Sensitization or CBD.
Madl et al., 2007Longitudinal study of 27 casesMachining 1980-1995 median −0.33 μg/m3; 1996-1999 median—0.16 μg/m3; 2000-2005 median—0.09 μg/m3; Non-machining 1980-1995 median—0.12 μg/m3; 1996-1999 median—0.08 μg/m3; 2000-2005 median—0.06 μg/m3YesPersonal sampling: Required evidence of granulomas for CBD diagnosis.
Beryllium Oxide Ceramics
Kreiss et al., 1993bCross-sectional survey of 505 workers3.6 (18 cases)1.8 (9 cases)No
Kreiss et al., 1996Cross-sectional survey of 136 workers5.9 (8 cases)4.4 (6 cases)Machining median—0.6 μg/m3; Other Areas median—<0.3 μg/m3;NoSmall study populationBreathing Zone Sampling.
Henneberger et al., 2001Cross-sectional survey of 151 workers9.9 (15 cases)5.3 (8 cases)6.4% samples >2 μg/m3; 2.4% samples >5 μg/m3; 0.3% samples >25 μg/m3YesSmall study populationBreathing zone sampling.
Cummings et al., 2007Longitudinal study of 93 workers0.7-5.6 (4 cases)0.1—7.9 (3 cases)Production 1994-1999 median—0.1μg/m3; 2000-2003 median—0.04μg/m3; Administrative 1994-1999 median <0.2 μg/m3; 2000-2003 median—0.02 μg/m3YesSmall sample sizePersonal sampling was effective in reducing rates of new cases of sensitization.
Copper-Beryllium Alloy Processing and Distribution
Schuler et al., 2005Cross-sectional survey of 153 workers7.0 (10 cases)4.0 (6 cases)Rod and Wire Production median—0.12 μg/m3; Strip Metal Production median—0.02 μg/m3; Production Support median—0.02 μg/m3; Administration median—0.02 μg/m3Small study populationPersonal sampling.
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Thomas et al., 2009Cross-sectional study of 82 workers3.8 (3 cases)1.9 (1 case)Used exposure profile from Schuler studyAuthors noted workers may have been sensitized prior to available screening, underestimating sensitization rate in legacy workersInstituted PPE to reduce dermal exposures.
Stanton et al., 2006Cross-sectional study of 88 workers1.1 (1 case)1.1 (1 case)Bulk Products Production median 0.04 μg/m3; Strip Metal Production median—0.03 μg/m3; Production support median—0.01 μg/m3; Administration median 0.01 μg/m3Study did not report use of PPE or respiratorsPersonal sampling.
Bailey et al., 2010Cross-sectional study of 660 total workers (258 partial program, 290 full program)11.014.5 totalStudy reported prevalence rates for pre enhanced control-program, partial enhanced control program, and full enhanced control program
Nuclear Weapons Production Facilities and Cleanup of Former Facilities
Kreiss et al., 1989Cross-sectional survey of 51 workers11.8 (6 cases)7.8 (4 cases)NoSmall study population
Kreiss et al., 1993aCross-sectional survey of 895 workers1.9 (18 cases)1.7 (15 cases)NoStudy population includes some workers with no reported Be exposure
Stange et al., 1996Longitudinal Study of 4,397 BHSP participants2.4 (76 cases)0.7 (29 cases)Annual mean concentration 1970-1988 0.016 μg/m3; 1984-1987 1.04 μg/m3NoPersonal sampling.
Stange et al., 2001Longitudinal study of 5,173 workers4.5 (154 cases)1.6 (81 cases)No quantitative information presented in studyNoPersonal sampling.
Viet et al., 2000Case-control74 workers sensitized50 workers CBDMean exposure range: 0.083-0.622 μg/m3 Maximum exposures: 0.54-36.8 μg/m.3YesLikely underestimated exposuresFixed airhead sampling away from breathing zone: Matched controls for age, sex, smoking.
N/A = Information not available from study reports.
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Table A.2—Summary of Mechanistic Animal Studies for Sensitization and CBD

ReferenceSpeciesStudy lengthDose or exposure concentrationType of berylliumStudy resultsOther information
Intratracheal (intrabroncheal) or Nasal Instillation
Barna et al., 1981Guinea pig3 month10 mg-5μm particle sizeberyllium oxideGranulomas, interstitial infiltrate with fibrosis with thickening of alveolar septae
Barna et al., 1984Guinea pig3 month5 mgberyllium oxideGranulomatous lesions in strain 2 but not strain 13 indicating a genetic component
Benson et al., 2000Mouse0, 12.5, 25, 100μg; 0, 2, 8 μgberyllium copper alloy; beryllium metalAcute pulmonary toxicity associated with beryllium/copper alloy but not beryllium metal
Haley et al., 1994Cynomolgus monkey14, 60, 90 days0, 1, 50, 150 μg 0, 2.5, 12.5, 37.5 μgBeryllium metal, beryllium oxideBeryllium oxide particles were less toxic than the beryllium metal
Huang et al., 1992Mouse5 μg 1-5 μgBeryllium sulfate immunization; beryllium metal challengeGranulomas produced in A/J strain but not BALB/c or C57BL/6
Votto et al., 1987Rat3 month2.4 mg 8 mg/mlBeryllium sulfate immunization; beryllium sulfate challengeGranulomas, however, no correlation between T-cell subsets in lung and BAL fluid
Inhalation—Single Exposure
Haley et al., 1989aBeagle dogChronic—one dose0, 6 μg/kg, 18 μg/kg500 °C; 1000 °C beryllium oxidePositive BeLPT results—developed granulomas; low-calcined beryllium oxide more toxic than high-calcinedGranulomas resolved with time, no full-blown CBD.
Haley et al., 1989bBeagle dogChronic—one dose/2 year recovery0, 17 μg/kg, 50 μg/kg500 °C; 1000 °C beryllium oxideGranulomas, sensitization, low-fired more toxic than high firedGranulomas resolved over time.
Robinson et al., 1968DogChronic0. 115mg/m3Beryllium oxide, beryllium fluoride, beryllium chlorideForeign body reaction in lung
Sendelbach et al., 1989Rat2 week0, 4.05 μg/LBeryllium as beryllium sulfateInterstial pneumonitis
Sendelbach and Witschi, 1987Rat2 week0, 3.3, 7 μg/LBeryllium as beryllium sulfateEnzyme changes in BAL fluid
Inhalation—Repeat Exposure
Conradi et al., 1971Beagle dogChronic—2 year0. 3300 μg/m3, 4380 μg/m3 once/month for 3 months1400 °C beryllium oxideNo changes detectedMay have been due to short exposure time followed by long recovery.
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Macaca irus MonkeyChronic—2 year0. 3300 μg/m3, 4380 μg/m3 once/month for 3 months1400 °C beryllium oxideNo changes detectedMay have been due to short exposure time followed by long recovery.
Haley et al., 1992Beagle dogChronic—repeat dose (2.5 year intervals)17, 50 μg/kg500 °C; 1000 °C beryllium oxideGranulomatous pneumonitis
Harmsen et al., 1985Beagle dog 5 dogs per groupChronic0, 20 μg/kg, 50 μg/kg500°C; 1000 °C beryllium oxide
Dermal or Intradermal
Kang et al., 1977Rabbit10mgBeryllium sulfateSkin sensitization and skin granulomas
Tinkle et al., 2003Mouse3 month25 μL 70 μgBeryllium sulfate Beryllium oxideMicrogranulomas with some resolution over time of study
Intramuscular
Eskenasy, 1979Rabbit35 days (injections at 7 day intervals)10mg.mlBeryllium sulfateSensitization, evidence of CBD
Intraperitoneal Injection
Marx and Burrell, 1973Guinea pig24 weeks (biweekly injections)2.6 mg + 10 μg dermal injectionsBeryllium sulfateSensitization

Table A-3—Summary of Beryllium Lung Cancer Epidemiological Studies

ReferenceStudy typeExposure rangeStudy numberMortality ratioConfounding factorsStudy limitationsAdditional comments
Beryllium Case Registry
Infante et al., 1980CohortN/D421 cases from the BCRSMR 2.12 7 lung cancer deathsNot reportedExposure concentration data or smoking habits not reported
Steenland and Ward, 1991CohortN/D689 cases from the BCRSMR 2.00 (95% CI 1.33-2.89) 28 lung cancer deathsIncluded women: 93% women diagnosed with CBD; 50% men diagnosed with CBD; SMR 157 for those with CBD and SMR 232 for those with ABD.
Beryllium Manufacturing and/or Processing Plants (Extraction, Fabrication, and Processing)
Ward et al., 1992Retrospective Mortality CohortN/D9,225 malesSMR 1.26 (95% CI 1.12-1.42) 280 lung cancer deathsLack of job history and air monitoring dataEmployment period 1940-1969.
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Levy et al., 2002CohortN/D9225 malesStatistically non-significant elevation in lung cancer deathsAdjusted for smokingLack of job history and air monitoring dataMajority of workers studied employed for less than one year
Bayliss et al., 1971Nested cohort8,000 workersSMR 1.06 36 lung cancer deathsEmployed prior to 1947 for almost half lung cancer deaths.
Mancuso, 1970Cohort411-43,300 μg/m3 annual exposure (reported from Zielinsky, 1961)1,222 workers at OH plant; 2,044 workers at PA plantSMR 1.42 (95% CI 1.1-1.8) 80 lung cancer deathsOnly partial smoking historyPartial smoking history; No job analysis by title or exposure categoryEmployment period from 1937-1948.
Mancuso, 1980CohortN/DSame OH and PA plant analysisSMR 1.40No smoking adjustmentNo adjustment by job title or exposureEmployment period from 1942-1948; Used workers at rayon plant for comparison.
Mancuso and El Attar, 1969CohortN/D3,685 white malesSMR 1.49Adjusted for age and localNo job exposure data or smoking adjustmentEmployment history from 1937-1944.
Wagner et al., 1980CohortN/D3,055 white males PA plantSMR 1.25 (95% CI 0.9-1.7) 47 lung cancer deathsInadequately adjusted for smoking; Used national lung-cancer risk for cancer not PAReanalysis using PA lung-cancer rate revealed 19% underestimation of beryllium lung cancer deaths.
Sanderson et al., 2001Nested case-control— Average exposure 22.8μg/m3 — Maximum exposure 32.4μg/m33,569 males PA plantSMR 1.22 (95% CI 1.03-1.43) 142 lung cancer deathsSmoking was found not to be a confounding factorMay not have adjusted properly for birth-year or age at hireFound association with 20 year latency.
Levy et al., 2007Nested case-controlUsed log transformed exposure dataReanalysis of Sanderson et al., 2001SMR 1.04 (95% CI 0.92-1.17)Different methodology for smoking adjustmentFound no association between beryllium exposure and increased risk of lung cancer.
Schubauer-Berigan et al., 2008Nested case-controlUsed exposure data from Sanderson et al., 2001, Chen 2001, and Couch et al., 2010Reanalysis of Sanderson et al., 2001Used Odds ratio: 1.91 (95% CI 1.06-3.44) unadjusted; 1.29 (95% CI 0.61-2.71) birth-year adjusted; 1.24 (95% CI 0.58-2.65) age-hire adjustedAdjusted for smoking, birth cohort, age— Controlled for birth-year and age at hire; — Found similar results to Sanderson et al., 2001; — Found association with 10 year latency — “0” = used minuscule value at start to eliminate the use of 0 in a logarithmic analysis
Schubauer-Berigan et al., 2010aCohortN/D9199 workers from 7 processing plantsSMR 1.17 (95%CI 1.08-1.28) 545 deathsAdjusted for smokingMale workers employed at least 2 days between 1940 and 1970.
Schubauer-Berigan et al., 2010bCohortUsed exposure data from Sanderson et al., 20015436 workers OH and PA plantsEvaluated using hazard ratios and excess absolute risk 293 deathsAdjusted for age, birth cohort, asbestos exposure, short-term work status— Exposure response was found between 0-10μg/m3 mean DWA; — Increased with statistical significance at 4μg/m3; — 1 in 1000 risk at 0.033μg/m3 mean DWA.
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Re-evaluation of Published Studies
Hollins et al., 2009ReviewRe-examination of weight-of-evidence from more than 50 publicationsFound lung cancer excess risk was associated with higher levels of exposure not relevant in today's industrial settings.
IARC, 2012MultipleInsufficient exposure concentration DataSufficient evidence for carcinogenicity of berylliumIARC concluded beryllium lung cancer risk was not associated with smoking— Greater lung cancer risk in the BCR cohort — Correlation between highest lung cancer rates and highest amounts of ABD or other non-malignant lung diseases — Increased risk with longer latency — Greater excess lung cancers among those hired prior to 1950.
N/D = information not determined for most studies
DWA—daily weighted average

VI. Preliminary Beryllium Risk Assessment

The Occupational Safety and Health (OSH) Act and court cases arising under it have led OSHA to rely on risk assessment 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 OSH Act states that “The Secretary [of Labor], in promulgating standards dealing with toxic materials or harmful physical 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. 655(b)(5)).

In Industrial Union Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607 (1980) (Benzene), the United States Supreme Court 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 [the Secretary] can promulgate any permanent 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” (Id. at 642). The Court also stated “that the Act does limit the Secretary's power to requiring the elimination of significant risks” (488 U.S. at 644 n.49), and that “OSHA is not required to support its finding that a significant risk exists with anything approaching scientific certainty” (Id. at 656).

OSHA's approach for the risk assessment incorporates both a review of the recent literature on populations of workers exposed to beryllium below the current Permissible Exposure Limit (PEL) of 2 μg/m3 and a statistical exposure-response analysis. OSHA evaluated risk at several alternate PELs under consideration by the Agency: 2 μg/m3, 1 μg/m3, 0.5 μg/m3, 0.2 μg/m3, and 0.1 μg/m3. A number of recently published epidemiological studies evaluate the risk of sensitization and CBD for workers exposed at and below the current PEL and the effectiveness of exposure control programs in reducing risk. OSHA also conducted a statistical analysis of the exposure-response relationship for sensitization and CBD at the current PEL and alternate PELs the Agency is considering. For this analysis, OSHA used data provided by National Jewish Medical and Research Center (NJMRC) on a population of workers employed at a beryllium machining plant in Cullman, AL. The review of the epidemiological studies and OSHA's own analysis show substantial risk of sensitization and CBD among workers exposed at and below the current PEL of 2 μg/m3. They also show substantial reduction in risk where employers have implemented a combination of controls, including stringent control of airborne beryllium levels and additional measures such as respirators, dermal personal protective equipment (PPE), and strict housekeeping to protect workers against dermal and respiratory beryllium exposure. To evaluate lung cancer risk, OSHA relied primarily on a quantitative risk assessment published in 2011 by NIOSH. This risk assessment was based on an update of the Reading cohort analyzed by Sanderson et al., as well as workers from two smaller plants (Schubauer-Berigan et al., 2011) where workers were exposed to lower levels of beryllium and worked for longer periods than at the Reading plant. The authors found that lung cancer risk was strongly and significantly related to mean, cumulative, and maximum measures of workers' exposure; they predicted substantial risk of lung cancer at the current PEL, and substantial reductions in risk at the alternate PELs OSHA considered for the proposed rule (Schubauer-Berigan et al., 2011).Start Printed Page 47625

A. Review of Epidemiological Literature on Sensitization and Chronic Beryllium Disease From Occupational Exposure

As discussed in the Health Effects section, studies of beryllium-exposed workers conducted using the beryllium lymphocyte proliferation test (BeLPT) have found high rates of beryllium sensitization and CBD among workers in many industries, including at some facilities where exposures were primarily below OSHA's PEL of 2 μg/m3 (Kreiss et al., 1993; Henneberger et al., 2001; Schuler et al., 2005; Schuler et al., 2012). In the mid-1990s, some facilities using beryllium began to aggressively monitor and reduce workplace exposures. Four plants where several rounds of BeLPT screening were conducted before and after implementation of new exposure control methods provide the best currently available evidence on the effectiveness of various exposure control measures in reducing the risk of sensitization and CBD. The experiences of these plants—a copper-beryllium processing facility in Reading, PA, a beryllia ceramics facility in Tucson, AZ; a beryllium processing facility in Elmore, OH; and a machining facility in Cullman, AL—show that efforts to prevent sensitization and CBD by using engineering controls to reduce workers' beryllium exposures to median levels at or around 0.2 μg/m3 and did not emphasize PPE and stringent housekeeping methods, had only limited impact on risk. However, exposure control programs implemented more recently, which drastically reduced respiratory exposure to beryllium via a combination of engineering controls and respiratory protection, controlled dermal contact with beryllium using PPE, and employed stringent housekeeping methods to keep work areas clean and prevent transfer of beryllium between work areas, sharply curtailed new cases of sensitization among newly-hired workers. There is additional, but more limited, information available on the occurrence of sensitization and CBD among aluminum smelter workers with low-level beryllium exposures (Taiwo et al., 2008; Taiwo et al., 2010; Nilsen et al., 2010). A discussion of the experiences at these plants follows.

The Health Effects section also discussed the role of particle characteristics and beryllium compound solubility in the development of sensitization and CBD among beryllium-exposed workers. Respirable particles small enough to reach the deep lung are responsible for CBD. However, larger inhalable particles that deposit in the upper respiratory tract may lead to sensitization. The weight of evidence indicates that both soluble and insoluble forms of beryllium are able to induce sensitization and CBD. Insoluble forms of beryllium that persist in the lung for longer periods may pose greater risk of CBD while soluble forms may more easily trigger immune sensitization. Although these factors potentially influence the toxicity of beryllium, the available data are too limited to reliably account for solubility and particle size in the Agency estimates of risk. The qualitative impact on conclusions and uncertainties with regard to risk are discussed in a later section.

1. Reading, PA, Plant

Schuler et al. conducted a study of workers at a copper-beryllium processing facility in Reading, PA, screening 152 workers with the BeLPT (Schuler et al., 2005). Exposures at this plant were believed to be low throughout its history due to the low percentage of beryllium in the metal alloys used, and the relatively low exposures found in general area samples collected starting in 1969 (sample median ≤ 0.1 μg/m3, 97% < 0.5 μg/m3). The reported prevalences of sensitization (6.5 percent) and CBD (3.9 percent) showed substantial risk at this facility, even though airborne exposures were primarily below OSHA's current PEL of 2 μg/m3.

Personal lapel samples were collected in production and production support jobs between 1995 and May 2000. These samples showed primarily very low airborne beryllium levels, with a median of 0.073 μg/m[3] .[6] The wire annealing and pickling process had the highest personal lapel sample values, with a median of 0.149 μg/m3. Despite these low exposure levels, cases of sensitization continued to occur among workers whose first exposures to beryllium occurred in the 1990s. Five (11.5 percent) workers of 43 hired after 1992 who had no prior beryllium exposure became sensitized, including four in production work and one in production support (Thomas et al., 2009; evaluation for CBD not reported). Two (13 percent) of these sensitized workers were among 15 workers in this group who had been hired less than a year before the screening.

After the BeLPT screening was conducted in 2000, the company began implementing new measures to further reduce workers' exposure to beryllium. Requirements designed to minimize dermal contact with beryllium, including long-sleeve facility uniforms and polymer gloves, were instituted in production areas in 2000. In 2001 the company installed local exhaust ventilation (LEV) in die grinding and polishing. Personal lapel samples collected between June 2000 and December 2001 show reduced exposures plant-wide. Of 2,211 exposure samples collected during this “pre-enclosure program” period, 98 percent were below 0.2 μg/m3 (Thomas et al., 2009, p. 124). Median, arithmetic mean, and geometric mean values ≤ 0.03 μg/m3 were reported in this period for all processes except the wire annealing and pickling process. Samples for this process remained elevated, with a median of 0.1 μg/m3 (arithmetic mean of 0.127 μg/m3, geometric mean of 0.083 μg/m3). In January 2002, the plant enclosed the wire annealing and pickling process in a restricted access zone (RAZ), required respiratory PPE in the RAZ, and implemented stringent measures to minimize the potential for skin contact and beryllium transfer out of the zone. While exposure samples collected by the facility were sparse following the enclosure, they suggest exposure levels comparable to the 2000-01 samples in areas other than the RAZ. Within the RAZ, required use of powered air-purifying respirators (PAPRs) indicates that respiratory exposure was negligible. A 2009 publication on the facility reported that outside the RAZ, “the vast majority of employees do not wear any form of respiratory protection due to very low airborne beryllium concentrations” (Thomas et al., 2009, p. 122).

To test the efficacy of the new measures in preventing sensitization and CBD, in June 2000 the facility began an intensive BeLPT screening program for all new workers. The company screened workers at the time of hire; at intervals of 3, 6, 12, 24, and 48 months; and at 3-year intervals thereafter. Among 82 workers hired after 1999, three cases of sensitization were found (3.7 percent). Two (5.4 percent) of 37 workers hired prior to enclosure of the wire annealing and pickling process were found to be sensitized within 3 and 6 months of beginning work at the plant. One (2.2 percent) of 45 workers hired after the enclosure was confirmed as sensitized. Among these early results, it appears that the greatest reduction in sensitization risk was achieved after median exposures in all areas of the plant were reduced to below 0.1 μg/m3 Start Printed Page 47626and PPE to prevent dermal contact was instituted.

2. Tucson, AZ, Plant

Kreiss et al. conducted a study of workers at a beryllia ceramics plant, screening 136 workers with the BeLPT in 1992 (Kreiss et al., 1996). Full-shift area samples collected between 1983 and 1992 showed primarily low airborne beryllium levels at this facility. Of 774 area samples, 76 percent were at or below 0.1 μg/m3 and less than 1 percent exceeded 2 μg/m3. A small set (75) of personal lapel samples collected at the plant beginning in 1991 had a median of 0.2 μg/m3 and ranged from 0.1 to 1.8 μg/m3 (arithmetic and geometric mean values not reported) (Kreiss et al., 1996, p. 19). However, area samples and short-term breathing zone samples also showed occasional instances of very high beryllium exposure levels, with extreme values of several hundred μg/m3 and 3.6 percent of short-term breathing zone samples in excess of 5 μg/m3.

Kreiss et al. reported that eight (5.9 percent) of 136 workers tested were sensitized, six (4.4 percent) of whom were diagnosed with CBD. Seven of the eight sensitized employees had worked in machining, where general area samples collected between October 1985 and March 1988 had a median of 0.3 μg/m3, in contrast to a median value of less than 0.1 μg/m3 in other areas of the plant (Kreiss et al., 1996, p. 20; mean values not reported). Short-term breathing zone measurements associated with machining had a median of 0.6 μg/m3, double the median of 0.3 μg/m3 for breathing zone measurements associated with other processes (id., p. 20; mean values not reported). One sensitized worker was one of 13 administrative workers screened, and was among those diagnosed with CBD. Exposures of administrative workers were not well-characterized, but were believed to be among the lowest in the plant. Of three personal lapel samples reported for administrative staff during the 1990s, all were below the then detection limit of 0.2 μg/m3 (Cummings et al., 2007, p.138).

Following the 1992 screening, the facility reduced exposures in machining areas by enclosing machines and installing HEPA filter exhaust systems. Personal samples collected between 1994 and 1999 had a median of 0.2 μg/m3 in production jobs and 0.1 μg/m3 in production support (geometric means 0.21 μg/m3 and 0.11 μg/m3, respectively; arithmetic means not reported. Cummings et al., 2007, p. 138). In 1998, a second screening found that 9 percent of tested workers hired after the 1992 screening were sensitized, of whom one was diagnosed with CBD. All of the sensitized workers had been employed at the plant for less than two years (Henneberger et al., 2001).

Following the 1998 screening, the company continued efforts to reduce exposures and risk of sensitization and CBD by implementing additional engineering and administrative controls and PPE. Respirator use was required in production areas beginning in 1999, and latex gloves were required beginning in 2000. The lapping area was enclosed in 2000, and enclosures were installed for all mechanical presses in 2001. Between 2000 and 2003, water-resistant or water-proof garments, shoe covers, and taped gloves were incorporated to keep beryllium-containing fluids from wet machining processes off the skin. The new engineering measures did not appear to substantially reduce airborne beryllium levels in the plant. Personal lapel samples collected in production processes between 2000 and 2003 had a median and geometric mean of 0.18 μg/m3, similar to the 1994-1999 samples (Cummings et al., 2007, p. 138). However, respiratory protection requirements were instituted in 2000 to control workers' airborne beryllium exposures.

To test the efficacy of the new measures instituted after 1998, in January 2000 the company began screening new workers for sensitization at the time of hire and at 3, 6, 12, 24, and 48 months of employment (Cummings et al., 2007). These more stringent measures appear to have substantially reduced the risk of sensitization among new employees. Of 97 workers hired between 2000 and 2004, one case of sensitization was identified (1 percent). This worker had experienced a rash after an incident of dermal exposure to lapping fluid through a gap between the glove and uniform sleeve, indicating that sensitization may have occurred via skin exposure.

3. Elmore, OH, Plant

Kreiss et al., Schuler et al., and Bailey et al. conducted studies of workers at a beryllium metal, alloy, and oxide production plant. Workers participated in BeLPT surveys in 1992 (Kreiss et al., 1997) and in 1997 and 1999 (Schuler et al., 2012). Exposure levels at the plant between 1984 and 1993 were characterized by a mixture of general area, short-term breathing zone, and personal lapel samples. Kreiss et al. reported that the median area samples for various work areas ranged from 0.1 to 0.7 μg/m3, with the highest values in the alloy arc furnace and alloy melting-casting areas (other measures of central tendency not reported). Personal lapel samples were available from 1990-1992, and showed high exposures overall (median value of 1.0 μg/m3) with very high exposures for some processes. The authors reported median sample values of 3.8 μg/m3 for beryllium oxide production, 1.75 μg/m3 for alloy melting and casting, and 1.75 μg/m3 for the arc furnace.

Kreiss et al. reported that 43 (6.9 percent) of 627 workers tested in 1992 were sensitized, six of whom were diagnosed with CBD (4.4 percent). Workers with less than one year tenure at the plant were not tested in this survey (Bailey et al., 2010, p. 511). The work processes that appeared to carry the highest risk for sensitization and CBD (e.g., ceramics) were not those with the highest reported exposure levels (e.g., arc furnace and melting-casting). The authors noted several possible reasons for this, including factors such as solubility, particle size/number, and particle surface area that could not be accounted for in their analysis (Kreiss et al., 1997).

In 1996-1999, the company took steps to reduce workers' beryllium exposures: some high-exposure processes were enclosed, special restricted-access zones were set up, HEPA filters were installed in air handlers, and some ventilation systems were updated. In 1997 workers in the pebble plant restricted access zone were required to wear half-face air-purifying respirators, and beginning in 1999 all new employees were required to wear loose-fitting powered air-purifying respirators (PAPR) in manufacturing buildings (Bailey et al., 2010, p. 506). Skin protection became part of the protection program for new employees in 2000, and glove use was required in production areas and for handling work boots beginning in 2001. Also beginning in 2001, either half-mask respirators or PAPRs were required in the production facility (type determined by airborne beryllium levels), and respiratory protection was required for roof work and during removal of work boots (Bailey et al., 2010, p. 506). Respirator use was reported to be used on about half or less of industrial hygiene sample records for most processes in 1990-1992 (Kreiss et al., 1996).

Beginning in 2000, workers were offered periodic BeLPT testing to evaluate the effectiveness of a new exposure control program implemented by the company. Bailey et al. (2010) reported on the results of this surveillance for 290 workers hired between February 21, 2000 and December 18, 2006. They compared the Start Printed Page 47627occurrence of beryllium sensitization and disease among 258 employees who began work at the Elmore plant between January 15, 1993 and August 9, 1999 (the `pre-program group') and among 290 employees who were hired between February 21, 2000 and December 18, 2006 and were tested at least once after hire (the `program group'). They found that, as of 1999, 23 (8.9 percent) of the pre-program group were sensitized to beryllium. Six (2.1 percent) of the program group had confirmed abnormal results on their final round of BeLPTs, which occurred in different years for different employees. In addition, another five employees had confirmed abnormal BeLPT results at some point during the testing period, followed by at least one instance of a normal test result. One of these employees had a confirmed abnormal baseline BeLPT at hire, and had two subsequent normal BeLPT results at 6 and 12 months after hire. Four others had confirmed abnormal BeLPT results at 3 or 6 months after hire, later followed by a normal test. Including these four in the count of sensitized workers, there were a total of ten (3.5 percent) workers sensitized after hire in the program group. It is not clear whether the occurrence of a normal result following an abnormal result reflects an error in one of the test results, a change in the presence or level of memory T-cells circulating in the worker's blood, or other possibilities. Because most of the workers in the study had been employed at the facility for less than two years, Bailey et al. did not report the incidence of CBD among the sensitized workers (Bailey et al., 2010, p. 511).

In addition, Bailey et al. divided the program group into the `partial program subgroup' (206 employees hired between February 21, 2000 and December 31, 2003) and the `full program subgroup' (84 employees hired between January 1, 2004 and December 18, 2006) to account for the greater effectiveness of the exposure control program after the first three years of implementation (Bailey et al., pp 506-507). Four (1.9 percent) of the partial program group were found to be sensitized on their final BeLPT (excluding one with a confirmed abnormal BeLPT from their baseline test at hire). Two (2.4 percent) of the full program group were found to be sensitized on their final BeLPT (Bailey et al., 2010, p. 509). An additional three employees in the partial program group and one in the full program group were confirmed sensitized at 3 or 6 months after hire, then later had a single normal BeLPT (Bailey et al., 2010, p. 509).

Schuler et al. (2012) published a study examining beryllium sensitization and CBD among short-term workers at the Elmore, OH plant, using exposure estimates created by Virji et al. (2012). The study population included 264 workers employed in 1999 with up to six years tenure at the plant (91 percent of the 291 eligible workers). By including only short-term workers, Virji et al. were able to construct participants' exposures with more precision than was possible in studies involving workers exposed for longer durations and in time periods with less exposure sampling. Each participant completed a work history questionnaire and was tested for beryllium sensitization. The overall prevalence of sensitization was 9.8 percent (26/264). Sensitized workers were offered further evaluation for CBD. Twenty-two sensitized workers consented to clinical testing for CBD via transbronchial biopsy. Six of those sensitized were diagnosed with CBD (2.3 percent, 6/264).

Exposure estimates were constructed using two exposure surveys conducted in 1999: a survey of total mass exposures (4022 full-shift personal samples) and a survey of size-separated impactor samples (198 samples). The 1999 exposure surveys and work histories were used to estimate long-term lifetime weighted (LTW) average, cumulative, and highest-job-worked exposure for total, respirable, and submicron beryllium mass concentrations. Schuler et al. (2012) found no cases of sensitization among workers with total mass LTW average exposures below 0.09 μg/m3, among workers with total mass cumulative exposures below 0.08 μg/m3-yr, or among workers with total mass highest job worked exposures below 0.12 μg/m3. Twenty-four percent, 16 percent, and 25 percent of the study population were exposed below those levels, respectively. Both total and respirable beryllium mass concentration estimates were positively associated with sensitization (average and highest job), and CBD (cumulative) in logistic regression models.

4. Cullman, AL, Plant

Newman et al. conducted a series of BeLPT screenings of workers at a precision machining facility between 1995 and 1999 (Newman et al., 2001). A small set of personal lapel samples collected in the early 1980s and in 1995 suggests that exposures in the plant varied widely during this time period. In some processes, such as engineering, lapping, and electrical discharge machining (EDM), exposures were apparently low (≤ 0.1 μg/m[3] ). Madl et al. reported that personal lapel samples from all machining processes combined had a median of 0.33 μg/m[3] , with a much higher arithmetic mean of 1.63 μg/m[3] (Madl et al., 2007, Table IV, p. 457). The majority of these samples were collected in the high-exposure processes of grinding (median of 1.05 μg/m[3] , mean of 8.48 μg/m[3] ), milling (median of 0.3 μg/m[3] , mean of 0.82 μg/m[3] ), and lathing (median of 0.35 μg/m[3] , mean of 0.88 μg/m[3] ) (Madl et al., 2007, Table IV, p. 457). As discussed in greater detail in the background document,[7] the data set of machining exposure measurements included a few extremely high values (41-73 μg/m3) that a NIOSH researcher identified as probable errors, and that appear to be included in Madl et al.' s arithmetic mean calculations. Because high single-data point exposure errors influence the arithmetic mean far more than the median value of a data range, OSHA believes the median values reported by Madl et al. are more reliable than the arithmetic means they reported.

After a sentinel case of CBD was diagnosed at the plant in 1995, the company began BeLPT screenings to identify workers at increased risk of CBD and implemented engineering and administrative controls and PPE designed to reduce workers' beryllium exposures in machining operations. Newman et al. reported 22 (9.4 percent) sensitized workers among 235 tested, 13 of whom were diagnosed with CBD within the study period. Between 1995 and 1997, the company built enclosures and installed or updated local exhaust ventilation (LEV) for several machining departments, removed pressurized air hoses, and required the use of company uniforms. Madl et al. reported that historically, engineering and work process controls, rather than personal protective equipment, were used to limit workers' exposure to beryllium; respirators were used only in cases of high exposure, such as during sandblasting (Madl et al., 2007, p. 450). In contrast to the Reading and Tucson plants, gloves were not required at this plant.

Personal lapel samples collected extensively between 1996 and 1999 in machining jobs have an overall median of 0.16 μg/m3, showing that the new controls achieved a marked reduction in machinists' exposures during this Start Printed Page 47628period. Nearly half of the samples were collected in milling (median = 0.18 μg/m3). Exposures in other machining processes were also reduced, including grinding (median of 0.18 μg/m3) and lathing (median of 0.13 μg/m3). However, cases of sensitization and CBD continued to occur.

At the time that Newman et al. reviewed the results of BeLPT screenings conducted in 1995-1999, a subset of 60 workers had been employed at the plant for less than a year. Four (6.7 percent) of these workers were found to be sensitized, of whom two were diagnosed with CBD and one with probable CBD (Newman et al., 2001). All four had been hired in 1996. Two (one CBD case, one sensitized only) had worked only in milling, and had worked for approximately 3-4 months (0.3-0.4 yrs) at the time of diagnosis. One of those diagnosed with CBD worked only in EDM, where lapel samples collected between 1996 and 1999 had a median of 0.03 μg/m3. This worker was diagnosed with CBD in the same year that he began work at the plant. The last CBD case worked as a shipper, where exposures in 1996-1999 were similarly low, with a median of 0.09 μg/m3.

Beginning in 2000, exposures in all jobs at the machining facility were reduced to extremely low levels. Personal lapel samples collected in machining processes between 2000 and 2005 had a median of 0.09 μg/m3, where more than a third of samples came from the milling process (n = 765, median of 0.09 μg/m3). A later publication on this plant by Madl et al. reported that only one worker hired after 1999 became sensitized. This worker had been employed for 2.7 years in chemical finishing, where exposures were roughly similar to other machining processes (n = 153, median of 0.12 μg/m3). Madl et al. did not report whether this worker was evaluated for CBD.

5. Aluminum Smelting Plants

Taiwo et al. (2008) studied a population of 734 employees at four aluminum smelters located in Canada (2), Italy (1), and the United States (1). In 2000, a beryllium exposure limit of 0.2 μg/m3 8-hour TWA (action level 0.1 μg/m3) and a short-term exposure limit (STEL) of 1.0 μg/m3 (15-minute sample) were instituted at these plants. Sampling to determine compliance with the exposure limit began at all smelters in 2000. Table VI-1 below, adapted from Taiwo et al. (2008), shows summary information on samples collected from the start of sampling through 2005.

Table VI-1—Exposure Sampling Data by Plant—2000-2005

SmelterNumber of samplesMedian (μg/m3)Arithmetic mean (μg/m3)Geometric mean (μg/m3)
Canadian smelter 12460.030.090.03
Canadian smelter 23290.110.290.08
Italian smelter440.120.140.10
U.S. smelter3460.030.260.04
Adapted from Taiwo et al., 2008, Table 1.

All employees potentially exposed to beryllium levels at or above the action level for at least 12 days per year, or exposed at or above the STEL 12 or more times per year, were offered medical surveillance including the BeLPT (Taiwo et al., 2008, p. 158). Table VI-2 below, adapted from Taiwo et al. (2008), shows test results for each facility between 2001 and 2005.

Table VI-2—BeLPT Results by Plant—2001-2005

SmelterEmployees testedNormalAbnormal BeLPT (unconfirmed)Confirmed Sensitized
Canadian smelter 110910711
Canadian smelter 229129010
Italian smelter646301
U.S. smelter27026820
Adapted from Taiwo et al., 2008, Table 2.

The two workers with confirmed beryllium sensitization were offered further evaluation for CBD. Both were diagnosed with CBD, based on broncho-alveolar lavage (BAL) results in one case and pulmony function tests, respiratory symptoms, and radiographic evidence in the other.

In 2010, Taiwo et al. published a study of beryllium-exposed workers from smelters at four companies, including some of the workers from the 2008 publication. 3,185 workers were determined to be “significantly exposed” to beryllium and invited to participate in BeLPT screening. Each company used different criteria to determine “significant” exposure, which appeared to vary considerably (p. 570). About 60 percent of invited workers participated in the program between 2000 and 2006, of whom nine were determined to be sensitized (see Table VI-3 below). The authors state that all nine workers were referred to a respiratory physician for further evaluation for CBD. Two were diagnosed with CBD, as described above (Taiwo et al., 2008). The authors do not report the details of other sensitized workers' evaluation for CBD.Start Printed Page 47629

Table VI-3—Medical Surveillance for BeS in ALUMINUM Smelters

CompanyNumber of smeltersAt-risk employeesEmployees testedBeS
A412787344
B34233280
C111005084
D13843621
Total9318519329
Adapted from Taiwo et al., 2011, Table 1.

In general, there appeared to be a low level of sensitization and CBD among employees at the aluminum smelters studied by Taiwo et al. This is striking in light of the fact that many of the employees tested had worked at the smelters long before the institution of exposure limits for beryllium at some smelters in 2000. However, the authors note that respiratory protection had long been used at these plants to protect workers from other hazards. The results are roughly consistent with the observed prevalence of sensitization following the institution of respiratory protection at the Tucson beryllium ceramics plant discussed previously. A study by Nilsen et al. (2010) also found a low rate of sensitization among aluminum workers in Norway. Three-hundred sixty-two workers and thirty-one control individuals received BeLPT testing for beryllium sensitization. The authors found one sensitized worker (0.28 percent). No borderline results were reported. The authors reported that current exposures in this plant ranged from 0.1 µg/m3 to 0.31 µg/m3 (Nilsen et al., 2010) and that respiratory protection was in use, as is the case in the smelters studied by Taiwo et al. (2008, 2010).

B. Preliminary Conclusions

The published literature on beryllium sensitization and CBD shows that risk of both can be substantial in workplaces in compliance with OSHA's current PEL (Kreiss et al., 1993; Schuler et al., 2005). The experiences of several facilities in developing effective industrial hygiene programs have shown that minimizing both airborne and dermal exposure, using a combination of engineering and administrative controls, respiratory protection, and dermal PPE, has substantially lowered workers' risk of beryllium sensitization. In contrast, risk-reduction programs that relied primarily on engineering controls to reduce workers' exposures to median levels in the range of 0.1-0.2 µg/m3, such as those implemented in Tucson following the 1992 survey and in Cullman during 1996-1999, had only limited impact on reducing workers' risk of sensitization. The prevalence of sensitization among workers hired after such controls were installed at the Cullman plant remained high (Newman et al. (6.7 percent) and Henneberger et al. (9 percent)). A similar prevalence of sensitization was found in the screening conducted in 2000 at the Reading plant, where the available sampling data show median exposure levels of less than 0.2 µg/m3 (6.5 percent). The risk of sensitization was found to be particularly high among newly-hired workers (≤1 year of beryllium exposure) in the Reading 2000 screening (13 percent) and the Tucson 1998 screening (16 percent).

Cases of CBD have also continued to develop among workers in facilities and jobs where exposures were below 0.2 µg/m3. One case of CBD was found in the Tucson 1998 screening among nine sensitized workers hired less than two years previously (Henneberger et al., 2001). At the Cullman plant, at least two cases of CBD were found among four sensitized workers screened in 1995-1999 and hired less than a year previously (Newman et al., 2001). These results suggest a substantial risk of progression from sensitization to CBD among workers exposed at levels well below the current PEL, especially considering the extremely short time of exposure and follow-up for these workers. Six of 10 sensitized workers identified at Reading in the 2000 screening were diagnosed with CBD. The four sensitized workers who did not have CBD at their last clinical evaluation had been hired between one and five years previously; therefore, the time may have been too short for CBD to develop.

In contrast, more recent exposure control programs that have used a combination of engineering controls, PPE, and stringent housekeeping measures to reduce workers' airborne and dermal exposures have substantially lowered risk of sensitization among newly-hired workers. Of 97 workers hired between 2000 and 2004 in Tucson, where respiratory and skin protection was instituted for all workers in production areas, only one (1 percent) worker became sensitized, and in that case the worker's dermal protection had failed during wet-machining work (Thomas et al., 2009). In the aluminum smelters discussed by Taiwo et al., where available exposure samples indicated median beryllium levels of about 0.1 μg/m3 or below (measured as an 8-hour TWA) and workers used respiratory and dermal protection, confirmed cases of sensitization were rare (zero or one case per location). Sensitization was also rare among workers at a Norwegian aluminum smelter (Nilsen et al., 2010), where estimated exposures in the plant ranged from 0.1 μg/m3 to 0.3 μg/m3 and respiratory protection was regularly used. In Reading, where in 2000-2001 airborne exposures in all jobs were reduced to a median of 0.1 μg/m3 or below (measured as an 8-hour TWA) and dermal protection was required for production-area workers, two (5.4 percent) of 37 newly hired workers became sensitized (Thomas et al., 2009). After the process with the highest exposures (median of 0.1 μg/m3) was enclosed in 2002 and workers in that process were required to use respiratory protection, the remaining jobs had very low exposures (medians ~ 0.03 μg/m3). Among 45 workers hired after the enclosure, one was found to be sensitized (2.2 percent). In Elmore, where all workers were required to wear respirators and skin PPE in production areas beginning in 2000-2001, the estimated prevalence of sensitization among workers hired after these measures were put in place was around 2-3 percent (Bailey et al., 2010). In addition, Schuler et al. (2012) found no cases of sensitization among short-term Elmore workers employed in 1999 who had total mass LTW average exposures below 0.09 μg/m3, among workers with total mass cumulative exposures below 0.08 μg/m3-yr, or among workers with total mass highest job worked exposures below 0.12 μg/m3.

Madl et al. reported one case of sensitization among workers at the Cullman plant hired after 2000. The median personal exposures were about Start Printed Page 476300.1 μg/m3 or below for all jobs during this period. Several changes in the facility's exposure control methods were instituted in the late 1990s that were likely to have reduced dermal as well as respiratory exposure to beryllium. For example, the plant installed change/locker rooms for workers entering the production facility, instituted requirements for work uniforms and dedicated work shoes for production workers, implemented annual beryllium hazard awareness training that encouraged glove use, and purchased high efficiency particulate air (HEPA) filter vacuum cleaners for workplace cleanup and decontamination.

The results of the Reading, Tucson, and Elmore studies show that reducing airborne exposures to below 0.1 μg/m3 and protecting workers from dermal exposure, in combination, have achieved a substantial reduction in sensitization risk among newly-hired workers. Because respirator use, dermal protection, and engineering changes were often implemented concurrently at these plants, it is difficult to attribute the reduced risk to any single control measure. The reduction is particularly evident when comparing newly-hired workers in the most recent Reading screenings (2.2-5.4 percent), and the rate of sensitization found among workers hired within the year before the 2000 screening (13 percent). There is a similarly striking difference between the rate of prevalence found among newly-hired workers in the most recent Tucson study (1 percent) and the rate found among workers hired within the year before the 1998 screening at that plant (16 percent). These results are echoed in the Cullman facility, which combined engineering controls to reduce airborne exposures to below 0.1 μg/m3 with measures such as housekeeping improvements and worker training to reduce dermal exposure.

The studies on recent programs to reduce workers' risk of sensitization and CBD were conducted on populations with very short exposure and follow-up time. Therefore, they could not address the question of how frequently workers who become sensitized in environments with extremely low airborne exposures (median <0.1 μg/m3) develop CBD. Clinical evaluation for CBD was not reported for sensitized workers identified in the most recent Tucson, Reading, and Elmore studies. In Cullman, however, two of the workers with CBD had been employed for less than a year and worked in jobs with very low exposures (median 8-hour personal sample values of 0.03-0.09 μg/m3). The body of scientific literature on occupational beryllium disease also includes case reports of workers with CBD who are known or believed to have experienced minimal beryllium exposure, such as a worker employed only in shipping at a copper-beryllium distribution center (Stanton et al., 2006), and workers employed only in administration at a beryllium ceramics facility (Kreiss et al., 1996).

Arjomandi et al. published a study of 50 sensitized workers from a nuclear weapons research and development facility (Arjomandi et al., 2010). Occupational and medical histories including physical examination and chest imaging were available for the great majority (49) of these individuals. Forty underwent testing for CBD via bronchoscopy and transbronchial biopsies. In contrast to the studies of low-exposure populations discussed previously, this group had much longer follow-up time (mean time since first exposure = 32 years) and length of employment at the facility (mean of 18 years). Quantitative exposure estimates for the workers were not presented; however, the authors characterized their probable exposures as “low” (13 workers), “moderate” (28 workers), or “high” (nine workers) based on the jobs they performed at the facility.

Five of the 50 sensitized workers (10 percent) were diagnosed with CBD based on histology or high-resolution computed tomography. An additional three (who had not undergone full clinical evaluation for CBD) were identified as probable CBD cases, bringing the total prevalence of CBD and probable CBD in this group to 16 percent. As discussed in the epidemiology section of the Health Effects chapter, the prevalence of CBD among worker populations regularly exposed at higher levels (e.g., median > 0.1 μg/m3) is typically much greater, approaching 80-100% in several studies. The lower prevalence of CBD in this group of sensitized workers, who were believed to have primarily low exposure levels, suggests that controlling respiratory exposure to beryllium may reduce risk of CBD among sensitized workers as well as reducing risk of CBD via prevention of sensitization. However, it also demonstrates that some workers in low-exposure environments can become sensitized and go on to develop CBD. The next section discusses an additional source of information on low-level beryllium exposure and CBD: studies of community-acquired CBD in residential areas surrounding beryllium production facilities.

C. Review of Community-Acquired CBD Literature

The literature on community-acquired chronic beryllium disease (CA-CBD) documents cases of CBD among individuals exposed to airborne beryllium at concentrations below the proposed PEL. OSHA notes that these case studies do not provide information on how frequently individuals exposed to very low airborne levels develop CBD and that reconstructed exposure estimates for CA-CBD cases are less reliable than exposure estimates for working populations reviewed in the previous sections. In addition, the cumulative exposure that an occupationally exposed person would accrue at any given exposure concentration is far less than would typically accrue from long-term environmental exposure. The literature on CA-CBD thus has important limitations and is not used as a basis for quantitative risk assessment for CBD from low-level beryllium exposure. Nevertheless, these case reports and the broader CA-CBD literature indicate that individuals exposed to airborne beryllium below the proposed PEL can develop CBD.

Cases of CA-CBD were first reported among residents of Lorain, OH, and Reading, PA, who lived in the vicinity of beryllium plants. More recently, BeLPT screening has been used to identify additional cases of CA-CBD in Reading.

1. Lorain, OH

In 1948, the State of Ohio Department of Public Health conducted an X-ray program surveying more than 6,000 people who lived within 1.5 miles of a Lorain beryllium plant (Eisenbud, 1949; Eisenbud, 1982; Eisenbud, 1998). This survey, together with a later review of all reported cases of CBD in the area, found 13 cases of CBD. All of the residents who developed CBD lived within 0.75 miles of the plant, and none had occupational exposure or lived with beryllium-exposed workers. Among the population of 500 people living within 0.25 miles of the plant, seven residents (1.4 percent) were diagnosed with CBD. Five cases were diagnosed among residents living between 0.25 and 0.5 miles from the plant, one case was diagnosed among residents living between 0.5 and 0.75 miles from the plant, and no cases were found among those living farther than 0.75 miles from the plant (total populations not reported) (Eisenbud, 1998).

Beginning in January 1948, air sampling was conducted using a mobile sampling station to measure Start Printed Page 47631atmospheric beryllium downwind from the plant. An approximate concentration of 0.2 μg/m3 was measured at 0.25 miles from the plant's exhaust stack, and concentrations decreased with greater distance from the plant, to 0.003 μg/m3 at a distance of 5 miles (Eisenbud, 1982). A 10-week sampling program was conducted using three fixed monitoring stations within 700 feet of the plant and one station 7,000 feet from the plant. Interpolating the measurements collected at these locations, Eisenbud and colleagues estimated an average airborne beryllium concentration of between 0.004 and 0.02 μg/m3 at a distance of 0.75 miles from the plant. Accounting for the possibility that previous exposures may have been higher due to production level fluctuations and greater use of rooftop emissions, they concluded that the lowest airborne beryllium level associated with CA-CBD in this community was somewhere between 0.01 μg/m3 and 0.1 μg/m3 (Eisenbud, 1982).

2. Reading, PA

Thirty-two cases of CA-CBD were reported in a series of papers published in 1959-1969 concerning a beryllium refinery in Reading (Lieben and Metzner, 1959; Metzner and Lieben, 1961; Dattoli et al., 1964; Lieben and Williams, 1969). The plant, which opened in 1935, manufactured beryllium oxide, alloys and metal, and beryllium tools and metal products (Maier et al., 2008; Sanderson et al., 2001b). In a follow-up study, Maier et al. presented eight additional cases of CA-CBD who had lived within 1.5 miles of the plant (Maier et al., 2008). Individuals with a history of occupational beryllium exposure and those who had resided with occupationally exposed workers were not classified as having CA-CBD.

The Pennsylvania Department of Health conducted extensive environmental sampling in the area of the plant beginning in 1958. Based on samples collected in 1958, Maier et al. stated that most cases identified in their study would typically have been exposed to airborne beryllium at levels between 0.0155 and 0.028 μg/m3 on average, with the potential for some excursions over 0.35 μg/m3 (Maier et al 2008, p. 1015). To characterize exposures to cases identified in the earlier publications, Lieben and Williams cited a sampling program conducted by the Department of Health between January and July 1962, using nine sampling stations located between 0.2 and 4.8 miles from the plant. They reported that 72 percent of 24-hour samples collected were below 0.01 μg/m3. Of samples that exceeded 0.01 μg/m3, most were collected at close proximity to the plant (e.g., 0.2 miles from the plant).

In the early series of publications, cases of CA-CBD were reported among people living both close to the plant (Maier et al., 2008; Dutra, 1948) and up to several miles away. Of new cases identified in the 1968 update, all lived between 3 and 7.5 miles from the plant. Lieben and Williams suggested that some cases of CA-CBD found among more distant residents might have resulted from working or visiting a graveyard closer to the plant (Lieben and Williams, 1969). For example, a milkman who developed CA-CBD had a route in the neighborhood of the plant. Another resident with CA-CBD had worked as a cleaning woman in the area of the plant, and a third worked within a half-mile of the plant.

At the time of the final follow-up study (1968), 11 residents diagnosed with CA-CBD were alive and 21 were deceased. Among those who had died, berylliosis was listed as the cause of death for three, including a 10-year-old girl and two women in their sixties. Fibrosis, granuloma or granulomatosis, and chronic or fibrous pneumonitis were listed as the cause of death for eight more of those deceased. Histologic evidence of CBD was reported for nine of 12 deceased individuals who had been evaluated for it. In addition to showing radiologic abnormalities associated with CBD, all living cases were dyspneic.

Following the 1969 publication by Liebman and Williams, no additional CA-CBD cases were reported in the Reading area until 1999, when a new case was diagnosed. The individual was a 72-year-old woman who had had abnormal chest x-rays for the previous six years (Maier et al., 2008). After the diagnosis of this case, Maier et al. reviewed medical records and/or performed medical evaluations, including BeLPT results for 16 community residents who were referred by family members or an attorney.

Among those referred, eight cases of definite or probable CBD were identified between 1999 and 2002. All eight were women who lived between 0.1 and 1.05 miles from the plant, beginning between 1943-1953 and ending between 1956-2001. Five of the women were considered definite cases of CA-CBD, based on an abnormal blood or lavage cell BeLPT and granulomatous inflammation on lung biopsy. Three probable cases of CA-CBD were identified. One had an abnormal BeLPT and radiography consistent with CBD, but granulomatous disease was not pathologically proven. Two met Beryllium Case Registry epidemiologic criteria for CBD based on radiography, pathology and a clinical course consistent with CBD, but both died before they could be tested for beryllium sensitization. One of the probable cases, who could not be definitively diagnosed with CBD because she died before she could be tested, was the mother of both a definite case and the probable case who had an abnormal BeLPT but did not show granulomatous disease.

The individuals with CA-CBD identified in this study suffered significant health impacts from the disease, including obstructive, restrictive, and gas exchange pulmonary defects in the majority of cases. All but two had abnormal pulmonary physiology. Those two were evaluated at early stages of disease following their mother's diagnosis. Six of the eight women required treatment with prednisone, a step typically reserved for severe cases due to the adverse side effects of steroid treatment. Despite treatment, three had died of respiratory impairment from CBD as of 2002 (Maier et al., 2008). The authors concluded that “low levels of exposures with significant disease latency can result in significant morbidity and mortality” (id., p. 1017).

OSHA notes that compared with the occupational studies discussed in the previous section, there is comparatively sparse information on exposure levels of Lorain and Reading residents. There remains the possibility that some individuals with CA-CBD may have had higher exposures than were known and reported in these studies, or have had unreported exposure to beryllium dust via contact with beryllium-exposed workers. Nevertheless, the studies conducted in Lorain and Reading demonstrate that long-term exposure to the apparent low levels of airborne beryllium, with sufficient disease latency, can lead to serious or fatal CBD. Genetic susceptibility may play a role in cases of CBD among individuals with very low or infrequent exposures to beryllium. The role of genetic susceptibility in the CBD disease process is discussed in detail in section V.D.3.

D. Exposure-Response Literature on Beryllium Sensitization and CBD

To further examine the relationship between exposure level and risk of both sensitization and disease, we next review exposure-response studies in the CBD literature. Many publications have reported that exposure levels correlate with risk, including a small number of Start Printed Page 47632exposure-response analyses. Most of these studies examined the association between job-specific beryllium air measurements and prevalence of sensitization and CBD. This section focuses on studies at three facilities that included a more rigorous historical reconstruction of individual worker exposures in their exposure-response analyses.

1. Rocky Flats, CO, Facility

In 2000, Viet et al. published a case-control study of participants in the Rocky Flats Beryllium Health Surveillance Program (BHSP), which was established in 1991 to screen workers at the Department of Energy's Rocky Flats, CO, nuclear weapons facility for beryllium sensitization and evaluate sensitized workers for CBD (Viet et al., 2000). The program, which at the time of publication had tested over 5,000 current and former Rocky Flats employees, had identified a total of 127 sensitized individuals as of 1994 when Viet et al. initiated their study.

Workers were considered sensitized if two BeLPT results were positive, either from two blood draws or from a single blood draw analyzed by two different laboratories. All sensitized individuals were offered clinical evaluation, and 51 were diagnosed with CBD based on positive lung LPT and evidence of noncaseating granulomas upon lung biopsy. The number of sensitized individuals who declined clinical evaluation was not reported. Two cases, one with CBD and one who was sensitized but not diagnosed with CBD, were excluded from the case-control analysis due to reported or potential prior beryllium exposure at a ceramics plant. Another sensitized individual who had not been diagnosed with CBD was excluded because she could not be matched by the study's criteria to a non-sensitized control within the BHSP database. Viet et al. matched a total of 50 CBD cases to 50 controls who were negative on the BeLPT and had the same age (± 3 years), gender, race and smoking status, and were otherwise randomly selected from the database. Using the same matching criteria, 74 sensitized workers who were not diagnosed with CBD were age-, gender-, race-, and smoking status-matched to 74 control individuals who tested negative by the BeLPT from the BHSP database.

Viet et al. developed exposure estimates for the cases and controls based on daily beryllium air samples collected in one of 36 buildings where beryllium was used at Rocky Flats, the Building 444 Beryllium Machine Shop. Over half of the approximately 500,000 industrial hygiene samples collected at Rocky Flats were taken from this building. Air monitoring in other buildings was reported to be limited and inconsistent and, thus, not utilized in the exposure assessment. The sampling data used to develop worker exposure estimates were exclusively Building 444 fixed airhead (FAH) area samples collected at permanent fixtures placed around beryllium work areas and machinery.

Exposure estimates for jobs in Building 444 were constructed for the years 1960-1988 from this database. Viet et al. worked with Rocky Flats industrial hygienists and staff to assign a “building area factor” (BAF) to each of the other buildings, indicating the likely level of exposure in a building relative to exposures in Building 444. Industrial hygienists and staff similarly assigned a job factor (JF) to all jobs, representing the likely level of beryllium exposure relative to the levels experienced by beryllium machinists. A JF of 1 indicated the lowest exposures, and a JF of 10 indicated the highest exposures. For example, administrative work and vehicle operation were assigned a JF of 1, while machining, mill operation, and metallurgical operation were each assigned a JF of 10. Estimated FAH values for each combination of job, building and year in the study subjects' work histories were generated by multiplying together the job and building factors and the mean annual FAH exposure level. Using data collected by questionnaire from each BHSP participant, Viet et al. reconstructed work histories for each case and control, including job title and building location in each year of their employment at Rocky Flats. These work histories and the estimated FAH values were used to generate a cumulative exposure estimate (CEE) for each case and control in the study. A long-term mean exposure estimate (MEE) was generated by dividing each CEE by the individual's number of years employed at Rocky Flats.

Viet et al.' s statistical analysis of the resulting data set included conditional logistic regression analysis, modeling the relationship between risk of each health outcome and log-transformed CEE and MEE. They found highly statistically significant relationships between log-CEE and risk of CBD (coef = 0.837, p = 0.0006) and between log-MEE (coef = 0.855, p = 0.0012) and risk of CBD, indicating that risk of CBD increases with exposure level. These coefficients correspond to odds ratios of 6.9 and 7.2 per 10-fold increase in exposure, respectively. Risk of sensitization without CBD did not show a statistically significant relationship with log-CEE (coef = 0.111, p = 0.32), but showed a nearly-significant relationship with log-MEE (coef = 0.230, p = 0.097).

2. Cullman, AL, Facility

The Cullman, AL, precision machining facility discussed previously was the subject of a case-control study published by Kelleher et al. in 2001. After the diagnosis of an index case of CBD at the plant in 1995, NJMRC researchers worked with the plant to conduct a medical surveillance program using the BeLPT to screen workers biennially for beryllium sensitization and CBD. Of 235 employees screened between 1995 and 1999, 22 (9.4 percent) were found to be sensitized, including 13 diagnosed with CBD (Newman et al., 2001). Concurrently, research was underway by Martyny et al. to characterize the particle size distribution of beryllium exposures generated by processes at this plant (Martyny et al., 2000). The exposure research showed that the machining operations during this time period generated respirable particles (10 μm or less) at the worker breathing zone that made up greater than 50 percent of the beryllium mass. Kelleher et al. used the dataset of 100 personal lapel samples collected by Martyny et al. and other NJMRC researchers in 1996, 1997, and 1999 to characterize exposures for each job in the plant. Following a statistical analysis comparing the samples collected by NJMRC with earlier samples collected at the plant, Kelleher et al. concluded that the 1996-1999 data could be used to represent job-specific exposures from earlier periods.

Detailed work history information gathered from plant data and worker interviews was used in combination with job exposure estimates to characterize cumulative and LTW average beryllium exposures for workers in the surveillance program. In addition to cumulative and LTW exposure estimates based the total mass of beryllium reported in their exposure samples, Kelleher et al. calculated cumulative and LTW estimates based specifically on exposure to particles < 6 μm and particles < 1 μm in diameter.

To analyze the relationship between exposure level and risk of sensitization and CBD, Kelleher et al. performed a case-control analysis using measures of both total beryllium exposure and particle size-fractionated exposure. The analysis included sensitization cases identified in the 1995-1999 surveillance and 206 controls from the group of 215 non-sensitized workers. For nine workers, the researchers could not Start Printed Page 47633reconstruct complete job histories. Logistic regression models using categorical exposure variables showed positive associations between risk of sensitization and the six exposure measures tested: Total CEE, total MEE, and variations of CEE and MEE constructed based on particles < 6 μm and < 1 μm in diameter. None of the associations were statistically significant (p < 0.05); however, the authors noted that the dataset was relatively small, with limited power to detect a statistically significant exposure-response relationship.

Although the Viet et al. and Kelleher et al. exposure-response analyses provide valuable insight into exposure-response for beryllium sensitization and CBD, both studies have limitations that affect their suitability as a basis for quantitative risk assessment. Their limitations primarily involve the exposure data used to estimate workers' exposures. Viet et al.' s exposure reconstruction was based on area samples from a single building within a large, multi-building facility. Where possible, OSHA prefers to base risk estimates on exposure data collected in the breathing zone of workers rather than area samples, because data collected in the breathing zone more accurately represent workers' exposures. Kelleher's analysis, on the other hand, was based on personal lapel samples. However, the samples Kelleher et al. used were collected between 1996 and 1999, after the facility had initiated new exposure control measures in response to the diagnosis of a case of CBD in 1995. OSHA believes that industrial hygiene samples collected at the Cullman plant prior to 1996 better characterize exposures prior to the new exposure controls. In addition, since the publication of the Kelleher study, the population has continued to be screened for sensitization and CBD. Data collected on workers hired in 2000 and later, after most exposure controls had been completed, can be used to characterize risk at lower levels of exposure than have been examined in many previous studies.

To better characterize the relationship between exposure level and risk of sensitization and CBD, OSHA developed an independent exposure-response analysis based on a dataset maintained by NJMRC on workers at the Cullman, AL, machining plant. The dataset includes exposure samples collected between 1980 and 2005, and has updated work history and screening information for several hundred workers through 2003. OSHA's analysis of the NJMRC data set is presented in the next section, E. OSHA's Exposure-Response Analysis.

3. Elmore, OH, Facility

After OSHA completed its analysis of the NJMRC data set, Schuler et al. (2012) published a study examining beryllium sensitization and CBD among 264 short-term workers employed at the previously described Elmore, OH plant in 1999. The analysis used a high-quality exposure reconstruction by Virji et al. (2012) and presented a regression analysis of the relationship between beryllium exposure levels and beryllium sensitization and CBD in the short-term worker population. By including only short-term workers, Virji et al. were able to construct participants' exposures with more precision than was possible in studies involving workers exposed for longer durations and in time periods with less exposure sampling. In addition, the focus on short-term workers allowed more precise knowledge of when sensitization and CBD occurred than had been the case for previously published cross-sectional studies of long-term workers. Each participant completed a work history questionnaire and was tested for beryllium sensitization, and sensitized workers were offered further evaluation for CBD. The overall prevalence of sensitization was 9.8 percent (26/264). Twenty-two sensitized workers consented to clinical testing for CBD via transbronchial biopsy. Six of those sensitized were diagnosed with CBD (2.3 percent, 6/264).

Schuler et al. (2012) used logistic regression to explore the relationship between estimated beryllium exposure and sensitization and CBD, using estimates of total, respirable, and submicron mass concentrations. Exposure estimates were constructed using two exposure surveys conducted in 1999: a survey of total mass exposures (4,022 full-shift personal samples) and a survey of size-separated impactor samples (198 samples). The 1999 exposure surveys and work histories were used to estimate long-term lifetime weighted (LTW) average, cumulative, and highest-job-worked exposure for total, respirable, and submicron beryllium mass concentrations.

For beryllium sensitization, logistic models showed elevated odds ratios for average (OR 1.48) and highest job (OR 1.37) exposure for total mass exposure; the OR for cumulative exposure was smaller (OR 1.23) and borderline statistically significant (95 percent CI barely included unity). Relationships between sensitization and respirable exposure estimates were similarly elevated for average (OR 1.37) and highest job (OR 1.32). Among the submicron exposure estimates, only highest job (OR 1.24) had a 95 percent CI that just included unity for sensitization. For CBD, elevated odds ratios were observed only for the cumulative exposure estimates and were similar for total mass and respirable exposure (total mass OR 1.66, respirable (OR 1.68). Cumulative submicron exposure showed an elevated, borderline significant odds ratio (OR 1.58). The odds ratios for average exposure and highest-exposed job were not statistically significantly elevated. Schuler et al. concluded that both total and respirable mass concentrations of beryllium exposure were relevant predictors of risk for beryllium sensitization and CBD.

E. OSHA's Exposure-Response Analysis

OSHA evaluated exposure and health outcome data on a population of workers employed at the Cullman machining facility. NJMRC researchers, with consent and information provided by the facility, compiled a dataset containing employee work histories, medical diagnoses, and air sampling results and provided it to OSHA for analysis. OSHA's contractors from Eastern Research Group (ERG) gathered additional information from (1) two surveys of the Cullman plant conducted by OSHA's contractor (ERG, 2003 and ERG, 2004a), (2) published articles of investigations conducted at the plant by researchers from NJMRC (Kelleher et al., 2001; Madl et al., 2007; Martyny et al., 2000; and Newman et al., 2001), (3) a case file from a 1980 OSHA complaint inspection at the plant, (4) comments submitted to the OSHA docket office in 1976 and 1977 by representatives of the metal machining plant regarding their beryllium control program, and (5) personal communications with the plant's current industrial hygienist (ERG, 2009b) and an industrial hygiene researcher at NJMRC (ERG, 2009a).

1. Plant Operations

The Cullman plant is a leading fabricator of precision-machined and processed materials including beryllium and its alloys, titanium, aluminum, quartz, and glass (ERG, 2009b). The plant has approximately 210 machines, primarily mills and lathes, and processes large quantities of beryllium on an annual basis. The plant provides complete fabrication services including ultra-precision machining; ancillary processing (brazing, ion milling, photo etching, precision cleaning, heat treating, stress relief, thermal cycling, mechanical assembly, and chemical Start Printed Page 47634milling/etching); and coatings (plasma spray, anodizing, chromate conversion coating, nickel sulfamate plate, nickel plate, gold plate, black nickel plate, copper plate/strike, passivation, and painting). Most of the plant's beryllium operations involve machining beryllium metal and high beryllium content composite materials (beryllium metal/beryllium oxide metal composites called E-Metal or E-Material), with occasional machining of beryllium oxide/metal matrix (such as AlBeMet, aluminum beryllium matrix) and beryllium-containing alloys. E-Materials such as E-20 and E-60 are currently processed in the E-Cell department.

The 120,000 square-foot plant has two main work areas: a front office area and a large, open production shop. Operations in the production shop include inspection of materials, machining, polishing, and quality assurance. The front office is physically separated from the production shop. Office workers enter through the front of the facility and have access to the production shop through a change room where they must don laboratory coats and shoe covers to enter the production area. Production workers enter the shop area at the rear of the facility where a change/locker room is available to change into company uniforms and work shoes. Support operations are located in separate areas adjacent to the production shop and include management and administration, sales, engineering, shipping and receiving, and maintenance. Management and administrative personnel include two groups: those primarily working in the front offices (front office management) and those primarily working on the shop floor (shop management).

In 1974, the company moved its precision machining operations to the plant's current location in Cullman. Workplace exposure controls reportedly did not change much until the diagnosis of an index case of CBD in 1995. Prior to 1995, exposure controls for machining operations primarily included a low volume/high velocity (LVHV) central exhaust system with operator-adjusted exhaust pickups and wet machining methods. Protective clothing, gloves, and respiratory protection were not required. After the diagnosis, the facility established an in-house target exposure level of 0.2 μg/m3, installed change/locker rooms for workers entering the production facility, eliminated pressurized air hoses, discouraged the use of dry sweeping, initiated biennial medical surveillance using the BeLPT, and implemented annual beryllium hazard awareness training.

In 1996, the company instituted requirements for work uniforms and dedicated work shoes for production workers, eliminated dry sweeping in all departments, and purchased high-efficiency particulate air (HEPA) filter vacuum cleaners for workplace cleanup and decontamination. Major engineering changes were also initiated in 1996, including the purchase of a new local exhaust ventilation (LEV) system to exhaust machining operations producing finer aerosols (e.g., dust and fume versus metal chips). The facility also began installing mist eliminators for each machine. Departments affected by these changes included cutter grind (tool and die), E-cell, electrical discharge machining (EDM), flow lines, grind, lapping, and optics. Dry machining operations producing chips were exhausted using the existing LVHV exhaust system (ERG, 2004a). In the course of making the ventilation system changes, old ductwork and baghouses were dismantled and new ductwork and air cleaning devices were installed. The company also installed Plexiglas enclosures on machining operations in 1996-1997, including the lapping, deburring, grinding, EDM, and tool and die operations. In 1998, LEV was installed in EDM and modified in the lap, deburr, and grind departments.

Most exposure controls were reportedly in place by 2000 (ERG, 2009a). In 2004, the plant industrial hygienist reported that all machines had LEV and about 65 percent were also enclosed with either partial or full enclosures to control the escape of machining coolant (ERG, 2004b). Over time, the facility has built enclosures for operations that consistently produce exposures greater than 0.2 μg/m3. The company has never required workers to use gloves or other PPE.

2. Air Sampling Database and Job Exposure Matrix (JEM)

The NJMRC dataset includes industrial hygiene sampling results collected by the plant (1980-1984 and 1995-2005) and NJMRC researchers (June 1996 to February 1997 and September 1999), including 4,370 breathing zone (personal lapel) samples and 712 area samples (ERG, 2004b). Limited air sampling data is available before 1980 and no exposure data appears to be available for the 10-year time period 1985 through 1994. A review of the NJMRC air sampling database from 1995 through 2005 shows a significant increase in the number of air samples collected beginning in 2000, which the plant industrial hygienist attributes to an increase in the number of air sampling pumps (from 5 to 23) and the purchase of an automated atomic absorption spectrophotometer.

ERG used the personal breathing zone sampling results contained in the sample database to quantify exposure levels for each year and for several-year periods. Separate exposure statistics were calculated for each job included in the job history database. For each job included in the job history database, ERG estimated the arithmetic mean, geometric mean, median, minimum, maximum, and 95th percentile value for the available exposure samples. Prior to generating these statistics ERG made several adjustments. After consultation with researchers at NJMRC, four particularly high exposures were identified as probably erroneous and excluded from calculations. In addition, a 1996 sample for the HS (Health and Safety) process was removed from the sample calculations after ERG determined it was for a non-employee researcher visiting the facility.

Most samples in the sample database for which sampling times were recorded were long-term samples: 2,503 of the 2,557 (97.9 percent) breathing zone samples with sampling time recorded had times greater than or equal to 400 minutes. No adjustments were made for sampling time, except in the case of four samples for the “maintenance” process for 1995. These results show relatively high values and exceptionally short sampling times consistent with the nature of much maintenance work, marked by short-term exposures and periods of no exposure. The four 1995 maintenance samples were adjusted for an eight-hour sampling time assuming that the maintenance workers received no further beryllium exposure over the rest of their work shift.

OSHA examined the database for trends in exposure by reviewing sample statistics for individual years and grouping years into four time periods that correspond to stages in the plant's approach to beryllium exposure control. These were: 1980-1995, a period of relatively minimal control prior to the 1995 discovery of a case of CBD among the plant's workers; 1996-1997, a period during which some major engineering controls were in the process of being installed on machining equipment; 1998-1999, a period during which most engineering controls on the machining equipment had been installed; and 2000-2003, a period when installation of all exposure controls on machining equipment was complete and exposures very low throughout the plant. Table VI-4 below summarized the available data for each time period. As the four probable sampling errors identified in Start Printed Page 47635the original data set are excluded here, arithmetic mean values are presented.

Table VI-4—Exposure Values for Machining Job Titles, Excluding Probable Sampling Errors (μg/m3) in NJMRC Data Set

Job title1980-19951996-19971998-19992000-2003
SamplesMeanSamplesMeanSamplesMeanSamplesMean
Deburring271.17191.290NA670.1
Electrical Discharge Machining20.0621.32160.08630.1
Grinding123.0760.49150.24680.1
Lapping90.15160.24420.211030.1
Lathe180.8881.13400.172000.1
Milling430.64150.23950.174340.1

Reviewing the revised statistics for individual years for different groupings, OSHA noted that exposures in the 1996-1997 period were for some machining jobs equivalent to, or even higher than, exposure levels recording during the 1980-1995 period. During 1996-1997, major engineering controls were being installed, but exposure levels were not yet consistently reduced.

Table VI-5 below summarizes exposures for the four time periods in jobs other than beryllium machining. These include jobs such as administrative work, health and safety, inspection, toolmaking (`Tool' and `Cgrind'), and others. A description of jobs by title is available in the risk assessment background document.

Table VI-5—Exposure Values for Non-Machining Job Titles (μg/m3) in NJMRC Data Set

Job title1980-19951996-19971998-19992000-2003
SamplesmeanSamplesmeanSamplesmeanSamplesmean
Administration0NA0NA390.052740.061
Assembly0NA0NA80.13620.051
Cathode0NA0NA0NA90.156
Cgrind10.1200NA140.105760.112
Chem0NA10.529210.277910.152
Ecell0NA131.8730NA260.239
Engineering10.0650NA490.0691250.062
Flow Lines0NA0NA0NA1130.083
Gas0NA0NA0NA1210.058
Glass0NA0NA0NA380.068
Health and Safety 80NA0NA0NA50.076
Inspection0NA0NA320.1011500.066
Maintenance41.25710.160160.200700.126
Msupp0NA0NA470.094680.081
Optics0NA0NA0NA410.090
PCIC10.0400NA130.071420.083
Qroom10.2800NA0NA20.130
Shop0NA0NA40.0600NA
Spec30.2470NA240.083190.087
Tool0NA0NA0NA10.070

From Table VI-5, it is evident that exposure samples are not available for many non-machining jobs prior to 2000. Where samples are available before 2000, sample numbers are small, particularly prior to 1998. In jobs for which exposure values are available in 1998-1999 and 2000-2003, exposures appear either to decline from 1998-1999 to 2000-2003 (Assembly, Chem, Inspection, Maintenance) or to be roughly equivalent (Administration, Cgrind, Engineering, Msupp, PCIC, and Spec). Among the jobs with exposure samples prior to 1998, most had very few (1-5) samples, with the exception of Ecell (13 samples in 1996-1997). Based on this limited information, it appears that exposures declined from the period before the first dentification of a CBD case to the period in which exposure controls were introduced.

Because exposure results from 1996-1997 were not found to be consistently reduced in comparison to the 1985-1995 period in primary machining jobs, these two periods were grouped together in the JEM. Exposure monitoring for jobs other than the primary machining operations were represented by a single mean exposure value for 1980-2003. As respiratory protection was not routinely used at the plant, there was no adjustment for respiratory protection in workers' exposure estimates. The job exposure matrix is presented in full in the background document for the quantitative risk assessment.

3. Worker Exposure Reconstruction

The work history database contains job history records for 348 workers, including start years, duration of employment, and percentage of worktime spent in each job. One hundred ninety-eight of the workers had been employed at some point in primary machining jobs, including deburring, Start Printed Page 47636EDM, grinding, lapping, lathing, and milling. The remainder worked only in non-primary machining jobs, such as administration, engineering, quality control, and shop management. The total number of years worked at each job are presented as integers, leaving some uncertainty regarding the worker's exact start and end date at the job.

Based on these records and the JEM described previously, ERG calculated cumulative and average exposure estimates for each worker in the database. Cumulative exposure was calculated as, Σieiti, where e(i) is the exposure level for job (i), and t(i) is the time spent in job (i). Cumulative exposure was divided by total exposure time to estimate each worker's long-term average exposure. These exposures were computed in a time-dependent manner for the statistical modeling. For workers with beryllium sensitization or CBD, exposure estimates excluded exposures following diagnosis.

Workers who were employed for long time periods in jobs with low-level exposures tend to have low average and cumulative exposures due to the way these measures are constructed, incorporating the worker's entire work history. As discussed in the Health Effects chapter, higher-level exposures or short-term peak exposures such as those encountered in machining jobs may be highly relevant to risk of sensitization. Unfortunately, because it is not possible to continuously monitor individuals' beryllium exposure levels and sensitization status, it is not known exactly when workers became sensitized or what their “true” peak exposures leading up to sensitization were. Only a rough approximation of the upper levels of exposure a worker experienced is possible. ERG constructed a third type of exposure estimate reflecting the exposure level associated with the highest-exposure job (HEJ) and time period experienced by each worker. This exposure estimate (HEJ), the cumulative exposure estimate, and the average exposure were used in the quartile analysis and statistical analyses.

4. Prevalence of Sensitization and CBD

In the database provided to OSHA, seven workers were reported as sensitized only. Sixteen workers were listed as sensitized and diagnosed with CBD upon initial clinical evaluation. Three workers, first shown to be sensitized only, were later diagnosed with CBD. Tables VI-6, VI-7, and VI-8 below present the prevalence of sensitization and CBD cases across several categories of lifetime-weighted (LTW) average, cumulative, and highest-exposed job (HEJ) exposure. Exposure values were grouped by quartile. Note that all workers with CBD are also sensitized. Thus, the columns “Total Sensitized” and “Total %” refer to all sensitized workers in the dataset, including workers with and without a diagnosis of CBD.

Table VI-6—Prevalence of Sensitization and CBD by LTW Average Exposure Quartile in NJMRC Data Set

Average exposure (μg/m3)Group sizeSensitized onlyCBDTotal sensitizedTotal %CBD %
0.0-0.080911122.21.0
0.081-0.18732468.25.5
0.19-0.51770667.87.8
0.51-2.1578481215.410.3
Total319719268.26.0

Table VI-7—Prevalence of Sensitization and CBD by Cumulative Exposure Quartile in NJMRC Data Set

Cumulative exposure (μg/m3-yrs)Group sizeSensitized onlyCBDTotal sensitizedTotal %CBD %
0.0-0.147812244.92.5
0.148-1.467790222.52.5
1.468-7.00879381113.98.0
7.009-61.868027911.38.8
Total319719268.26.0

Table VI-8—Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile in NJMRC Data Set

HEJ exposure (μg/m3)Group sizeSensitized onlyCBDTotal sensitizedTotal %CBD %
0.0-0.086861011.20.0
0.091-0.214811678.67.4
0.387-0.69176291114.511.8
0.954-2.213763479.25.3
Total319719268.26.0

Table VI-6 shows increasing prevalence of total sensitization and CBD with increasing LTW average exposure, measured both as average and cumulative exposure. The lowest prevalence of sensitization and CBD was observed among workers with average exposure levels less than or equal to 0.08 μg/m3, where two sensitized workers (2.2 percent) including one case of CBD (1.0 percent) were found. The sensitized worker in this category without CBD had worked at the facility as an inspector since 1972, one of the lowest-exposed jobs at the plant. Start Printed Page 47637Because the job was believed to have very low exposures, it was not sampled prior to 1998. Thus, estimates of exposures in this job are based on data from 1998-2003 only. It is possible that exposures earlier in this worker's employment history were somewhat higher than reflected in his estimated average exposure. The worker diagnosed with CBD in this group had been hired in 1996 in production control, and had an estimated average exposure of 0.08 μg/m3. He was diagnosed with CBD in 1997.

The second quartile of LTW average exposure (0.081—0.18 μg/m3) shows a marked rise in overall prevalence of beryllium-related health effects, with six workers sensitized (8.2 percent), of whom four (5.5 percent) were diagnosed with CBD. Among six sensitized workers in the third quartile (0.19—0.50 μg/m3), all were diagnosed with CBD (7.8 percent). Another increase in prevalence is seen from the third to the fourth quartile, with 12 cases of sensitization (15.4 percent), including eight (10.3 percent) diagnosed with CBD.

The quartile analysis of cumulative exposure also shows generally increasing prevalence of sensitization and CBD with increasing exposure. As shown in Table VI-7, the lowest prevalences of CBD and sensitization are in the first two quartiles of cumulative exposure (0.0-0.147 μg/m3-yrs, 0.148-1.467 μg/m3-yrs). The upper bound on this cumulative exposure range, 1.467 μg/m3-yrs, is the cumulative exposure that a worker would have if exposed to beryllium at a level of 0.03 μg/m3 for a working lifetime of 45 years; 0.15 μg/m3 for ten years; or 0.3 μg/m3 for five years.

A sharp increase in prevalence of sensitization and CBD and total sensitization occurs in the third quartile (1.468-7.008 μg/m3-yrs), with roughly similar levels of both in the highest group (7.009-61.86 μg/m3-yrs). Cumulative exposures in the third quartile would be experienced by a worker exposed for 45 years to levels between 0.03 and 0.16 μg/m3, for 10 years to levels between 0.15 and 0.7 μg/m3, or for five years to levels between 0.3 and 1.4 μg/m3.

When workers' exposures from their highest-exposed job are considered, the exposure-response pattern is similar to that for LTW average exposure in the lower quartiles (Table VI-8). The lowest prevalence is observed in the first quartile (0.0-0.86 μg/m3), with sharply rising prevalence from first to second and second to third exposure quartiles. The prevalence of sensitization and CBD in the top quartile (0.954-2.213 μg/m3) decreases relative to the third, with levels similar to the overall prevalence in the dataset. Many workers in the highest exposure quartiles are long-time employees, who were hired during the early years of the shop when exposures were highest. One possible explanation for the drop in prevalence in the highest exposure quartiles is that highly-exposed workers from early periods may have developed CBD and left the plant before sensitization testing began in 1995.

It is of some value to compare the prevalence analysis of the Cullman (NJMRC) data set with the results of the Reading and Tucson studies discussed previously. An exact comparison is not possible, in part because the Reading and Tucson exposure values are associated with jobs and the NJMRC values are estimates of lifetime weighted average, cumulative, and highest-exposed job (HEJ) exposures for individuals in the data set. Nevertheless, OSHA believes it is possible to very roughly compare the results of the Reading and Tucson studies and the results of the NJMRC prevalence analysis presented above. As discussed in detail below, OSHA found a general consistency between the prevalence of sensitization and CBD in the quartiles of average exposure in the NJMRC data set and the prevalence of sensitization and CBD at the Reading and Tucson plants for similar exposure values.

Personal lapel samples collected at the Reading plant between 1995 and 2000 were relatively low overall (median of 0.073 μg/m3), with higher exposures (median of 0.149 μg/m3) concentrated in the wire annealing and pickling process (Schuler et al., 2005). Exposures in the Reading plant in this time period were similar to the second-quartile average (Table VI-6-0.081-0.18 μg/m3). The prevalence of sensitization observed in the NJMRC second quartile was 8.2 percent and appears roughly consistent with the prevalence of sensitization among Reading workers in the mid-1990s (11.5 percent). The reported prevalence of CBD (3.9 percent) among the Reading workforce was also consistent with that observed in the second NJMRC quartile (5.5 percent), After 2000, exposure controls reduced exposures in most Reading jobs to median levels below 0.03 μg/m3, with a median value of 0.1 μg/m3 for the wire annealing and pickling process. The wire annealing and pickling process was enclosed and stringent respirator and skin protection requirements were applied for workers in that area after 2002, essentially eliminating airborne and dermal exposures for those workers. Thomas et al. (2009) reported that one of 45 workers (2.2 percent) hired after the enclosure in 2002 was confirmed as sensitized, a value in line with the sensitization prevalence observed in the lowest quartiles of average exposure (2.2 percent, 0.0-0.08 μg/m3).

As with Reading, the prevalence of sensitization observed at Tucson and in the NJMRC data set are not exactly comparable due to the different natures of the exposure estimates. Nevertheless, in a rough sense the results of the Tucson study and the NJMRC prevalence analysis appear similar. In Tucson, a 1998 BeLPT screening showed that 9.5 percent of workers hired after 1992 were sensitized (Henneberger et al., 2001). Personal full-shift exposure samples collected in production jobs between 1994 and 1999 had a median of 0.2 μg/m3 (0.1 μg/m3 for non-production jobs). In the NJMRC data set, a sensitization prevalence of 8.2 percent was seen among workers with average exposures between 0.081 and 0.18 μg/m3. At the time of the 1998 screening, workers hired after 1992 had a median one year since first beryllium exposure and, therefore, CBD prevalence was only 1.4 percent. This prevalence is likely an underestimate since CBD often requires more than a year to develop. Longer-term workers at the Tucson plant with a median 14 years since first beryllium exposure had a 9.1 percent prevalence of CBD. There was a 5.5 percent prevalence of CBD among the entire workforce (Henneberger et al., 2001). As with the Reading plant employees, this reported prevalence is reasonably consistent with the 5.5 percent CBD prevalence observed in the second NJMRC quartile.

Beginning in 1999, the Tucson facility instituted strict requirements for respiratory protection and other PPE, essentially eliminating airborne and dermal exposure for most workers. After these requirements were put in place, Cummings et al. (2007) reported only one case of sensitization (1 percent; associated with a PPE failure) among 97 workers hired between 2000 and 2004. This appears roughly in line with the sensitization prevalence of 2.2 percent observed in the lowest quartiles of average exposure (0.0-0.08 μg/m3) in the NJMRC data set.

While the literature analysis presented here shows a clear reduction in risk with well-controlled airborne exposures (≤ 0.1 μg/m3 on average) and protection from dermal exposure, the level of detail presented in the published studies limits the Agency's ability to characterize risk at all the alternate PELs OSHA is considering. To better understand these risks, OSHA Start Printed Page 47638used the NJMRC dataset to characterize risk of sensitization and CBD among workers exposed to each of the alternate PELs under consideration in the proposed beryllium rule.

F. OSHA's Statistical Modeling

OSHA's contractor performed a complementary log-log proportional hazards model using the NJMRC data set. The proportional hazards model is a generalization of logistic regression that allows for time-dependent exposures and differential time at risk. The proportional hazards model accounts for the fact that individuals in the dataset are followed for different amounts of time, and that their exposures change over time. The proportional hazards model provides hazards ratios, which estimate the relative risk of disease at a specified time for someone with exposure level 1 compared to exposure level 2. To perform this analysis, OSHA's contractor constructed exposure files with time-dependent cumulative and average exposures for each worker in the data set in each year that a case of sensitization or CBD was identified. Workers were included in only those years after they started working at the plant and continued to be followed. Sensitized cases were not included in analysis of sensitization after the year in which they were identified as being sensitized, and CBD cases were not included in analyses of CBD after the year in which they were diagnosed with CBD. Follow-up is censored after 2002 because work histories were deemed to be less reliable after that date.

The results of the discrete proportional hazards analyses are summarized in Tables VI-9-12 below. All coefficients used in the models are displayed, including the exposure coefficient, the model constant for diagnosis in 1995, and additional exposure-independent coefficients for each succeeding year (1996-1999 for sensitization and 1996-2002 for CBD) of diagnosis that are fit in the discrete time proportional hazards modeling procedure. Model equations and variables are explained more fully in the companion risk assessment background document.

Relative risk of sensitization increased with cumulative exposure (p = 0.05). A positive, but not statistically significant, association was observed with LTW average exposure (p = 0.09). The association was much weaker for exposure duration (p = 0.31), consistent with the expected biological action of an immune hypersensitivity response where onset is believed to be more dependent on the concentration of the sensitizing agent at the target site rather than the number of years of occupational exposure. The association was also much weaker for highest-exposed job (HEJ) exposure (p = 0.3).

Table VI-9—Proportional Hazards Model—Cumulative Exposure and Sensitization

VariableCoefficient95% Confidence intervalP-value
Cumulative Exposure (μg/m3-yrs)0.0310.00 to 0.0630.05
constant−3.48−4.27 to −2.69<0.001
1996−1.49−3.04 to 0.060.06
1997−0.29−1.31 to 0.720.57
1998−1.56−3.11 to −0.010.05
1999−1.57−3.12 to −0.020.05

Table VI-10—Proportional Hazards Model—LTW Average Exposure and Sensitization

VariableCoefficient95% Confidence intervalP-value
Average Exposure (μg/m3)0.54−0.09 to 1.170.09
constant−3.55−4.42 to −2.69<0.001
1996−1.48−3.03 to 0.070.06
1997−0.29−1.31 to 0.720.57
1998−1.54−3.09 to 0.010.05
1999−1.53−3.08 to 0.030.05

Table VI-11—Proportional Hazards Model—Exposure Duration and Sensitization

VariableCoefficient95% Confidence intervalP-value
Exposure Duration (years)0.03−0.03 to 0.080.31
constant−3.55−4.57 to −2.53<0.001
1996−1.48−3.03 to 0.700.06
1997−0.30−1.31 to 0.720.57
1998−1.59−3.14 to −0.040.05
1999−1.62−3.17 to −0.720.04

Table VI-12—Proportional Hazards Model—HEJ Exposure and Sensitization

VariableCoefficient95% Confidence intervalP-value
HEJ Exposure (μg/m3)0.31−0.27 to 0.880.30
constant−3.42−4.27 to −2.56<0.001
1996−1.49−3.04 to 0.060.06
1997−0.31−1.33 to 0.700.55
1998−1.59−3.14 to −0.040.05
1999−1.60−3.15 to −0.050.04
Start Printed Page 47639

The proportional hazards models for the CBD endpoint (Tables VI-13 through 16 below) showed positive relationships with cumulative exposure (p = 0.09) and duration of exposure (p = 0.10). However, the association with the cumulative exposure metric was not as strong as that for sensitization, probably due to the smaller number of CBD cases. LTW average exposure and HEJ exposure were not closely related to relative risk of CBD (p-values > 0.5).

Table VI-13—Proportional Hazards Model—Cumulative Exposure and CBD

VariableCoefficient95% Confidence intervalP-value
Cumulative Exposure (μg/m3-yrs)0.03.00 to 0.070.09
constant−3.77−4.67 to −2.86<0.001
1997−0.59−1.86 to 0.680.36
1998−2.01−4.13 to 0.110.06
1999−0.63−1.90 to 0.640.33
2002−2.13−4.25 to −0.010.05

Table VI-14—Proportional Hazards Model—LTW Average Exposure and CBD

VariableCoefficient95% Confidence intervalP-value
Average Exposure (μg/m3)0.24−0.59 to 1.060.58
constant−3.62−4.60 to −2.64<0.001
1997−0.61−1.87 to 0.660.35
1998−2.02−4.14 to 0.100.06
1999−0.64−1.92 to 0.630.32
2002−2.15−4.28 to −0.020.05

Table VI-15—Proportional Hazards Model—Exposure Duration and CBD

VariableCoefficient95% Confidence intervalP-value
Exposure Duration (yrs)0.05−0.01 to 0.110.10
constant−4.18−5.40 to −2.96<0.001
1997−0.531.84 to 0.690.38
1998−2.01−4.13 to 0.110.06
1999−0.67−1.94 to 0.600.30
2002−2.22−4.34 to −0.100.04

Table VI-16—Proportional Hazards Model—HEJ Exposure and CBD

VariableCoefficient95% Confidence intervalP-value
HEJ Exposure (μg/m3)0.03−0.70 to 0.770.93
constant−3.49−4.45 to −2.53<0.001
1997−0.62−1.88 to 0.650.34
1998−2.05−4.16 to 0.070.06
1999−0.68−1.94 to 0.590.30
2002−2.21−4.33 to −0.090.04

In addition to the models reported above, comparable models were fit to the upper 95 percent confidence interval of the HEJ exposure; log-transformed cumulative exposure; log-transformed LTW average exposure; and log-transformed HEJ exposure. Each of these measures was positively but not significantly associated with sensitization.

OSHA used the proportional hazards models based on cumulative exposure, shown in Tables VI-9 and VI-13, to derive quantitative risk estimates. Of the metrics related to exposure level, the cumulative exposure metric showed the most consistent association with sensitization and CBD in these models. Table VI-17 summarizes these risk estimates for sensitization and the corresponding 95 percent confidence intervals separately for 1995 and 1999, the years with the highest and lowest baseline rates, respectively. The estimated risks for CBD are presented in VI-18. The expected number of cases is based on the estimated conditional probability of being a case in the given year. The models provide time-specific point estimates of risk for a worker with any given exposure level, and the corresponding interval is based on the uncertainty in the exposure coefficient (i.e., the predicted values based on the 95 percent confidence limits for the exposure coefficient).

Each estimate represents the number of sensitized workers the model predicts in a group of 1000 workers at risk during the given year with an exposure history at the specified level and duration. For example, in the exposure scenario where 1000 workers are occupationally exposed to 2 μg/m3 for 10 years in 1995, the model predicts that about 56 (55.7) workers would be sensitized that year. The model for CBD predicts that about 42 (41.9) workers would be diagnosed with CBD that year.Start Printed Page 47640

Table VI-17a—Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient

[1995 Baseline]

1995 Exposure level (μg/m3)Exposure duration
5 years10 years20 years45 years
Cumulative (μg/m3-yrs)cases/ 1000μg/m3-yrscases/ 1000μg/m3-yrscases/ 1000μg/m3-yrscases/ 1000
2.010.041.1 30.3-56.220.055.7 30.3-102.940.0101.0 30.3-318.190.0394.4 30.3-999.9
1.05.035.3 30.3-41.310.041.1 30.3-56.220.055.7 30.3-102.945.0116.9 30.3-408.2
0.52.532.7 30.3-35.45.035.3 30.3-41.310.041.1 30.3-56.222.560.0 30.3-119.4
0.21.031.3 30.3-32.32.032.2 30.3-34.34.034.3 30.3-38.99.039.9 30.3-52.9
0.10.530.8 30.3-31.31.031.3 30.3-32.32.032.2 30.3-34.34.534.8 30.3-40.1

Table VI-17b—Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient

[1999 Baseline]

1999 Exposure level (μg/m3)Exposure duration
5 years10 years20 years45 years
Cumulative (μg/m3-yrs)cases/ 1000μg/m3-yrscases/ 1000μg/m3-yrscases/ 1000μg/m3-yrscases/ 1000
2.010.08.4 6.2-11.620.011.5 6.2-21.740.021.3 6.2-74.490.096.3 6.2-835.4
1.05.07.2 6.2-8.510.08.4 6.2-11.620.011.5 6.2-21.745.024.8 6.2-100.5
0.52.56.7 6.2-7.35.07.2 6.2-8.510.08.4 6.2-11.622.512.4 6.2-25.3
0.21.06.4 6.2-6.62.06.6 6.2-7.04.07.0 6.2-8.09.08.2 6.2-10.9
0.10.56.3 6.2-6.41.06.4 6.2-6.62.06.6 6.2-7.04.57.1 6.2-8.2

Table VI-18a—Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient

[1995 baseline]

1995 Exposure level (μg/m3)Exposure duration
5 years10 years20 years45 years
Cumulative (μg/m3-yrs)Estimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.
30.941.976.6312.9
2.010.022.8-44.020.022.8-84.340.022.8-285.590.022.8-999.9
26.630.941.988.8
1.05.022.8-31.710.022.8-44.020.022.8-84.345.022.8-375.0
24.626.630.945.2
0.52.522.8-26.95.022.8-31.710.022.8-44.022.522.8-98.9
23.524.225.830.0
0.21.022.8-24.32.022.8-26.04.022.8-29.79.022.8-41.3
23.123.524.226.2
0.10.522.8-23.61.022.8-24.32.022.8-26.04.522.8-30.7
Start Printed Page 47641

Table VI-18b—Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient

[2002 baseline]

2002 Exposure level (μg/m3)Exposure duration
5 years10 years20 years45 years
Cumulative (μg/m3-yrs)Estimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.μg/m3-yrsEstimated cases/1000 95% c.i.
3.75.19.443.6
2.010.02.7-5.320.02.7-10.440.02.7-39.290.02.7-679.8
3.23.75.111.0
1.05.02.7-3.810.02.7-5.320.02.7-10.445.02.7-54.3
3.03.23.75.5
0.52.52.7-3.25.02.7-3.810.02.7-5.322.52.7-12.3
2.82.93.13.6
0.21.02.7-2.92.02.7-3.14.02.7-3.69.02.7-5.0
2.82.82.93.1
0.10.52.7-2.81.02.7-2.92.02.7-3.14.52.7-3.7

The statistical modeling analysis predicts high risk of both sensitization (96-394 cases per 1000, or 9.6-39.4 percent) and CBD (44-313 cases per 1000, or 4.4-31.3 percent) at the current PEL of 2 μg/m3 for an exposure duration of 45 years (90 μg/m3-yr). The predicted risks of < 8.2-39.9 per 1000 (0.8-3.9 percent) cases of sensitization or 3.6 to 30.0 per 1000 (0.4-3 percent) cases of CBD are substantially less for a 45-year exposure at the proposed PEL, 0.2 μg/m3 (9 μg/m3-yr).

The model estimates are not directly comparable to prevalence values discussed in previous sections. They assume a group without turnover and are based on a comparison of unexposed and hypothetically exposed workers at specific points in time, whereas the prevalence analysis simply reports the percentage of workers at the Cullman plant with sensitization or CBD in each exposure category. Despite the difficulty of direct comparison, the level of risk seen in the prevalence analysis and predicted in the modeling analysis appear roughly similar at low exposures. In the second quartile of cumulative exposure (0.148-1.467 μg/m3-yr), prevalence of sensitization and CBD was 2.5 percent. This is roughly congruent with the model predictions for workers with cumulative exposures between 0.5 and 1 μg/m3-yr: 6.3-31.3 cases of sensitization per 1000 workers (0.6-3.1 percent) and 2.8 to 23.5 cases of CBD per 1000 workers (0.28-2.4 percent). As discussed in the background document for this analysis, most workers in the data set had low cumulative exposures (roughly half below 1.5 μg/m3-years). It is difficult to make any statement about the results at higher levels, because there were few workers with high exposure levels and the higher quartiles of cumulative exposure include an extremely wide range of exposures. For example, the highest quartile of cumulative exposure was 7.009-61.86 μg/m3-yr. This quartile, which showed an 11.3 percent prevalence of sensitization and 8.8 percent prevalence of CBD, includes the cumulative exposure that a worker exposed for 45 years at the proposed PEL would experience (9 μg/m3-yr) near its lower bound. Its upper bound approaches the cumulative exposure that a worker exposed for 45 years at the current PEL would experience (90 μg/m3-yr).

Due to limitations including the size of the dataset, relatively limited exposure data from the plant's early years, study size-related constraints on the statistical analysis of the dataset, and limited follow-up time on many workers, OSHA must interpret the model-based risk estimates presented in Tables VI-17 and VI-18 with caution. The Cullman study population is a relatively small group and can support only limited statistical analysis. For example, its size precludes inclusion of multiple covariates in the exposure-response models or a two-stage exposure-response analysis to model both sensitization and the subsequent development of CBD within the subpopulation of sensitized workers. The limited size of the Cullman dataset is characteristic of studies on beryllium-exposed workers in modern, low-exposure environments, which are typically small-scale processing plants (up to several hundred workers, up to 20-30 cases). However, these recent studies also have important strengths: They include workers hired after the institution of stringent exposure controls, and have extensive exposure sampling using full-shift personal lapel samples. In contrast, older studies of larger populations tend to have higher exposures, less exposure data, and exposure data collected in short-term samples or outside of workers' breathing zones.

Another limitation of the Cullman dataset, which is common to recent low-exposure studies, is the short follow-up time available for many of the workers. While in some cases CBD has been known to develop in short periods (< 2 years), it more typically develops over a longer time period. Sensitization occurs in a typically shorter time frame, but new cases of sensitization have been observed in workers exposed to beryllium for many years. Because the data set is limited to individuals then working at the plant, the Cullman data set cannot capture CBD occurring among workers who retire or leave the plant. OSHA expects that the dataset does not fully represent the risk of sensitization, and is likely to particularly under-represent CBD among workers exposed to beryllium at this facility. The Agency believes the short follow-up time to be a significant source of uncertainty in the statistical analysis, a factor likely to lead to underestimation of risk in this population.

A common source of uncertainty in quantitative risk assessment is the series of choices made in the course of statistical analysis, such as model type, inclusion or exclusion of additional explanatory variables, and the assumption of linearity in exposure-response. Sensitivity analyses and statistical checks were conducted to test the validity of the choices and Start Printed Page 47642assumptions in the exposure-response analysis and the impact of alternative choices on the end results. These analyses did not yield substantially different results, adding to OSHA's confidence in the conclusions of its preliminary risk assessment.

OSHA's contractor examined whether smoking and age were confounders in the exposure-response analysis by adding them as variables in the discrete proportional hazards model. Neither smoking status nor age was a statistically significant predictor of sensitization or CBD. The model coefficients, 95 percent confidence intervals, and p values can be found in the background document. A sensitivity analysis was done using the standard Cox model that treats survival time as continuous rather than discrete. The model coefficients with the standard Cox using cumulative exposure were 0.025 and very similar to the 0.03 reported in Tables VI-9 and VI-13 above. The interaction between exposure and follow-up time was not significant in these models, suggesting that the proportional hazard assumption should not be rejected. The proportional hazards model assumes a linear relationship between exposure level and relative risk. The linearity assumption was assessed using a fractional polynomial approach. For both sensitization and CBD, the best-fitting fractional polynomial model did not fit significantly better than the linear model. This result supports OSHA's use of the linear model to estimate risk. The details of these statistical analyses can be found in the background document.

The possibility that the number of times a worker has been tested for sensitization might influence the probability of a positive test was examined (surveillance bias). Surveillance bias could occur if workers were tested because they showed some sign of disease, and not tested otherwise. It is also possible that the original analysis included erroneous assumptions about the dates of testing for sensitization and CBD. OSHA's contractor performed a sensitivity analysis, modifying the original analysis to gauge the effect of different assumptions about testing dates. In the sensitivity analysis, the exposure coefficients increased for all four indices of exposure when the sensitization analysis was restricted to times when cohort members were assumed to be tested. The exposure coefficient was statistically significant for duration of exposure but not for cumulative, LTW average, or HEJ exposure. The increase in exposure coefficients suggests that the original models may have underestimated the exposure-response relationship for sensitization and CBD.

Errors in exposure measurement are a common source of uncertainty in quantitative risk assessments. Because errors in high exposures can heavily influence modeling results, OSHA's contractor performed sensitivity analyses excluding the highest 5 percent of cumulative exposures (those above 25.265 μg/m3-yrs) and the highest 10 percent of cumulative exposures (those above 18.723 μg/m3-yrs). As discussed in more detail in the background document, exposure coefficients were not statistically significant when these exposures were dropped. This is not surprising, given that the exclusion of high exposure values reduced the size of the data set. Prior to excluding high exposure values, the data set was already relatively small and many of the exposure coefficients were non-significant or weakly significant in the original analyses. As a result, the sensitivity analyses did not provide much information about uncertainty due to exposure measurement error and its effects on the modeling analysis.

Particle size, particle surface area, and beryllium compound solubility are believed to be important factors influencing the risk of sensitization and CBD among beryllium-exposed workers. The workers at the Cullman machining plant were primarily handling insoluble beryllium compounds, such as beryllium metal and beryllium metal/beryllium oxide composites. Particle size distributions from a limited number of airborne beryllium samples collected just after the 1996 installation of engineering controls indicate worker exposure to a substantial proportion of respirable particulates. There was no available particle size data for the 1980 to 1995 period prior to installation of engineering controls when total beryllium mass exposure levels were greatest. Particle size data was also lacking from 1998 to 2003 when additional control measures were in place and total beryllium mass exposures were lowest. For these reasons, OSHA was not able to quantitatively account for the influence of particle size and solubility in developing the risk estimates based on the Cullman data set. However, it is not unreasonable to expect the CBD experienced by this cohort to generally reflect the risk from exposure to beryllium that is relatively insoluble and enriched with respirable particles. As explained previously, the role of particle size and surface area on risk of sensitization is more difficult to predict.

Additional uncertainty is introduced when extrapolating the quantitative estimates presented above to operations that process beryllium compounds that have different solubility and particle characteristics than those encountered at the Cullman machining plant. OSHA does not have sufficient information to quantitatively assess the degree to which risks of beryllium sensitization and CBD based on the NJMRC data may be impacted in workplaces where such beryllium forms and processes are used. However, OSHA does not expect this uncertainty to alter its qualitative conclusions with regard to the risk at the current PEL and at alternate PELs as low as 0.1 μg/m3. The existing studies provide clear evidence of sensitization and CBD risk among workers exposed to a number of beryllium forms as a result of different processes such as beryllium machining, beryllium-copper alloy production, and beryllium ceramics production. The Agency believes all of these forms of beryllium exposure contribute to the overall risk of sensitization and CBD among beryllium-exposed workers.

G. Lung Cancer

OSHA considers lung cancer to be an important health endpoint for beryllium-exposed workers. The International Agency for Research on Cancer (IARC), National Toxicology Program (NTP), and American Conference of Governmental Industrial Hygienists (ACGIH) have all classified beryllium as a known human carcinogen. The National Academy of Sciences (NAS), Environmental Protection Agency, the Agency for Toxic Substances and Disease Registry (ATSDR), the National Institute of Occupational Safety and Health (NIOSH), and other reputable scientific organizations have reviewed the scientific evidence demonstrating that beryllium is associated with an increased incidence of cancer. OSHA also has performed an extensive review of the scientific literature regarding beryllium and cancer. This includes an evaluation of human epidemiological, animal cancer, and mechanistic studies described in the Health Effects section of this preamble. Based on the weight of evidence, the Agency has preliminarily determined beryllium to be an occupational carcinogen.

Although epidemiological and animal evidence supports a conclusion of beryllium carcinogenicity, there is considerable uncertainty surrounding the mechanism of carcinogenesis for beryllium. The evidence for direct genotoxicity of beryllium and its compounds has been limited and Start Printed Page 47643inconsistent (NAS, 2008; IARC, 1993; EPA, 1998; NTP, 2002; ATSDR, 2002). One plausible pathway for beryllium carcinogenicity described in the Health Effects section of this preamble includes a chronic, sustained neutrophilic inflammatory response that induces epigenetic alterations leading to the neoplastic changes necessary for carcinogenesis. The National Cancer Institute estimates that nearly one-third of all cancers are caused by chronic inflammation (NCI, 2009). This mechanism of action has also been hypothesized for crystalline silica and other agents that are known to be human carcinogens but have limited evidence of genotoxicity.

OSHA's review of epidemiological studies of lung cancer mortality among beryllium workers found that most did not characterize exposure levels sufficiently for exposure-response analysis. However, one NIOSH study evaluated the association between beryllium exposure and lung cancer mortality based on data from a beryllium processing plant in Reading, PA (Sanderson et al., 2001a). As discussed in the Health Effects section of this preamble, this case-control study evaluated lung cancer incidence in a cohort of workers employed at the plant from 1940 to 1969 and followed through 1992. For each lung cancer victim, 5 age- and race-matched controls were selected by incidence density sampling, for a total of 142 lung cancer cases and 710 controls.

Between 1971 and 1992, the plant collected close to 7,000 high volume filter samples consisting of both general area and short-term, task-based breathing zone measurements for production jobs and exclusively area measurements for office, lunch, and laboratory areas (Sanderson et al., 2001b). In addition, a few (< 200) impinger and high-volume filter samples were collected by other organizations between 1947 and 1961, and about 200 6-to-8-hour personal samples were collected in 1972 and 1975. Daily-weighted-average (DWA) exposure calculations based on the impinger and high-volume samples collected prior to the 1960s showed that exposures in this period were extremely high. For example, about half of production jobs had estimated DWAs ranging between 49 and 131 μg/m3 in the period 1935-1960, and many of the “lower-exposed” jobs had DWAs of approximately 20-30 μg/m3 (Table II, Sanderson et al., 2001b). Exposures were reported to have decreased between 1959 and 1962 with the installation of ventilation controls and improved housekeeping and following the passage of the OSH Act in 1970. While no exposure measurements were available from the period 1961-1970, measurements from the period 1971-1980 showed a dramatic reduction in exposures plant-wide. Estimated DWAs for all jobs in this period ranged from 0.1 μg/m3 to 1.9 μg/m3. Calendar-time-specific beryllium exposure estimates were made for every job based on the DWA calculations and were used to estimate workers' cumulative, average, and maximum exposures. Exposure estimates were lagged by 10 and 20 years in order to account for exposures that did not contribute to lung cancer because they occurred after the induction of cancer.

Results of a conditional logistic regression analysis showed an increased risk of lung cancer in workers with higher exposures when dose estimates were lagged by 10 and 20 years (Sanderson et al., 2001a). The authors noted that there was considerable uncertainty in the estimation of exposure in the 1940s and 1950s and the shape of the dose-response curve for lung cancer. NIOSH later reanalyzed the data, adjusting for potential confounders of hire age and birth year (Schubauer-Berigan et al., 2008). The study reported a significant increasing trend (p<0.05) in the odds ratio when increasing quartiles of average (log transformed) exposure were lagged by 10 years. However, it did not find a significant trend when quartiles of cumulative (log transformed) exposure were lagged by 0, 10, or 20 years.

OSHA is interested in lung cancer risk estimates from a 45-year (i.e., working lifetime) exposure to beryllium levels between 0.1 μg/m3 and 2 μg/m3. The majority of case and control workers in the Sanderson et al. case-control analysis were first hired during the 1940s when exposures were extremely high (estimated DWAs > 20 μg/m3 for most jobs). The cumulative, average, and maximum beryllium exposure concentration estimates for the 142 known lung cancer cases were: 46.06 ± 9.3μg/m3-days, 22.8 ± 3.4 μg/m3, and 32.4 ± 13.8 μg/m3, respectively. About two-thirds of cases and half of controls worked at the plant for less than a year. Thus, a risk assessment based on this exposure-response analysis would need to extrapolate from very high to very low exposures, based on a working population with extremely short tenure. While OSHA risk assessments must often make extrapolations to estimate risk within the range of exposures of interest, the Agency acknowledges that these issues of short tenure and extremely high exposures would create substantial uncertainty in a risk assessment based on this study population.

In addition, the relatively high exposures of even the least-exposed workers in the NIOSH study may create methodological issues for the lung cancer case-control study design. Mortality risk is expressed as an odds ratio that compares higher exposure quartiles to the lowest quartile. It is preferable that excess risks attributable to occupational beryllium be determined relative to an unexposed or minimally exposed reference population. However, in the NIOSH study workers in the lowest quartile were exposed well above the OSHA PEL (average exposure <11.2 μg/m3) and may have had a significant lung cancer risk. This issue would introduce further uncertainty in lung cancer risks estimated from this epidemiological study.

In 2010, researchers at NIOSH published a quantitative risk assessment based on an update of the Reading cohort analyzed by Sanderson et al., as well as workers from two smaller plants (Schubauer-Berigan et al., 2010b). This new risk assessment addresses several of OSHA's concerns regarding the Sanderson et al. analysis. The new cohort was exposed, on average, to lower levels of beryllium and had fewer short-term workers. Finally, the updated cohorts followed the populations through 2005, increasing the length of follow-up time overall by an additional 17 years of observation. For these reasons, OSHA considers the Schubauer-Berigan risk analysis more appropriate than the Sanderson et al. analysis for its preliminary risk assessment.

The cohort studied by Schubauer-Berigan et al. included 5,436 male workers who had worked for at least two days at the Reading facility and beryllium processing plants at Hazleton PA and Elmore OH prior to 1970. The authors developed job-exposure matrices (JEMs) for the three plants based on extensive historical exposure data, primarily short-term general area and personal breathing zone samples, collected on a quarterly basis from a wide variety of operations. These samples were used to create daily weighted average (DWA) estimates of workers' full-shift exposures, using records of the nature and duration of tasks performed by workers during a shift. Details on the JEM and DWA construction can be found in Sanderson et al. (2001a), Chen et al. (2001), and Couch et al. (2010).

Workers' cumulative exposures (μg/m3-days) were estimated by summing daily average exposures (assuming five Start Printed Page 47644workdays per week). To estimate mean exposure (μg/m3), cumulative exposure was divided by exposure time (in days). Maximum exposure (μg/m3) was estimated as the highest annual DWA on record for a worker prior to the study cutoff date of December 31, 2005 and accounting where appropriate for lag time. Exposure estimates were lagged by 5, 10, 15, and 20 years in order to account for exposures that may not have contributed to lung cancer because of the long latency required for manifestation of the disease. The authors also fit models with no lag time. As shown in Table VI-19 below, estimated exposure levels for workers from the Hazleton and Elmore plants were on average far lower than those for workers from the Reading plant. The median worker from Hazleton had a mean exposure across his tenure of less than 2 µg/m3, while the median worker from Elmore had a mean exposure of less than 1 µg/m3. The Elmore and Hazleton worker populations also had fewer short-term workers than the Reading population. This was particularly evident at Hazleton where the median value for cumulative exposure among cases was higher than at Reading despite the much lower mean and maximum exposure levels.

Table VI-19—Cohort Description and Distribution of Cases by Exposure Level

All plantsReading plantHazleton plantElmore plant
Number of cases2932183045
Number of non-cases514333375831223
Median value for mean exposureNo lag15.42251.4430.885
(µg/m3) among cases10-year lag15.15251.4430.972
Median value for cumulative exposureNo lag2843289539681654
(µg/m3-days) among cases10-year lag2583283236481449
Median value for maximum exposureNo lag2525.13.152.17
(µg/m3) among cases10-year lag25253.152.17
Number of cases with potential asbestos exposure100 (34%)68 (31%)16 (53%)16 (36%)
Number of cases who were professional workers26 (9%)21 (10%)3 (10%)2 (4%)
Table adapted from Schubauer-Berigan et al. 2011, Table 1.

Schubauer-Berigan et al. analyzed the data set using a variety of exposure-response modeling approaches, including categorical analyses and continuous-variable piecewise log-linear and power models, described in Schubauer-Berigan et al. (2011). All models adjusted for birth cohort and plant. As exposure values were log-transformed for the power model analyses, the authors added small values to exposures of 0 in lagged analyses (0.05 µg/m3 for mean and maximum exposure, 0.05 µg/m3-days for cumulative exposure). The authors used restricted cubic spline models to assess the shape of the exposure-response curve and suggest appropriate parametric model forms. The Akaike Information Criterion (AIC) value was used to evaluate the fit of different model forms and lag times.

Because smoking information was available for only about 25 percent of the cohort, smoking could not be controlled for directly in the models. The authors reported that within the subset with smoking information, there was little difference in smoking by cumulative or maximum exposure category (p. 6), suggesting that smoking was unlikely to act as a confounder in the cohort. In addition to models based on the full cohort, Schubauer-Berigan et al. also prepared risk estimates based on models excluding professional workers and workers believed to have asbestos exposure. These models were intended to mitigate the potential impact of smoking and asbestos as confounders. If professional workers had both lower beryllium exposures and lower smoking rates than production workers, smoking could be a confounder in the cohort comprising both production and professional workers. However, the authors reasoned that smoking was unlikely to be correlated with beryllium exposure among production workers, and would therefore probably not act as a confounder in a cohort excluding professional workers.

The authors found that lung cancer risk was strongly and significantly related to mean, cumulative, and maximum measures of workers' exposure (all models reported in Schubauer-Berigan et al., 2011). They selected the best-fitting categorical, power, and monotonic piecewise log-linear (PWL) models with a 10-year lag to generate hazard ratios for male workers with a mean exposure of 0.5 µg/m[3] (the current NIOSH Recommended Exposure Limit for beryllium).[9] To estimate excess lifetime risk of cancer, they multiplied this hazard ratio by the 2004-2006 background lifetime lung cancer rate among U.S. males who had survived, cancer-free, to age 30. In addition, they estimated the mean exposure that would be associated with an excess lifetime risk of one in 1000, a value often used as a benchmark for significant risk in OSHA regulations. At OSHA's request, they also estimated excess lifetime risks for workers with mean exposures at the current PEL of 2 μg/m3 each of the other alternate PELs under consideration: 1 μg/m3, 0.2 μg/m3, and 0.1 μg/m3 (Schubauer-Berigan, 4/22/11). The resulting risk estimates are presented in Table VI-20 below.

Start Printed Page 47645

Table VI-20—Excess Lifetime Risk per 1000 [95% Confidence Interval] for Male Workers at Alternate PELs

[NIOSH models]

Exposure-response modelMean exposure
0.1 µg/m30.2 µg/m30.5 µg/m31 µg/m32 µg/m3
Best monotonic PWL—all workers7.3[2.0-13]15[3.3-29]45[9-98]120[20-340]200[29-370]
Best monotonic PWL—excluding professional and asbestos workers3.1[<0-11]6.4[<0-23]17[<0-74]39[39-230]61[<0-280]
Best categorical—all workers4.4[1.3-8]9[2.7-17]25[6-48]59[13-130]170[29-530]
Best categorical—excluding professional and asbestos workers1.4[<0-6.0]2.7[<0-12]7.1[<0-35]15[<0-87]33[<0-290]
Power model—all workers12[6-19]19[9.3-29]30[15-48]40[19-66]52[23-88]
Power model—excluding professional and asbestos workers19[8.6-31]30[13-50]49[21-87]68[27-130]90[34-180]

Schubauer-Berigan et al. discuss several strengths, weaknesses, and uncertainties of their analysis. Strengths include long (> 30 years) follow-up time for members of the cohort and the extensive exposure and work history data available for the development of exposure estimates for workers in the cohort. Among the weaknesses and uncertainties of the study are the limited information available on workers' smoking habits: smoking information was available only for workers employed in 1968, about 25 percent of the cohort. In addition, the JEMs used did not account for possible respirator use among workers in the cohort. The authors note that workers' exposures may therefore have been overestimated, and that overestimation may have been especially severe for workers with high estimated exposures. They suggest that overestimation of exposures for workers in highly exposed positions may have caused attenuation of the exposure-response curve in some models at higher exposures.

The NIOSH publication did not discuss the reasons for basing risk estimates on mean exposure rather than cumulative exposure that is more commonly used for lung cancer risk analysis. OSHA believes the decision may involve the nonmonotonic relationship NIOSH observed between cancer risk and cumulative exposure level. As discussed previously, workers from the Reading plant frequently had very short tenures and high exposures yielding lower cumulative exposures compared to cohort workers from other plants with longer employment. Despite the low estimated cumulative exposures among the short-term Reading workers, they may be at high risk of lung cancer due to the tendency of beryllium to persist in the lung for long periods. This exposure misclassification could lead to the appearance of a nonmonotonic relationship between cumulative exposure and lung cancer risk. It is possible that a dose-rate effect may exist for beryllium, such that the risk from a cumulative exposure gained by long-term, low-level exposure is not equivalent to the risk from a cumulative exposure gained by very short-term, high-level exposure. In this case, mean exposure level may better correlate with the risk of lung cancer than cumulative exposure level. For these reasons OSHA considers the NIOSH choice of mean exposure metric to be appropriate and scientifically defensible for this particular dataset.

H. Preliminary Conclusions

As described above, OSHA's risk assessment for beryllium sensitization and CBD relied on two approaches: (1) review of the literature and (2) analysis of a dataset provided by NJRMC. First, the Agency reviewed the scientific literature to ascertain whether there is substantial risk to workers exposed at and below the current PEL and to characterize the expected impact of more stringent controls on workers' risk of sensitization and CBD. This review focused on facilities where exposures were primarily below the current PEL, and where several rounds of BeLPT and CBD screening had been conducted to evaluate the effectiveness of various exposure control measures. Second, OSHA investigated the exposure-response relationship for beryllium sensitization and CBD by analyzing a dataset that NJMRC provided on workers at a prominent, long-established beryllium machining facility. Although exposure-response studies have been published on sensitization and CBD, OSHA believes the nature and quality of their exposure data significantly limits their value for the Agency's risk assessment. Therefore, OSHA developed an independent exposure-response analysis using the NJMRC dataset, which was recently updated, includes workers exposed at low levels, and includes extensive exposure data collected in workers' breathing zones, as is preferred by OSHA.

OSHA's review of the scientific literature found substantial risk of both sensitization and CBD in workplaces in compliance with OSHA's current PEL (e.g., Kreiss et al., 1992; Schuler et al., 2000; Madl et al., 2007). At these plants, including a copper-beryllium processing facility, a beryllia ceramics facility, and a beryllium machining facility, exposure reduction programs that primarily used engineering controls to reduce airborne exposures to median levels at or around 0.2 μg/m3 had only limited impact on workers' risk. Cases of sensitization continued to occur frequently among newly hired workers, and some of these workers developed CBD within the short follow-up time.

In contrast, industrial hygiene programs that minimized both airborne and dermal exposure substantially lowered workers' risk of sensitization in the first years of employment. Programs that drastically reduced respiratory exposure via a combination of engineering controls and respiratory protection, minimized the potential for skin exposure via dermal PPE, and employed stringent housekeeping methods to keep work areas clean and prevent transfer of beryllium between areas sharply curtailed new cases of sensitization among newly-hired workers. For example, studies conducted at copper-beryllium processing, beryllium production, and beryllia ceramics facilities show that reduction of exposures to below 0.1 μg/m3 and protection from dermal exposure, in combination, achieved a substantial reduction in sensitization risk among newly-hired workers. However, even these stringent measures did not protect all workers from sensitization.Start Printed Page 47646

The most recent epidemiological literature on programs that have been successful in reducing workers' risk of sensitization have had very short follow-up time; therefore, they cannot address the question of how frequently workers sensitized in very low-exposure environments develop CBD. Clinical evaluation for CBD was not reported for workers at the copper-beryllium processing, beryllium production, and ceramics facilities. However, cases of CBD among workers exposed at low levels at a machining plant and cases of CA-CBD demonstrate that individuals exposed to low levels of airborne beryllium can develop CBD, and over time, can progress to severe disease. This conclusion is also supported by case reports within the literature of workers with CBD who may have been minimally exposed to beryllium, such as a worker employed only in administration at a beryllium ceramics facility (Kreiss et al., 1996).

The Agency's analysis of the Cullman dataset provided by NJMRC showed strong exposure-response trends using multiple analytical approaches, including examination of sensitization and disease prevalence by exposure categories and a proportional hazards modeling approach. In the prevalence analysis, cases of sensitization and disease were evident at all levels of exposure. The lowest prevalence of sensitization (2.0 percent) and CBD (1.0 percent) was observed among workers with LTW average exposure levels below 0.1 μg/m3, while those with LTW average exposure between 0.1-0.2 μg/m3 showed a marked increase in overall prevalence of sensitization (9.8 percent) and CBD (7.3 percent). Prevalence of sensitization and CBD also increased with cumulative exposure.

OSHA's proportional hazards analysis of the Cullman dataset found increasing risk of sensitization with both cumulative exposure and average exposure. OSHA also found a positive relationship between risk of CBD and cumulative exposure, but not between CBD and average exposure. The Agency used the cumulative exposure model results to estimate hazards ratios and risk of sensitization and CBD at the current PEL of 2 μg/m3 and each of the alternate PELs under consideration: 1 μg/m3, 0.5 μg/m3, 0.2 μg/m3, and 0.1 μg/m3. To estimate risk of CBD from a working lifetime of exposure, the Agency calculated the cumulative exposure associated with 45 years of exposure at each level, for total cumulative exposures of 90, 45, 22.5, 9, and 4.5 μg/m3-years. The risk estimates for sensitization and CBD ranged from 100-403 and 40-290 cases, respectively, per 1000 workers exposed at the current PEL of 2 μg/m3. The risks are projected to be substantially lower for both sensitization and CBD at 0.1 μg/m3 and range from 7.2-35 cases per 1000 and 3.1-26 cases per 1000, respectively. In these ways, the modeling results are similar to results observed from published studies of the Reading, Tucson, and Cullman plants and the OSHA analysis of sensitization and CBD prevalence within the Cullman plant.

OSHA has a high level of confidence in the finding of substantial risk of sensitization and CBD at the current PEL, and the Agency believes that a standard requiring a combination of more stringent controls on beryllium exposure will reduce workers' risk of both sensitization and CBD. Programs that have reduced median levels to below 0.1 μg/m3, tightly controlled both respiratory and dermal exposure, and incorporated stringent housekeeping measures have substantially reduced risk of sensitization within the first years of exposure. These conclusions are supported by the results of several studies conducted in state-of-the-art facilities dealing with a variety of production activities and physical forms of beryllium. In addition, these conclusions are supported by OSHA's statistical analysis of a dataset with highly detailed exposure and work history information on several hundred beryllium workers. While there is uncertainty regarding the precision of model-derived risk estimates, they provide further evidence that there is substantial risk of sensitization and CBD associated with exposure at the current PEL, and that this risk can be substantially lessened by stringent measures to reduce workers' beryllium exposure levels.

Furthermore, OSHA believes that beryllium-exposed workers' risk of lung cancer will be reduced by more stringent control of airborne beryllium exposures. The risk estimates from NIOSH's recent lung cancer study, described above, range from 33 to 140 excess lung cancers per 1000 workers exposed at the current PEL of 2 μg/m3. The NIOSH risk assessment's six best-fitting models each predict substantial reductions in risk with reduced exposure, ranging from 3 to 19 excess lung cancers per 1000 workers exposed at the proposed PEL of 0.1 μg/m3. The evidence of lung cancer risk from NIOSH's risk assessment provides additional support for OSHA's preliminary conclusions regarding the significance of risk to workers exposed to beryllium levels at and below the current PEL. However, the lung cancer risks require a sizable low dose extrapolation below beryllium exposure levels experienced by workers in the NIOSH study. As a result, there is a greater uncertainty in the lung cancer risk estimates and lesser confidence in their significance of risk below the current PEL than with beryllium sensitization and CBD. The preliminary conclusions with regard to significance of risk are presented and further discussed in section VIII of the preamble.

VII. Expert Peer Review of Health Effects and Preliminary Risk Assessment

In 2010, Eastern Research Group, Inc. (ERG), under contract to the Occupational Safety and Health Administration (OSHA) ,[10] conducted an independent, scientific peer review of (1) a draft Preliminary Beryllium Health Effects Evaluation (OSHA, 2010a), (2) a draft Preliminary Beryllium Risk Assessment (OSHA, 2010b), and (3) two NIOSH study manuscripts (Schubauer-Berigan et al., 2011 and 2011a). This section of the preamble describes the review process and summarizes peer reviewers' comments and OSHA's responses.

ERG conducted a search for nationally recognized experts in the areas of occupational epidemiology, occupational medicine, toxicology, immunology, industrial hygiene/exposure assessment, and risk assessment/biostatistics as requested by OSHA. ERG sought experts familiar with beryllium health effects research and who had no conflict of interest (COI) or apparent bias in performing the review. Interested candidates submitted evidence of their qualifications and responded to detailed COI questions. ERG also searched the Internet to determine whether qualified candidates had made public statements or declared a particular bias regarding beryllium regulation.

From the pool of qualified candidates, ERG selected five experts to conduct the review, based on:

○ Their qualifications, including their degrees, years of relevant experience, number of related peer-reviewed publications, experience serving as a peer reviewer for OSHA or other government organizations, and committee and association memberships related to the review topic;

○ Lack of any actual, potential, or perceived conflict of interest; and

○ The need to ensure that the panel collectively was sufficiently broad and Start Printed Page 47647diverse to fairly represent the relevant scientific and technical perspectives and fields of knowledge appropriate to the review.

OSHA reviewed the qualifications of the candidates proposed by ERG to verify that they collectively represented the technical areas of interest. ERG then contracted the following experts to perform the review.

(1) John Balmes, MD, Professor of Medicine, University of California-San Francisco

Expertise: pulmonary and occupational medicine, CBD, occupational lung disease, epidemiology, occupational exposures, medical surveillance.

(2) Patrick Breysse, Ph.D., Professor, Johns Hopkins University Bloomberg School of Public Health

Expertise: industrial hygiene, occupational/environmental health engineering, exposure monitoring/analysis, biomarkers, beryllium exposure assessment

(3) Terry Gordon, Ph.D., Professor, New York University School of Medicine.

Expertise: inhalation toxicology, pulmonary disease, beryllium toxicity and carcinogenicity, CBD genetic susceptibility, mode of action, animal models.

(4) Milton Rossman, MD, Professor of Medicine, Hospital of the University of Pennsylvania School of Medicine.

Expertise: pulmonary and clinical medicine, immunology, beryllium sensitization, BeLPT, clinical diagnosis for CBD.

(5) Kyle Steenland, Ph.D., Professor, Emory University, Rollins School of Public Health.

Expertise: occupational epidemiology, biostatistics, risk and exposure assessment, lung cancer, CBD, exposure-response models.

Reviewers were provided with the Technical Charge and Instructions (see ERG, 2010), a Request for Peer Review of NIOSH Manuscripts (see ERG, 2010), the draft Preliminary OSHA Health Effects Evaluation (OSHA, 2010a), the draft Preliminary Beryllium Risk Assessment (OSHA, 2010b), and access to relevant references. Each reviewer independently provided comments on the Health Effects, Risk Assessment, and NIOSH documents. A briefing call was held early in the review to ensure that reviewers understood the peer review process. ERG organized the call and OSHA representatives were available to respond to technical questions of clarification. Reviewers were invited to submit any subsequent questions of clarification.

The written comments from each reviewer were received and organized by ERG by charge questions. The unedited individual and reorganized comments were submitted to OSHA and the reviewers in preparation for a follow-up conference call. The conference call, organized and facilitated by ERG, provided an opportunity for OSHA to clarify individual reviewer's comments. After the call, reviewers were given the opportunity to revise their written comments to include the clarifications or additional information provided on the call. ERG submitted the revised comments to OSHA organized by both individual reviewer and by charge question. A final peer review report is available in the docket (ERG, 2010). Section VII.A of this preamble summarizes the comments received on the draft health effects document and OSHA's responses to those comments. Section VII.B summarizes comments received on the draft Preliminary Risk Assessment and the OSHA response.

A. Peer Review of Draft Health Effects Evaluation

The Technical Charge to peer reviewers posed general questions on the draft health effects document as well as specific questions pertaining to particle/chemical properties, kinetics and metabolism, acute beryllium disease, development of beryllium sensitization and CBD, genetic susceptibility, epidemiological studies of sensitization and CBD, animal models of chronic beryllium disease, genotoxicity, lung cancer epidemiological studies, animal cancer studies, other health effects, and preliminary conclusions drawn by OSHA.

OSHA asked the peer reviewers to generally comment on whether the draft health effects evaluation included the important studies, appropriately addressed their strengths and limitations, accurately described the results, and drew scientifically sound conclusions. Overall, the reviewers felt that the studies were described in sufficient detail, the interpretations accurate, and the conclusions reasonable. They agreed that the OSHA document covered the significant health endpoints related to occupational beryllium exposure. However, several reviewers requested that additional studies and other specific information be included in various sections of the document and these are discussed further below.

The reviewers had similar suggestions to improve the section V.A of this preamble on physical/chemical properties and section V.B on kinetics/metabolism. Dr. Balmes requested that physical and chemical characteristics of beryllium more clearly relate to development of sensitization and progression to CBD. Dr. Gordon requested greater consistency in the terminology used to describe particle characteristics, sampling methodologies, and the particle deposition in the respiratory tract. Dr. Breysse agreed and requested that the respiratory deposition discussion be better related to the onset of sensitization and CBD. Dr. Rossman suggested that the discussion of particle/chemical characteristics might be better placed after section V.D on the immunobiology of sensitization and CBD.

OSHA made a number of revisions to sections V.A and V.B to address the peer review comments above. Terminology used to describe particle characteristics in various studies was modified to be more consistent and better reflect the authors' intent in the published research articles. Section V.B.1 on respiratory kinetics of inhaled beryllium was modified to more clearly describe particle deposition in the different regions of the respiratory tract and their influence on CBD. At the recommendation of Dr. Gordon, a confusing figure was removed since it did not portray particle deposition in a clear manner. Rather than relocate the entire discussion of particle/chemical characteristics, a new section V.B.5 was added to specifically address the influence of beryllium particle characteristics and chemical form on the development of sensitization and CBD. Other section areas were shortened to remove information that was not necessarily relevant to the overall disease process. Statements were added on the effect of pre-existing diseases and smoking on beryllium clearance from the lung. It was made clear that the precise role of dermal exposure in beryllium sensitization is not completely understood. These smaller changes were made at the request of individual reviewers.

There were a couple of comments from reviewers pertaining to acute beryllium disease (ABD). Dr. Rossman commented that ABD did not make the development of CBD more likely. He requested that the document include a reference to the Van Ordstrand et al. (1943) article that first reported ABD in the U.S. Dr. Balmes pointed out that pathologists, rather than clinicians, interpret ABD pathology from lung tissue biopsy. Dr. Gordon commented that ABD is of lesser importance than CBD to the risk assessment and suggested that discussion of ABD be moved later in the document.

The Van Ordstrand reference was included in section V.C on acute beryllium diseases and statements were modified to address the peer review comments above. While OSHA agrees that ABD does not have a great impact on the Agency risk findings, the Agency believes the current organization does Start Printed Page 47648not create confusion on this point and decided not to move the ABD section later in the document. A statement that ABD is only relevant at exposures higher than the current PEL has been added to section V.C. Other reviewers did not feel the ABD discussion needed to be moved to a later section.

Most reviewers found the description of the development and pathogenesis of CBD in section V.D to be accurate and understandable. Dr. Breysse felt the section could better delineate the steps in disease development (e.g., development of beryllium sensitization, CBD progression) and recommended the 2008 National Academy of Sciences report as a model. He and Dr. Gordon felt the section overemphasized the role of apoptosis in CBD development. Dr. Breysse and Dr. Balmes recommended avoiding the phrase `subclinical' to describe sensitization and asymptomatic CBD, preferring the term `early stage' as a more appropriate description. Dr. Balmes requested clarification regarding accumulation of inflammatory cells in the bronchoalveolar lavage (BAL) fluid during CBD development. Dr. Rossman suggested some additional description of beryllium binding with the HLA-class II receptor and subsequent interaction with the naïve CD4+ T cells in the development of sensitization.

OSHA extensively reorganized section V.D to clearly delineate the disease process in a more linear fashion starting with the formation of beryllium antigen complex, its interaction with naïve T-cells to trigger CD4+ T-cell proliferation, and development of beryllium sensitization. This is presented in section V.D.1. A figure has been added that schematically presents this process in its entirety and the steps at which dermal exposure and genetic factors are believed to influence disease development (Figure 2 in section V.D). Section V.D.2 describes how subsequent inhalation and the persistent residual presence of beryllium in the lung leads to CD4+ T cell differentiation, cytokine production, accumulation of inflammatory cells in the alveolar region, granuloma formation, and progression of CBD. The section was modified to present apoptosis as only one of the plausible mechanisms for development/progression of CBD. The `early stage' terminology was adopted and the role of inflammatory cells in BAL was clarified.

While peer reviewers felt genetic susceptibility was adequately characterized, Dr. Rossman, Dr. Gordon, and Dr. Breysse suggested that additional study data be discussed to provide more depth on the subject, particularly the role genetic polymorphisms in providing a negatively charged HLA protein binding site for the positively charged beryllium ion. Section V.D.3 on genetic susceptibility now includes more information on the importance of gene-environment interaction in the development of CBD in low-exposed workers. The section expands on HLA-DPB1 alleles that influence beryllium-hapten binding and its impact on CBD risk.

All reviewers found the definition of CBD to be clear and understandable. However, several reviewers commented on the document discussion of the BeLPT which operationally defines beryllium sensitization. Drs. Balmes and Rossman requested a more clear statement that two abnormal blood BeLPT results were generally necessary to confirm sensitization. Dr. Balmes and Dr. Breysse requested more discussion of historical changes in the BeLPT method that have led to improvement in test performance and reductions in interlaboratory variability. These comments were addressed in an expanded document section V.D.5.b on criteria for sensitization and CBD case definition following development of the BeLPT.

Reviewers made suggestions to improve presentation of the many epidemiological studies of sensitization and CBD in the draft health effects document. Dr. Breysse and Dr. Gordon recommended that common weaknesses that apply to multiple studies be more rigorously discussed. Dr. Gordon requested that the discussion of the Beryllium Case Registry be modified to clarify the case inclusion criteria. Most reviewers called for the addition of tables to assist in summarizing the epidemiological study information.

A paragraph has been added near the beginning of section V.D.5 that identifies the common challenges to interpreting the epidemiological evidence that supports the occurrence of sensitization and CBD at occupational beryllium exposures below the current PEL. These include studies with small numbers of subjects and CBD cases, potential exposure misclassification resulting from lack of personal and short-term exposure data prior to the late 1990s, and uncertain dermal contribution among other issues. Table A.1 summarizing the key sensitization and CBD epidemiological studies was added to this preamble in appendix A of section V. Subsection V.D.5.a on studies conducted prior to the BeLPT has been reorganized to more clearly present the need for the Registry prior to listing the inclusion criteria.

Several reviewers requested that the draft health effects document discuss additional occupational studies on sensitization and CBD. Dr. Balmes suggested including Bailey et al. (2010) on reduction in sensitization at a beryllium production plant and Arjomandi et al. (2010) on CBD among workers in a nuclear weapons facility. Dr. Breysse recommended adding a brief discussion of Taiwo et al. (2008) on sensitization in aluminum smelter workers. Dr. Gordon and Dr. Rossman suggested mention of Curtis, (1951) on cutaneous hypersensitivity to beryllium as important for the role of dermal exposure. Dr. Rossman also provided a reference to a number of other sensitization and CBD articles of historical significance.

The above studies have been incorporated in several subsections of V.D.5 on human epidemiological evidence. The 1951 Curtis study is mentioned in the introduction to section V.D.5 as evidence of sensitization from dermal exposure. The Bailey et al. (2010) study is discussed in subsection V.D.5.d on beryllium metal processing and alloy production. The Arjomandi et al. (2010) study is discussed subsection V.D.5.h on nuclear weapons facilities and cleanup of former facilities. The Taiwo et al. (2008) study is discussed in subsection V.D.5.i on aluminum smelting. The other historical studies of historical significance are referenced in subsection V.D.5.a on studies conducted prior to the BeLPT.

Dr. Gordon suggested that the draft health effects document make clear that limitations in study design and lack of an appropriate model limited extrapolation of animal findings to the human immune-based respiratory disease. Dr. Rossman also remarked on the lack of a good animal model that consistently demonstrates a specific cell-mediated immune response to beryllium. Section V.D.6 was modified to include a statement that lack of a dependable animal model combined with studies that used single doses, few animals or abbreviated observation periods have limited the utility of the data. Table A.2 was added that summarizes important information on key animal studies of beryllium-induced immune response and lung inflammation.

In general, peer reviewers considered the preliminary conclusions with regard to sensitization and CBD to be reasonable and well presented in the draft health effects evaluation. All reviewers agreed that the scientific evidence supports sensitization as a necessary condition and an early endpoint in the development of CBD. Start Printed Page 47649The peer reviewers did not consider the presented evidence to convincingly show lung burden to be an important dose metric. Dr. Gordon explained that some animal studies in dogs have indicated that lung dose does influence granuloma formation but the importance of dose relative to genetic susceptibility, and physical/chemical form is unclear. He suggested the document indicate that many factors, including lung burden, affect the pulmonary tissue response to beryllium particles in the workplace.

There were other suggested improvements to the preliminary conclusion section of the draft document. Dr. Breysse felt that presenting the range of observed prevalence from occupational studies would help support the Agency findings. He also recommended that the preliminary conclusions make clear that CBD is a very complex disease and certain steps involved in the onset and progression are not yet clearly understood. Dr. Rossman pointed out that a report from Mroz et al. (2009) updated information on the rate at which beryllium sensitized individuals progress to CBD.

A statement has been added to section V.D.7 on the preliminary sensitization and CBD conclusions to indicate that all facets of development and progression of sensitization and CBD are not fully understood. Study references and prevalence ranges were provided to support the conclusion that epidemiological evidence demonstrates that sensitization and CBD occur from present-day exposures below OSHA's PEL. Statements were modified to indicate animal studies provide important insights into the roles of chemical form, genetic susceptibility, and residual lung burden in the development of beryllium lung disease. Updated information on rate of progression from sensitization to CBD was also included.

Reviewers made suggestions to improve presentation of the epidemiological studies of lung cancer that were similar to their comments on the CBD studies. Dr. Steenland requested that a table summarizing the lung cancer studies be added. He also recommended that more emphasis be placed on the SMR results from the Ward et al. (1992) study. Dr. Balmes felt that more detail was presented on the animal cancer studies than necessary to convey the relevant message. All reviewers thought that the Schubauer-Berigan et al. (2010) cohort mortality study that addressed some of the shortcomings of earlier lung cancer mortality studies should be discussed in the health effects document.

The recent Schubauer-Berigan et al. (2010) study conducted by the NIOSH Division of Surveillance, Hazard Evaluations, and Field Studies is now described and discussed in section V.E.2 on human epidemiology studies. Table A.3 summarizing the range of exposure measurements, study strengths and limitations, and other key lung cancer epidemiological study information was added to the health effects preamble. Section V.E.3 on the animal cancer studies already contained several tables that present study data so OSHA decided a summary table was not needed in this section.

Reviewers were asked two questions regarding the OSHA preliminary conclusions on beryllium-induced lung cancer: was the inflammation mechanism presented in the lung cancer section reasonable; and were there other mechanisms or modes of action to be considered? All reviewers agreed that inflammation was a reasonable mechanistic presentation as outlined in the document. Dr. Gordon requested OSHA clarify that inflammation may not be the sole mechanism for carcinogenicity. OSHA inserted statements in section V.E.5 on the preliminary lung cancer conclusions clarifying that tumorigenesis secondary to inflammation is a reasonable mechanism of action but other plausible mechanisms independent of inflammation may also contribute to the lung cancer associated with beryllium exposure.

There were a few comments from reviewers on health effects other than sensitization/CBD and lung cancer in the draft document. Dr. Balmes requested that the term “beryllium poisoning” not be used when referring to the hepatic effects of beryllium. He also offered language to clarify that the cardiovascular mortality among beryllium production workers in the Ward study cohort was probably due to ischemic heart disease and not the result of impaired lung function. Dr. Gordon requested removal of references to hepatic studies from in vitro and intravenous administration done at very high dose levels of little relevance to the occupational exposures of interest to OSHA. These changes were made to section V.F on other health effects.

B. Peer Review of the Draft Preliminary Risk Assessment

The Technical Charge to peer reviewers for review of the draft preliminary risk assessment was to ensure OSHA selected appropriate study data, assessed the data in a scientifically credible manner, and clearly explained its analysis. Specific charge questions were posed regarding choice of data sets, risk models, and exposure metrics; the role of dermal exposure and dermal protection; construction of the job exposure matrix; characterization of the risk estimates and their uncertainties; and whether a quantitative assessment of lung cancer risk, in addition to sensitization and CBD, was warranted.

Overall, the peer reviewers were highly supportive of the Agency's approach and major conclusions. They offered valuable suggestions for revisions and additional analysis to improve the clarity and certain technical aspects of the risk assessment. These suggestions and the steps taken by OSHA to address them are summarized here. A final peer review report (ERG, 2010c) and a risk assessment background document (OSHA, 2014a) are available in the docket.

OSHA asked peer reviewers a series of questions regarding its selection of surveys from a beryllium ceramics facility, a beryllium machining facility, and a beryllium alloy processing facility as the critical studies that form the basis of the preliminary risk assessment. Research showed that these workplaces had well characterized and relatively low beryllium exposures and underwent plant-wide screenings for sensitization and CBD before and after implementation of exposure controls. The reviewers were requested to comment on whether the study discussions were clearly presented, whether the role of dermal exposure and dermal protection were adequately addressed, and whether the preliminary conclusions regarding the observed exposure-related prevalence and reduction in risk were reasonable and scientifically credible. They were also asked to identify other studies that should be reviewed as part of the sensitization/CBD risk assessment.

Every peer reviewer felt the key studies were appropriate and their selection clearly explained in the document. Every peer reviewer regarded the preliminary conclusions from the OSHA review of these studies to be reasonable and scientifically sound. This conclusion stated that substantial risk of sensitization and CBD were observed in facilities where the highest exposed processes had median full-shift beryllium exposures around 0.2 μg/m3 or higher and that the greatest reduction in risk was achieved when exposures for all processes were lowered to 0.1 μg/m3 or below.

The reviewers suggested that three additional studies be added to the risk assessment review of the Start Printed Page 47650epidemiological literature. Dr. Balmes felt the document would be strengthened by including the Bailey et al. (2010) investigation of sensitization in a population of workers at the beryllium metal, alloy, and oxide production plant in Elmore, OH and the Arjomandi et al. (2010) publication on a group of 50 sensitized workers from a nuclear plant. Dr. Breysse suggested the study by Taiwo et al. (2008) on sensitization among workers in four aluminum smelters be considered.

A new subsection VI.A.3 was added to the preliminary risk assessment that describes the changes in beryllium exposure measurements, prevalence of sensitization and CBD, and implementation of exposure controls between 1992 and 2006 at the Elmore plant. This subsection includes a discussion of the Bailey et al. study. A summary of the Taiwo et al. (2008) study was added as subsection VI.A.5. A discussion of the Arjomandi et al. (2010) study was added in subsection VI.B as evidence that sensitized workers with primarily low beryllium exposure go on to develop CBD. However, the low rates of CBD among this group of sensitized workers also suggest that low beryllium exposure may reduce CBD risk when compared to worker populations with higher exposure levels.

While the majority of reviewers stated that OSHA adequately addressed the role of dermal exposure in sensitization and the importance of dermal protection for workers, a few had additional suggestions for OSHA's discussion. Dr. Breysse and Dr. Gordon pointed out that because the beryllium exposure control programs featured steps to reduce both skin contact and inhalation, it was difficult to distinguish between the effects of reducing airborne and dermal exposure. A statement was added to subsection VI.B that concurrent implementation of respirator use, dermal protection and engineering changes made it difficult to attribute reduced risk to any single control measure. Since the Cullman plant did not require glove use, OSHA believes it to be the best data set available for evaluating the effects of airborne exposure control on risk of sensitization.

Dr. Breysse requested additional discussion of the role of respiratory protection in achieving reduction in risk. Dr. Gordon suggested some additional clarification regarding mean and median exposure measures. Additional information on respiratory programs and exposure measures (e.g., median, arithmetic and geometric means), where available, were presented for each of the studies discussed in subsection VI.A.

The peer reviewers generally agreed that it was reasonable to conclude that community-acquired CBD (CA-CBD) resulted from low beryllium exposures. Drs. Breysse, Balmes and others noted that higher short-term excursions could not be ruled out. Dr. Gordon suggested that genetic susceptibility may have a role in cases of CA-CBD. Dr. Rossman raised the possibility that some CA-CBD cases could occur from contact with beryllium workers. All these points were added to subsection VI.C.

OSHA asked the peer reviewers to evaluate the choice of the National Jewish Medical and Research Center (NJMRC) data set on the Cullman, AL machinist population as a basis for exposure-response analysis and the reliance on cumulative exposure as the basis for the exposure-response analysis of sensitization and CBD. All peer reviewers indicated that the choice of the NJMRC data set for exposure-response analysis was clearly explained and reasonable and that they knew of no better data set for the analysis. Dr. Rossman commented that the NJMRC data set was an excellent source of exposures to different levels of beryllium and testing and evaluation of the workers. Dr. Steenland and Dr. Gordon suggested that the results from the OSHA analysis of the NJMRC data be compared with the available data from the studies of other beryllium facilities discussed in the epidemiological literature analysis. While a rigorous quantitative comparison (e.g., meta analysis) is difficult due to differences in the study designs and data types available for each study, subsection VI.E.4 compares the results of OSHA's prevalence analysis from the Cullman data with results from studies of the Tucson and Reading facilities.

OSHA asked the peer reviewers to evaluate methods used to construct the job exposure matrix (JEM) and to estimate beryllium exposure for each worker in the NJMRC data set. The JEM procedure was briefly summarized in the review document and described in detail as part of a risk assessment technical background document made available to the reviewers (OSHA, 2014a). Dr. Balmes felt that a more thorough discussion of the JEM would strengthen the preamble document. Dr. Gordon requested information about values assigned exposures below the limit of detection. Dr. Steenland requested that both the preamble and technical background document contain additional information on aspects of the JEM construction such as the job categories, job-specific exposure values, how jobs were grouped, and how non-machining jobs were handled in the JEM. He suggested the entire JEM be included in the technical background document. OSHA greatly expanded subsection VI.E.2 on air sampling and JEM to include more detailed discussion of the JEM construction. Exposure values for machining and non-machining job titles were provided in Tables VI-4 and VI-5. The procedures and rationale for grouping job-specific measurements into four time periods was explained. Jobs were not grouped in the JEM; rather, individual exposure estimates were created for each job in the work history data set. The technical background document further clarifies the JEM construction and the full JEM is included as an appendix to the revised background document (OSHA, 2014a). Subsection VI.E.3 on worker exposure reconstruction contains further detail about the work histories.

Peer reviewers fully supported OSHA's choice of the cumulative exposure metric to estimate risk of CBD from the NJMRC data set. As explained by Dr. Steenland, “cumulative exposure is often the choice for many chronic diseases as opposed to average or highest exposure.” He pointed out that the cumulative exposure metric also fit the CBD data better than other metrics. The reviewers generally felt that short-term peak exposure was probably the measure of airborne exposure most relevant to risk of beryllium sensitization. However, peer reviewers agreed that data required to capture workers' short-term peak exposures and to relate the peak exposure levels to sensitization were not available. Dr. Breysse explained that “short-term (hrs to minutes) peak exposures may be important to sensitization risk, while long term averages are more important for CBD risk. Unfortunately data for short-term peak exposures may not exist.” Dr. Steenland explained that of the available metrics “cumulative exposure fits the sensitization data better than the two alternatives, and hence is the best metric.” Statements were added to subsection VI.E.3 to indicate that while short-term exposures may be highly relevant to risk of sensitization, the individual peak exposures leading up to onset of sensitization was not able to be determined in the NJRMC Cullman study.

Peer reviewers found the methods used in the statistical exposure-response analysis to be clearly described. With the exception of Dr. Steenland, reviewers believed that a detailed critique of the statistical approach was Start Printed Page 47651beyond their level of expertise. Dr. Steenland supported OSHA's overall approach to the risk modeling and recommended additional analyses to explore the sensitivity of OSHA's results to alternate choices and to test the validity of aspects of the analysis. Dr. Steenland recommended that the logistic regression used by OSHA as a preliminary first analysis be dropped as an inappropriate model for a situation where it is important to account for changing exposures and case onset over time. Instead, he suggested a sensitivity analysis in which exposure-response coefficients generated using a traditional Cox proportionate hazards model be compared to the discrete time Cox model analog (i.e., complementary log-log Cox model) used by OSHA. The sensitivity analysis would facilitate examination of the proportional hazard assumption implied by the use of these models. Dr. Steenland advocated that OSHA include a table that displayed the mean number of BeLPT tests for the study population in order to address whether the number of sensitization tests introduced a potential bias. He inquired about the possibility of determining a sensitization incidence rate using cumulative or average exposure. Dr. Steenland suggested that the model control for additional potential confounders, such as age, smoking status, race and gender. He wanted a more complete explanation of the model constant for the year of diagnosis in Tables VI-9 through VI-12 to be included in the preamble as it was in the technical background document. Dr. Steenland recommended a sensitivity analysis that excludes the highest 5 to 10 percent of cumulative exposures which might address potential model uncertainty at the high end exposures. He requested that the results of statistical tests for non-linearity be included and confidence intervals for the risk estimates in Tables VI-17 and VI-18 be determined.

Many of Dr. Steenland's comments were addressed in subsection VI.F on the statistical modeling. The logistic regression analysis was removed from the section. A sensitivity analysis using the standard Cox model that treats survival time as continuous rather than discrete was added to the risk assessment background document and results were described in subsection VI.F. The interaction between exposure and follow-up time was not significant in the models suggesting that the proportional hazard assumption should not be rejected. The model coefficients using the standard Cox model were similar to model coefficients for the discrete model. Given this, OSHA did not feel it necessary to further estimate risks using the continuous Cox model at specific exposure levels.

A table of the mean number of BeLPT tests across the study population was added to the risk assessment background document. Subsection VI.F describes the table results and its impact on the statistical modeling. Smoking status and age were included in the discrete Cox proportional hazards model and not found to be significant predictors of beryllium sensitization. However, the available study population composition did not allow a confounder analysis of race and gender. OSHA chose not to include a detailed explanation of the model constant for the year of diagnosis in the preamble section. OSHA agrees with Dr. Steenland that the risk assessment background document adequately describes the model terms. For that reason, OSHA prefers that the risk assessment preamble focus on the results and major points of the analysis and refer the reader to the more technical background document for an explanation of model parameters. The linearity assumption was assessed using a fractional polynomial approach. The best fitting polynomials did not fit significantly better than the linear model. The details of the analysis were included in the risk assessment background document. Tables VI-17 and VI-18 now include the upper 95 percent confidence limits on the model-predicted cases of sensitization and CBD for the current and alternative PELs.

Most peer reviewers felt the major uncertainties of the risk assessment were clearly and adequately discussed in the documents they reviewed. Dr. Breysse requested that the risk assessment cover potential underestimation of risk from exposure misclassification bias. He requested further discussion of the degree to which the risk estimates from the Cullman machining plant could be extrapolated to workplaces that use other physical (e.g., particle size) and chemical forms of beryllium. He went on to question the strength of evidence that insoluble forms of beryllium cause CBD. Dr. Breysse also suggested that the assumptions used in the risk modeling be consolidated and more clearly presented. Dr. Steenland felt that there was potential underestimation of CBD risk resulting from exclusion of former workers and case status of current workers after employment.

Discussion of these uncertainties was added in the final paragraphs of section VI.F. The section was modified to more clearly identify assumptions with regard to the risk modeling such as an assumed linearity in exposure-response and cumulative dose equivalency when extrapolating risks over a 45-year working lifetime. Section VI.F recognizes the uncertainties in risk that can result from reconstructing individual exposures with very limited sampling data prior to 1994. The potential exposure misclassification can limit the strength of exposure-response relationships and result in the underestimation of risk. A more technical discussion of modeling assumptions and exposure measurement error are provided in the risk assessment background document. Section VI.F points out that the NJMRC data set does not capture CBD that occurred among workers who retired or left the Cullman plant. This and the short follow-up time is a source of uncertainty that likely leads to underestimation of risk. The section indicates that it is not unreasonable to expect the risk estimates to generally reflect onset of sensitization and CBD from exposure to beryllium forms that are relatively insoluble and enriched with respirable particles as encountered at the Cullman machining plant. Additional uncertainty is introduced when extrapolating the risk estimates to beryllium compounds of vastly different solubility and particle characteristics. OSHA does not agree with the comment suggesting that the association between CBD and insoluble forms of beryllium is weak. The principle sources of beryllium encountered at the Cullman machining plant, the Reading copper beryllium processing plant and the Tucson ceramics plant where excessive CBD was observed are insoluble forms of beryllium, such as beryllium metal, beryllium alloy, and beryllium oxide.

Finally, OSHA asked the peer reviewers to evaluate its treatment of lung cancer in the earlier draft preliminary risk assessment (OSHA, 2010b). When that document was prepared, OSHA had elected not to conduct a lung cancer risk assessment. The Agency believed that the exposure-response data available to conduct a lung cancer risk assessment from a Sanderson et al. study of a Reading, PA beryllium plant by was highly problematic. The Sanderson study primarily involved workers with extremely high and short-term exposures above airborne exposure levels of interest to OSHA (2 μg/m3 and below).

Just prior to arranging the peer review, a NIOSH study was published by Schubauer-Berigan et al. updating the Reading, PA cohort studied by Sanderson et al. and adding cohorts Start Printed Page 47652from two additional plants in Elmore, OH and Hazleton, PA (Schubauer-Berigan, 2011). At OSHA's request, the peer reviewers reviewed this study to determine whether it could provide a better basis for lung cancer risk analysis than the Sanderson et al. study. The reviewers found that the NIOSH update addressed the major concerns OSHA had expressed about the Sanderson study. In particular, they pointed out that workers in the Elmore and Hazleton cohorts had longer tenure at the plants and experienced lower exposures than those at the Reading, PA plant. Dr. Steenland recommended that “OSHA consider the new NIOSH data and develop risk estimates for lung cancer as well as sensitization and CBD.” Dr. Breysse believed that the NIOSH data “suggest that a risk assessment for lung cancer should be conducted by OSHA and the results be compared to the CBD/sensitization risk assessment before recommending an appropriate exposure concentration.” While acknowledging the improvements in the quality of the data, other reviewers were more restrained in their support for quantitative estimates of lung cancer risk. Dr. Gordon stated that despite improvements, there was “still uncertainty associated with the paucity of data below the current PEL of 2 μg/m3.” Dr. Rossman noted that the NIOSH study “did not address the problem of the uncertainty of the mechanism of beryllium carcinogenicity.” He felt that the updated NIOSH lung cancer mortality data “should not change the Agency's rationale for choosing to establish its risk findings for the proposed rule on its analysis for beryllium sensitization and CBD.” Dr. Balmes agreed that “the agency will be on firmer ground by focusing on sensitization and CBD.”

The preliminary risk assessment preamble subsection VI.G on lung cancer includes a discussion of the quantitative lung cancer risk assessment published by NIOSH researchers in 2010 (Schubauer-Berigan, 2011). The discussion describes the lower exposure levels, longer tenure, fewer short-term workers and additional years of observation that make the data more suitable for risk assessment. NIOSH relied on several modeling approaches to show that lung cancer risk was significantly related to both mean and cumulative beryllium exposure. Subsection VI.G provides the excess lifetime lung cancer risks predicted from several best-fitting NIOSH models at beryllium exposures of interest to OSHA (Table VI-20). Using the piecewise log-linear proportional hazards model favored by NIOSH, there is a projected drop in excess lifetime lung cancer risks from approximately 61 cases per 1000 exposed workers at the current PEL of 2.0 μg/m3 to approximately 6 cases per 1000 at the proposed PEL of 0.2 μg/m3. Subsection VI.H on preliminary conclusions indicates that these projections support a reduced risk of lung cancer from more stringent control of beryllium exposures but that the lung cancer risk estimates are more uncertain than those for sensitization and CBD.

VIII. Significance of Risk

To promulgate a standard that regulates workplace exposure to toxic materials or harmful physical agents, OSHA must first determine that the standard reduces a “significant risk” of “material impairment.” The first part of this requirement, “significant risk,” refers to the likelihood of harm, whereas the second part, “material impairment,” refers to the severity of the consequences of exposure.

The Agency's burden to establish significant risk is based on the requirements of the OSH Act (29 U.S.C. 651 et seq). Section 3(8) of the Act requires that workplace safety and health standards be “reasonably necessary or appropriate to provide safe or healthful employment” (29 U.S.C. 652(8)). The Supreme Court, in the Benzene decision, interpreted section 3(8) to mean that “before promulgating any standard, the Secretary must make a finding that the workplaces in question are not safe” (Industrial Union Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607, 642 (1980) (plurality opinion)). Examining section 3(8) more closely, the Court described OSHA's obligation to demonstrate significant risk:

“[S]afe” is not the equivalent of “risk-free.” A workplace can hardly be considered “unsafe” unless it threatens the workers with a significant risk of harm. Therefore, before the Secretary can promulgate any permanent health or safety standard, he must make a threshold finding that the place of employment is unsafe in the sense that significant risks are present and can be eliminated or lessened by a change in practices (Id).

As the Court made clear, the Agency has considerable latitude in defining significant risk and in determining the significance of any particular risk. The Court did not specify a means to distinguish significant from insignificant risks, but rather instructed OSHA to develop a reasonable approach to making a 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,” (448 U.S. at 655) 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 . . . . [T]he 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 656).

Thus, 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 to evaluate exposed workers' risk of these impairments.

The OSH Act also requires that the Agency make a finding that the toxic material or harmful physical agent at issue causes material impairment to worker health. In that regard, the Act directs the Secretary of Labor to set standards based on the available evidence where no employee, over his/her working life time, will suffer from material impairment of health or functional capacity, even if such employee has regular exposure to the hazard, to the exent feasible (29 U.S.C. 655(b)(5)).

As with significant risk, what constitutes material impairment in any given case is a policy determination for which OSHA is given substantial leeway. “OSHA is not required to state with scientific certainty or precision the exact point at which each type of [harm] becomes a material impairment” (AFL-CIO v. OSHA, 965 F.2d 962, 975 (11th Cir. 1992)). Courts have also noted that OSHA should consider all forms and degrees of material impairment—not just death or serious physical harm—and that OSHA may act with a “pronounced bias towards worker safety” (Id; Bldg & Constr. Trades Dep't v. Brock, 838 F.2d 1258, 1266 (D.C. Cir. 1988)). OSHA's long-standing policy is to consider 45 years as a “working life,” Start Printed Page 47653over which it must evaluate material impairment and risk.

In formulating this proposed beryllium standard, OSHA has reviewed the best available evidence pertaining to the adverse health effects of occupational beryllium exposure, including lung cancer and chronic beryllium disease (CBD), and has evaluated the risk of these effects from exposures allowed under the current standard as well as the expected impact of the proposed standard on risk. Based on its review of extensive epidemiological and experimental research, OSHA has preliminarily determined that long-term exposure at the current Permissible Exposure Limit (PEL) would pose a significant risk of material impairment to workers' health, and that adoption of the new PEL and other provisions of the proposed rule will substantially reduce this risk.

A. Material Impairment of Health

In this preamble at section V, Health Effects, OSHA reviewed the scientific evidence linking occupational beryllium exposure to a variety of adverse health effects, including CBD and lung cancer. Based on this review, OSHA preliminarily concludes that beryllium exposure causes these effects. The Agency's preliminary conclusion was strongly supported by a panel of independent peer reviewers, as discussed in section VII.

Here, OSHA discusses its preliminary conclusion that CBD and lung cancer constitute material impairments of health, and briefly reviews other adverse health effects that can result from beryllium exposure. Based on this preliminary conclusion and on the scientific evidence linking beryllium exposure to both CBD and lung cancer, OSHA concludes that occupational exposure to beryllium causes “material impairment of health or functional capacity” within the meaning of the OSH Act.

1. Chronic Beryllium Disease

CBD is a respiratory disease in which the body's immune system reacts to the presence of beryllium in the lung, causing a progression of pathological changes including chronic inflammation and tissue scarring. CBD can also impair other organs such as the liver, skin, spleen, and kidneys and cause adverse health effects such as granulomas of the skin and lymph nodes and cor pulmonale (i.e., enlargement of the heart) (Conradi et al., 1971; ACCP, 1965; Kriebel et al., 1988a and b). In early, asymptomatic stages of CBD, small granulomatous lesions and mild inflammation occur in the lungs. Early stage CBD among some workers has been observed to progress to more serious disease even after the worker is removed from exposure (Mroz, 2009), probably because common forms of beryllium have slow clearance rates and can remain in the lung for years after exposure. Sood et al. has reported that cessation of exposure can sometimes have beneficial effects on lung function (Sood et al., 2004). However, this was based on a small study of six patients with CBD, and more research is needed to better determine the relationship between exposure duration and disease progression. In general, progression of CBD from early to late stages is understood to vary widely, responding differently to exposure cessation and treatment for different individuals (Sood, 2009; Mroz, 2009).

Over time, the granulomas can spread and lead to lung fibrosis (scarring) and moderate to severe loss of pulmonary function, with symptoms including a persistent dry cough and shortness of breath (Saber and Dweik, 2000). Fatigue, night sweats, chest and joint pain, clubbing of fingers (due to impaired oxygen exchange), loss of appetite, and unexplained weight loss may occur as the disease progresses. Corticosteroid therapy, in workers whose beryllium exposure has ceased, has been shown to control inflammation, ease symptoms (e.g., difficulty breathing, fever, cough, and weight loss) and in some cases prevent the development of fibrosis (Marchand-Adam et al., 2008). Thus early treatment can lead to CBD regression in some patients, although there is no cure (Sood, 2004). Other patients have shown short-term improvements from corticosteroid treatment, but then developed serious fibrotic lesions (Marchand-Adam et al., 2008). Once fibrosis has developed in the lungs, corticosteroid treatment cannot reverse the damage (Sood, 2009). Persons with late-stage CBD experience severe respiratory insufficiency and may require supplemental oxygen (Rossman, 1991). Historically, late-stage CBD often ended in death (NAS, 2008).

While the use of steroid therapy has mitigated CBD mortality, treatment with corticosteroids has side effects that need to be measured against the possibility of progression of disease (Trikudanathan and McMahon, 2008; Lipworth, 1999; Gibson et al., 1996; Zaki et al., 1987). Adverse effects associated with long-term corticosteroid use include, but are not limited to, increased risk of opportunistic infections (Lionakis and Kontoyiannis, 2003; Trikudanathan and McMahon, 2008); accelerated bone loss or osteoporosis leading to increased risk of fractures or breaks (Hamida et al., 2011; Lehouck et al., 2011; Silva et al., 2011; Sweiss et al., 2011; Langhammer et al., 2009); psychiatric effects including depression, sleep disturbances, and psychosis (Warrington and Bostwick, 2006; Brown, 2009); adrenal suppression (Lipworth, 1999; Frauman, 1996); ocular effects including cataracts, ocular hypertension, and glaucoma (Ballonzolli and Bourchier, 2010; Trikudanathan and McMahon, 2008; Lipworth, 1999); an increase in glucose intolerance (Trikudanathan and McMahon, 2008); excessive weight gain (McDonough et al., 2008; Torres and Nowson, 2007; Dallman et al., 2007; Wolf, 2002; Cheskin et al., 1999); increased risk of atherosclerosis and other cardiovascular syndromes (Franchimont et al., 2002); skin fragility (Lipworth, 1999); and poor wound healing (de Silva and Fellows, 2010). Studies relating the long-term effect of corticosteroid use for the treatment of CBD need to be undertaken to evaluate the treatment's overall effectiveness against the risk of adverse side effects from continued usage.

OSHA considers late-stage CBD to be a material impairment of health, as it involves permanent damage to the pulmonary system, causes additional serious adverse health effects, can have adverse occupational and social consequences, requires treatment associated with severe and lasting side effects, and may in some cases be life-threatening. Furthermore, OSHA believes that material impairment begins prior to the development of symptoms of the disease.

Although there are no symptoms associated with early-stage CBD, during which small lesions and inflammation appear in the lungs, the Agency has preliminarily concluded that the earliest stage of CBD is material impairment of health. OSHA bases this conclusion on evidence showing that early-stage CBD is a measurable change in the state of health which, with and sometimes without continued exposure, can progress to symptomatic disease. Thus, prevention of the earliest stages of CBD will prevent development of more serious disease. The OSHA Lead Standard established the Agency's position that a `subclinical' health effect may be regarded as a material impairment of health. In the preamble to that standard, the Agency said:

OSHA believes that while incapacitating illness and death represent one extreme of a spectrum of responses, other biological effects such as metabolic or physiological changes are precursors or sentinels of disease which should be prevented . . . Rather than revealing beginnings of illness the standard must be selected to prevent an earlier point Start Printed Page 47654of measurable change in the state of health which is the first significant indicator of possibly more severe ill health in the future. The basis for this decision is twofold—first, pathophysiologic changes are early stages in the disease process which would grow worse with continued exposure and which may include early effects which even at early stages are irreversible, and therefore represent material impairment themselves. Secondly, prevention of pathophysiologic changes will prevent the onset of the more serious, irreversible and debilitating manifestations of disease.[11] (43 FR 52952, 52954, November 14, 1978)

Since the Lead rulemaking, OSHA has also found other non-symptomatic health conditions to be material impairments of health. In the Bloodborne Pathogens (BP) rulemaking, OSHA maintained that material impairment includes not only workers with clinically “active” hepatitis from the hepatitis B virus (HBV) but also includes asymptomatic HBV “carriers” who remain infectious and are able to put others at risk of serious disease through contact with body fluids (e.g., blood, sexual contact) (56 FR 64004, December 6, 1991). OSHA stated: “Becoming a carrier [of Hepatitis B] is a material impairment of health even though the carrier may have no symptoms. This is because the carrier will remain infectious, probably for the rest of his or her life, and any person who is not immune to HBV who comes in contact with the carrier's blood or certain other body fluids will be at risk of becoming infected” (56 FR 64004, 64036).

OSHA preliminarily finds that early-stage CBD is the type of asymptomatic health effect the Agency determined to be a material impairment of health in the lead standard. Early stage CBD involves lung tissue inflammation without symptomatology that can worsen with—or without—continued exposure. The lung pathology progresses over time from a chronic inflammatory response to tissue scarring and fibrosis accompanied by moderate to severe loss in pulmonary function. Early stage CBD is clearly a precursor of advanced clinical disease, prevention of which will prevent symptomatic disease. OSHA argued in the Lead standard that such precursor effects should be considered material health impairments in their own right, and that the Agency should act to prevent them when it is feasible to do so. Therefore, OSHA preliminarily finds all stages of CBD to be material impairments of health.

2. Lung Cancer

OSHA considers lung cancer, a frequently fatal disease, to be a material impairment of health. OSHA's finding that inhaled beryllium causes lung cancer is based on the best available epidemiological data, reflects evidence from animal and mechanistic research, and is consistent with the conclusions of other government and public health organizations (see this preamble at section V, Health Effects). For example, the International Agency for Research on Cancer (IARC), National Toxicology Program (NTP), and American Conference of Governmental Industrial Hygienists (ACGIH) have all classified beryllium as a known human carcinogen (IARC, 2009).

The Agency's epidemiological evidence comes from multiple studies of U.S. beryllium workers (Sanderson et al., 2001a; Ward et al., 1992; Wagoner et al., 1980; Mancuso et al., 1979). Most recently, a NIOSH cohort study found significantly increased lung cancer mortality among workers at seven beryllium processing facilities (Schubauer-Berigan et al., 2011). The cohort was exposed, on average, to lower levels of beryllium than those in most previous studies, had fewer short-term workers, and had sufficient follow-up time to observe lung cancer in the population. OSHA considers the Schubauer-Berigan study to be the best available epidemiological evidence regarding the risk of lung cancer from beryllium at exposure levels near the PEL.[12]

Supporting evidence of beryllium carcinogenicity comes from various animal studies as well as in vitro genotoxicity and other studies (EPA, 1998; ATSDR, 2002; Gordon and Bowser, 2003; NAS, 2008; Nickell-Brady et al., 1994; NTP, 1999 and 2005; IARC, 1993 and 2009). Multiple mechanisms may be involved in the carcinogenicity of beryllium, and factors such as epigenetics, mitogenicity, reactive oxygen-mediated indirect genotoxicity, and chronic inflammation may contribute to the lung cancer associated with beryllium exposure, although the results of studies testing the direct genotoxicity of beryllium are mixed (EPA summary, 1998). While there is uncertainty regarding the exact mechanism of carcinogenesis for beryllium, the overall weight of evidence for the carcinogenicity of beryllium is strong. Therefore, the Agency has preliminarily determined beryllium to be an occupational carcinogen.

3. Other Impairments

While OSHA has relied primarily on the relationship between occupational beryllium exposure and CBD and lung cancer to demonstrate the necessity of the standard, the Agency has also determined that several other adverse health effects can result from exposure to beryllium. Inhalation of high airborne concentrations of beryllium (well above the 2 μg/m3 OSHA PEL) can cause acute beryllium disease, a severe (sometimes fatal), rapid-onset inflammation of the lungs. Hepatic necrosis, damage to the heart and circulatory system, chronic renal disease, mucosal irritation and ulceration, and urinary tract cancer have also reportedly been associated with occupational exposures well above the current PEL (see this preamble at section V, Health Effects, subsection E, Epidemiological Studies, and subsection F, Other Health Effects). These adverse systemic effects and acute beryllium disease mostly occurred prior to the introduction of occupational and environmental standards set in 1970-1972 (OSHA, 1971; ACGIH, 1971; ANSI, 1970) and 1974 (EPA, 1974) and therefore are less relevant today than in the past. Because they occur only rarely in current-day occupational environments, they are not addressed in OSHA's risk analysis or significance of risk determination.

The Agency has also determined that beryllium sensitization, a precursor which occurs before early stage CBD and is an essential step for worker development of the disease, can result from exposure to beryllium. The Agency takes no position at this time on whether sensitization constitutes a material impairment of health, because it was unnecessary to do so as part of this rulemaking. As discussed in Section V, Health Effects, only sensitized individuals can develop CBD (NAS, 2008). OSHA's risk assessment for sensitization informs the Agency's understanding of what exposure control measures have been successful in preventing sensitization, which in turn prevents development of CBD. Therefore sensitization is considered in the next section on significance of risk. Start Printed Page 47655In AFL-CIO v. Marshall, 617 F.2d 636, 654 n.83 (D.C. Cir. 1979) (Cotton Dust), the D.C. Circuit upheld OSHA's authority to regulate to prevent precursors to a material impairment of health without deciding whether the precursors themselves constituted material impairment of health.

B. Significance of Risk and Risk Reduction

To evaluate the significance of the health risks that result from exposure to hazardous chemical agents, OSHA relies on the best available epidemiological, toxicological, and experimental evidence. The Agency uses both qualitative and quantitative methods to characterize the risk of disease resulting from workers' exposure to a given hazard over a working lifetime at levels of exposure reflecting compliance with current standards and compliance with the new standards being proposed.

As discussed above, the Agency's characterization of risk is guided in part by the Benzene decision. In Benzene, 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 (Benzene, 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 (Id.).

In this preamble at section VI, Preliminary Risk Assessment, OSHA finds that the available epidemiological data are sufficient to evaluate risk for beryllium sensitization, CBD, and lung cancer among beryllium-exposed workers. The preliminary findings from this assessment are summarized below.

1. Risk of Beryllium Sensitization and CBD

OSHA's preliminary risk assessment for CBD and beryllium sensitization relies on studies conducted at a Tucson, AZ beryllium ceramics plant (Kreiss et al., 1996; Henneberger et al., 2001; Cummings et al., 2006); a Reading, PA alloy processing plant (Schuler et al., 2005; Thomas et al., 2009); a Cullman, AL beryllium machining plant (Kelleher et al., 2001; Madl et al., 2007); and an Elmore, OH metal, alloy, and oxide production plant (Kreiss et al., 1997; Bailey et al., 2010; Schuler et al., 2012). The Agency uses these studies to demonstrate the significance of risk at the current PEL and the significant reduction in risk expected with reduction of the PEL. In addition to the effects OSHA anticipates from reduction of airborne beryllium exposure, the Agency expects that dermal protection provisions in the proposed rule will further reduce risk. Studies conducted in the 1950s by Curtis et al. showed that soluble beryllium particles could penetrate the skin and cause beryllium sensitization (Curtis 1951, NAS 2008). Tinkle et al. established that 0.5- and 1.0-μm particles can penetrate intact human skin surface and reach the epidermis, where beryllium particles would encounter antigen-presenting cells and initiate sensitization (Tinkle et al., 2003). Tinkle et al. further demonstrated that beryllium oxide and beryllium sulfate, applied to the skin of mice, generate a beryllium-specific, cell-mediated immune response similar to human beryllium sensitization (Tinkle et al., 2003). In the epidemiological studies discussed below, the exposure control programs that most effectively reduced the risk of beryllium sensitization and CBD incorporated both respiratory and dermal protection. OSHA has preliminarily determined that an effective exposure control program should incorporate both airborne exposure reduction and dermal protection provisions.

In the Tucson ceramics plant, 4,133 short-term breathing zone measurements collected between 1981 and 1992 had a median of 0.3 μg/m3. Kreiss et al. reported that eight (5.9 percent) of 136 workers tested for beryllium sensitization in 1992 were sensitized, six (4.4 percent) of whom were diagnosed with CBD. Exposure control programs were initiated in 1992 to reduce workers' airborne beryllium exposure, but the programs did not address dermal exposure. Full-shift personal samples collected between 1994 and 1999 showed a median beryllium exposure of 0.2 μg/m3 in production jobs and 0.1 μg/m3 in production support (Cummings et al., 2007). In 1998, a second screening found that 6, (9 percent) of 69 tested workers hired after the 1992 screening, were sensitized, of whom 1 was diagnosed with CBD. All of the sensitized workers had been employed at the plant for less than 2 years (Henneberger et al., 2001), too short a time period for most people to develop CBD following sensitization. Of the 77 Tucson workers hired prior to 1992 who were tested in 1998, 8 (10.4 percent) were sensitized and all but 1 of these (9.7 percent) were diagnosed with CBD (Henneberger et al., 2001).

Kreiss et al., studied workers at a beryllium metal, alloy, and oxide production plant in Elmore, OH. Workers participated in a BeLPT survey in 1992 (Kreiss et al., 1997). Personal lapel samples collected during 1990-1992 had a median value of 1.0 μg/m3. Kreiss et al. reported that 43 (6.9 percent) of 627 workers tested in 1992 were sensitized, 6 of whom were diagnosed with CBD (4.4 percent).

Newman et al. conducted a series of BeLPT screenings of workers at a Cullman, AL precision machining facility between 1995 and 1999 (Newman et al., 2001). Personal lapel samples collected at this plant in the early 1980s and in 1995 from all machining processes combined had a median of 0.33 μg/m3 (Madl et al., 2007). After a sentinel case of CBD was diagnosed at the plant in 1995, the company implemented engineering and administrative controls and PPE designed to reduce workers' beryllium exposures in machining operations. Personal lapel samples collected extensively between 1996 and 1999 in machining jobs have an overall median of 0.16 μg/m3, showing that the new controls reduced machinists' exposures during this period. However, the results of BeLPT screenings conducted in 1995-1999 showed that the exposure control program initiated in 1995 did not sufficiently protect workers from beryllium sensitization and CBD. In a group of 60 workers who had been employed at the plant for less than a year, and thus would not have been working there prior to 1995, 4 (6.7 percent) were found to be sensitized. Two of these workers (3.35 percent) were diagnosed with CBD. (Newman et al., 2001).

Sensitization and CBD were studied in a population of workers at a Reading, PA copper beryllium plant, where alloys containing a low level of beryllium were processed (Schuler et al., 2005). Personal lapel samples were collected in production and production support jobs between 1995 and May 2000. These samples showed primarily very low airborne beryllium levels, with a median of 0.073 μg/m3. The wire Start Printed Page 47656annealing and pickling process had the highest personal lapel sample values, with a median of 0.149 μg/m3. Despite these low exposure levels, a BeLPT screening conducted in 2000 showed that 5, (11.5 percent) workers of 43 hired after 1992 were sensitized (evaluation for CBD not reported). Two of the sensitized workers had been hired less than a year before the screening (Thomas et al., 2009).

In summary, the epidemiological literature on beryllium sensitization and CBD that OSHA's risk assessment relied on show sensitization prevalences ranging from 6.5 percent to 11.5 percent and CBD prevalences ranging from 1.3 percent to 9.7 percent among workers who had full-shift exposures well below the current PEL and median full-shift exposures at or below the proposed PEL, and whose follow-up time was less than 45 years. As referenced earlier, OSHA is interested in the risk associated with a 45-year (i.e., working lifetime) exposure. Because CBD often develops over the course of years following sensitization, the risk of CBD that would result from 45 years' occupational exposure to airborne beryllium is likely to be higher than the prevalence of CBD observed among these workers.[13] In either case, based on these studies, the risks to workers appear to be significant.

The available epidemiological evidence shows that reducing workers' levels of airborne beryllium exposure can substantially reduce risk of beryllium sensitization and CBD. The best available evidence on effective exposure control programs comes partly from studies of programs introduced around 2000 at Reading, Tucson, and Elmore that used a combination of engineering controls, dermal and respiratory PPE, and stringent housekeeping measures to reduce workers' dermal exposures and airborne exposures to levels well below the proposed PEL of 0.2 μg/m3. These programs have substantially lowered the risk of sensitization among new workers. As discussed earlier, prevention of beryllium sensitization prevents subsequent development of CBD.

In the Reading, PA copper beryllium plant, full-shift airborne exposures in all jobs were reduced to a median of 0.1 μg/m3 or below and dermal protection was required for production-area workers beginning in 2000-2001 (Thomas et al., 2009). After these adjustments were made, 2 (5.4 percent) of 37 newly hired workers became sensitized. Thereafter, in 2002, the process with the highest exposures (median 0.1 μg/m3) was enclosed and workers involved in that process were required to use respiratory protection. As a result, the remaining jobs had very low exposures (medians ~ 0.03 μg/m3). Among 45 workers hired after the enclosure was built and respiratory protection instituted, 1 was found to be sensitized (2.2 percent). This is a sharp reduction in sensitization from the 11.5 percent of 43 workers, discussed above, who were hired after 1992 and had been sensitized by the time of testing in 2000.

In the Tucson beryllium ceramics plant, respiratory and skin protection was instituted for all workers in production areas in 2000. BeLPT testing done in 2000-2004 showed that only 1 (1 percent) worker had been sensitized out of 97 workers hired during that time period (Cummings et al., 2007; testing for CBD not reported). This contrasts with the prevalence of sensitization in the 1998 Tucson BeLPT screening, which found that 6 (9 percent) of 69 workers hired after 1992 were sensitized (Cummings et al., 2007).

The modern Elmore facility provides further evidence that combined reductions in respiratory exposure (via respirator use) and dermal exposure are effective in reducing risk of beryllium sensitization. In Elmore, historical beryllium exposures were higher than in Tucson, Reading, and Cullman. Personal lapel samples collected at Elmore in 1990-1992 had a median of 1.0 µg/m3. In 1996-1999, the company took steps to reduce workers' beryllium exposures, including engineering and process controls (Bailey et al., 2010; exposure levels not reported). Skin protection was not included in the program until after 1999. Beginning in 1999 all new employees were required to wear loose-fitting powered air-purifying respirators (PAPR) in manufacturing buildings (Bailey et al., 2010). Skin protection became part of the protection program for new employees in 2000, and glove use was required in production areas and for handling work boots beginning in 2001. Bailey et al., (2010) compared the occurrence of beryllium sensitization and CBD in 2 groups of workers: 1) 258 employees who began work at the Elmore plant between January 15, 1993 and August 9, 1999 (the “pre-program group”) and were tested in 1997 and 1999, and 2) 290 employees who were hired between February 21, 2000 and December 18, 2006 and underwent BeLPT testing in at least one of frequent rounds of testing conducted after 2000 (the “program group”). They found that, as of 1999, 23 (8.9 percent) of the pre-program group were sensitized to beryllium. The prevalence of sensitization among the “program group” workers, who were hired after the respiratory protection and PPE measures were put in place, was around 2-3 percent. Respiratory protection and skin protection substantially reduced, but did not eliminate, risk of sensitization. Evaluation of sensitized workers for CBD was not reported.

OSHA's preliminary risk assessment also includes analysis of a data set provided to OSHA by the National Jewish Research and Medical Center (NJMRC). The data set describes a population of 319 beryllium-exposed workers at a Cullman, AL machining facility. It includes exposure samples collected between 1980 and 2005, and has updated work history and screening information for over three hundred workers through 2003. Seven (2.2 percent) workers in the data set were reported as sensitized only. Sixteen (5.0 percent) workers were listed as sensitized and diagnosed with CBD upon initial clinical evaluation. Three (1.0 percent) workers, first shown to be sensitized only, were later diagnosed with CBD. The data set includes workers exposed at airborne beryllium levels near the proposed PEL, and extensive exposure data collected in workers' breathing zones, as is preferred by OSHA. Unlike the Tucson, Reading, and Elmore facilities, respirator use was not generally required for workers at the Cullman facility. Thus, analysis of this data set shows the risk associated with varying levels of airborne exposure, rather than the virtual elimination of airborne exposure via respiratory PPE. Also unlike the Tucson, Elmore, and Reading facilities, glove use was not reported to be mandatory in the Cullman facility. Thus, OSHA believes reductions in risk at the Cullman facility to be the result of airborne exposure control, rather than the combination of airborne and dermal exposure controls at the Tucson, Elmore, and Reading facilities.

OSHA analyzed the prevalence of beryllium sensitization and CBD among workers at the Cullman facility who were exposed to airborne beryllium levels at and below the current PEL of 2 µg/m3. In addition, a statistical modeling analysis of the NJMRC Cullman data set was conducted under contract with Dr. Roslyn Stone of the University of Pittsburgh Graduate School of Public Heath, Department of Biostatistics. OSHA summarizes these analyses briefly below, and in more detail in this preamble at section VI, Preliminary Risk Assessment.Start Printed Page 47657

Tables 1 and 2 below present the prevalence of sensitization and CBD cases across several categories of lifetime-weighted (LTW) average and highest-exposed job (HEJ) exposure at the Cullman facility. The HEJ exposure is the exposure level associated with the highest-exposure job and time period experienced by each worker. The columns “Total” and “Total percent” refer to all sensitized workers in the dataset, including workers with and without a diagnosis of CBD.

Table 1—Prevalence of Sensitization and CBD by Lifetime Weighted Average Exposure Quartile, Cullman, AL Machining Facility

LTW Average exposure (μg/m3)Group sizeSensitized onlyCBDTotalTotal %CBD %
0.0-0.080911122.21.0
0.081-0.18732468.25.5
0.19-0.51770667.87.8
0.51-2.1578481215.410.3
Total319719268.26.0
Source: Section VI, Preliminary Risk Assessment.

Table 2—Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile, Cullman, AL Machining Facility

HEJ Exposure (μg/m3)Group sizeSensitized onlyCBDTotalTotal %CBD %
0.0-0.086861011.20.0
0.091-0.214811678.67.4
0.387-0.69176291114.511.8
0.954-2.213763479.25.3
Total319719268.26.0
Source: Section VI, Preliminary Risk Assessment.

The current PEL of 2 μg/m[3] is close to the upper bound of the highest quartile of LTW average (0.51-2.15 μg/m[3] ) and HEJ (0.954-2.213) exposure levels. In the highest quartile of LTW average exposure, there were 12 cases of sensitization (15.4 percent), including 8 (10.3 percent) diagnosed with CBD. Notably, the Cullman workers had been exposed to beryllium dust for considerably less than 45 years at the time of testing. A high prevalence of sensitization (9.2 percent) and CBD (5.3 percent) is seen in the top quartile of HEJ exposure as well, with even higher prevalences in the third quartile (0.387-0.691 μg/m[3] ).[14]

The proposed PEL of 0.2 μg/m3 is close to the upper bound of the second quartile of LTW average (0.81-0.18 μg/m3) and HEJ (0.091-0.214 μg/m3) exposure levels and to the lower bound of the third quartile of LTW average (0.19-0.50 μg/m3) exposures. The second quartile of LTW average exposure shows a high prevalence of beryllium-related health effects, with six workers sensitized (8.2 percent), of whom four (5.5 percent) were diagnosed with CBD. The second quartile of HEJ exposure also shows a high prevalence of beryllium-related health effects, with seven workers sensitized (8.6 percent), of whom 6 (7.4 percent) were diagnosed with CBD. Among six sensitized workers in the third quartile of LTW average exposures, all were diagnosed with CBD (7.8 percent). The prevalence of CBD among workers in these quartiles was approximately 5-8 percent, and overall sensitization (including workers with and without CBD) was about 8 percent. OSHA considers these rates as evidence that the risk of developing CBD is significant among workers exposed at and below the current PEL, even down to the proposed PEL. Much lower prevalences of sensitization and CBD were found among workers with exposure levels less than or equal to about 0.08 μg/m3. Two sensitized workers (2.2 percent), including 1 case of CBD (1.0 percent), were found among workers with LTW average exposure levels and HEJ exposure levels less than or equal to 0.08 μg/m3 and 0.086 μg/m3, respectively. Strict control of airborne exposure to levels below 0.1 μg/m3 can, therefore, significantly reduce risk of sensitization and CBD. Although OSHA recognizes that maintaining exposure levels below 0.1 μg/m3 may not be feasible in some operations (see this preamble at section IX, Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis), the Agency believes that workers in facilities that meet the proposed action level of 0.1 μg/m3 will be at less risk of sensitization and CBD than workers in facilities that cannot meet the action level.

Table 3 below presents the prevalence of sensitization and CBD cases across cumulative exposure quartiles, based on the same Cullman data used to derive Tables 1 and 2. Cumulative exposure is the sum of a worker's exposure across the duration of his employment.Start Printed Page 47658

Table 3—Prevalence of Sensitization and CBD by Cumulative Exposure Quartile Cullman, AL Machining Facility

Cumulative exposure (μg/m3 yrs)Group sizeSensitized onlyCBDTotalTotal %CBD %
0.0-0.147812244.92.5
0.148-1.467790222.52.5
1.468-7.00879381113.98.0
7.009-61.868027911.38.8
Total319719268.26.0
Source: Section VI, Preliminary Risk Assessment.

A 45-year working lifetime of occupational exposure at the current PEL would result in 90 μg/m 3-years, a value far higher than the cumulative exposures of workers in this data set, who worked for periods of time less than 45 years and whose exposure levels were mostly well below the PEL. Workers with 45 years of exposure to the proposed PEL would have a cumulative exposure (9 μg/m 3-years) in the highest quartile for this worker population. As with the average and HEJ exposures, the greatest risk of sensitization and CBD appears at high exposure levels (> 1.468 μg/m 3-years). The third cumulative quartile, at which a sharp increase in sensitization and CBD appears, is bounded by 1.468 and 7.008 μg/m 3-years. This is equivalent to 0.73-3.50 years of exposure at the current PEL of 2 μg/m 3, or 7.34-35.04 years of exposure at the proposed PEL of 0.2 μg/m 3. Prevalence of both sensitization and CBD is substantially lower in the second cumulative quartile (0.148-1.467 μg/m 3-years). This is equivalent to approximately 0.7 to 7 years at the proposed PEL of 0.2 μg/m 3, or 1.5 to 15 years at the proposed action level of 0.1 μg/m 3. This supports that maintaining exposure levels below the proposed PEL, where feasible, will help to protect long-term workers against risk of beryllium sensitization and early stage CBD.

As discussed in the Health Effects section (V.D), CBD often worsens with increased time and level of exposure. In a longitudinal study, workers initially identified as beryllium sensitized through workplace surveillance developed early stage CBD defined by granulomatous inflammation but no apparent physiological abnormalities (Newman et al., 2005). A study of workers with this early stage CBD showed significant declines in breathing capacity and gas exchange over the 30 years from first exposure (Mroz et al., 2009). Many of the workers went on to develop more severe disease that required immunosuppressive therapy despite being removed from exposure. While precise beryllium exposure levels were not available on the individuals in these studies, most started work in the 1980s and 1990s and were likely exposed to average levels below the current 2 μg/m 3 PEL. The evidence for time-dependent disease progression indicates that the CBD risk estimates for a 45-year lifetime exposure at the current PEL will include a higher proportion of individuals with advanced clinical CBD than found among the workers in the NJMRC data set.

Studies of community-acquired (CA) CBD support the occurrence of advanced clinical CBD from long-term exposure to airborne beryllium (Eisenbud, 1998; Maier et al., 2008). A discussion of the study findings can be found in this preamble at section VI.C, Preliminary Risk Assessment. For example, one study evaluated 16 potential cases of CA-CBD in individuals that resided near a beryllium production facility in the years between 1943 and 2001 (Maier et al., 2008). Five cases of definite CBD and three cases of probable CBD were found. Two of the subjects with probable cases died before they could be confirmed with the BeLPT; the third had an abnormal BeLPT and radiography consistent with CBD, but granulomatous disease was not pathologically proven. The individuals with CA-CBD identified in this study suffered significant health impacts from the disease, including obstructive, restrictive, and gas exchange pulmonary defects. Six of the eight cases required treatment with prednisone, a step typically reserved for severe cases due to the adverse side effects of steroid treatment. Despite treatment, three had died of respiratory impairment as of 2002. There was insufficient information to estimate exposure to the individuals, but the limited amount of ambient air sampling in the 1950s suggested that average beryllium levels in the area where the cases resided were below 2 μg/m 3. The authors concluded that “low levels of exposures with significant disease latency can result in significant morbidity and mortality” (Maier et al., 2008, p. 1017).

OSHA believes that the literature review, prevalence analysis, and the evidence for time-dependent progression of CBD described above provide sufficient information to draw preliminary conclusions about significance of risk, and that further quantitative analysis of the NJMRC data set is not necessary to support the proposed rule. The studies OSHA used to support its preliminary conclusions regarding risk of beryllium sensitization and CBD were conducted at modern industrial facilities with exposure levels in the range of interest for this rulemaking, so a model is not needed to extrapolate risk estimates from high to low exposures, as has often been the case in previous rules. Nevertheless, the Agency felt further quantitative analysis might provide additional insight into the exposure-response relationship for sensitization and CBD.

Using the NJMRC data set, Dr. Stone ran a complementary log-log proportional hazards model, an extension of logistic regression that allows for time-dependent exposures and differential time at risk. Relative risk of sensitization increased with cumulative exposure (p = 0.05). A positive, but not statistically significant association was observed with LTW average exposure (p = 0.09). There was little association with highest-exposed job (HEJ) exposure (p = 0.3). Similarly, the proportional hazards models for the CBD endpoint showed positive relationships with cumulative exposure (p = 0.09), but LTW average exposure and HEJ exposure were not closely related to relative risk of CBD (p-values > 0.5). Dr. Stone used the cumulative exposure models to generate risk estimates for sensitization and CBD.

Tables 4 and 5 below present risk estimates from these models, assuming 5, 10, 20, and 45 years of beryllium exposure. The tables present sensitization and CBD risk estimates based on year-specific intercepts, as Start Printed Page 47659explained in the section on Risk Assessment and the accompanying background document. Each estimate represents the number of sensitized workers the model predicts in a group of 1000 workers at risk during the given year with an exposure history at the specified level and duration. For example, in the exposure scenario for 1995, if 1000 workers were occupationally exposed to 2 μg/m 3 for 10 years, the model predicts that about 56 (55.7) workers would be identified as sensitized. The model for CBD predicts that about 42 (41.9) workers would be diagnosed with CBD that year. The year 1995 shows the highest risk estimates generated by the model for both sensitization and CBD, while 1999 and 2002 show the lowest risk estimates generated by the model for sensitization and CBD, respectively. The corresponding 95 percent confidence intervals are based on the uncertainty in the exposure coefficient.

Table 4a—Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1995 Baseline.

1995Exposure duration
Exposure level (μg/m3)5 years10 years20 years45 years
Cumulative (μg/m3-yrs)cases/1000μg/m3-yrscases/1000μg/m3-yrscases/1000μg/m3-yrscases/1000
2.010.041.1 30.3-56.220.055.7 30.3-102.940.0101.0 30.3-318.190.0394.4 30.3-999.9
1.05.035.3 30.3-41.310.041.1 30.3-56.220.055.7 30.3-102.945.0116.9 30.3-408.2
0.52.532.7 30.3-35.45.035.3 30.3-41.310.041.1 30.3-56.222.560.0 30.3-119.4
0.21.031.3 30.3-32.32.032.2 30.3-34.34.034.3 30.3-38.99.039.9 30.3-52.9
0.10.530.8 30.3-31.31.031.3 30.3-32.32.032.2 30.3-34.34.534.8 30.3-40.1
Source: Section VI, Preliminary Risk Assessment.

Table 4b—Predicted Cases of Sensitization per 1000 Workers Exposed at Current and Alternate PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1999 Baseline.

1999Exposure duration
Exposure level (μg/m3)5 years10 years20 years45 years
Cumulative (μg/m3-yrs)cases/1000μg/m3-yrscases/1000μg/m3-yrscases/1000μg/m3-yrscases/1000
2.010.08.4 6.2-11.620.011.5 6.2-21.740.021.3 6.2-74.490.096.3 6.2-835.4
1.05.07.2 6.2-8.510.08.4 6.2-11.620.011.5 6.2-21.745.024.8 6.2-100.5
0.52.56.7 6.2-7.35.07.2 6.2-8.510.08.4 6.2-11.622.512.4 6.2-25.3
0.21.06.4 6.2-6.62.06.6 6.2-7.04.07.0 6.2-8.09.08.2 6.2-10.9
0.10.56.3 6.2-6.41.06.4 6.2-6.62.06.6 6.2-7.04.57.1 6.2-8.2
Source: Section VI, Preliminary Risk Assessment.

Table 5a—Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 1995 Baseline.

1995Exposure duration
Exposure level (μg/m3)5 years10 years20 years45 years
Cumulative (μg/m3-yrs)Estimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)
2.010.030.9 22.8-44.020.041.9 22.8-84.340.076.6 22.8-285.590.0312.9 22.8-999.9
1.05.026.6 22.8-31.710.030.9 22.8-44.020.041.9 22.8-84.345.088.8 22.8-375.0
Start Printed Page 47660
0.52.524.6 22.8-26.95.026.6 22.8-31.710.030.9 22.8-44.022.545.2 22.8-98.9
0.21.023.5 22.8-24.32.024.2 22.8-26.04.025.8 22.8-29.79.030.0 22.8-41.3
0.10.523.1 22.8-23.61.023.5 22.8-24.32.024.2 22.8-26.04.526.2 22.8-30.7
Source: Section VI, Preliminary Risk Assessment.

Table 5b—Predicted Number of Cases of CBD per 1000 Workers Exposed at Current and Alternative PELs Based on Proportional Hazards Model, Cumulative Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient. 2002 Baseline.

2002Exposure duration
Exposure level (μg/m3)5 years10 years20 years45 years
Cumulative (μg/m3-yrs)Estimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)μg/m3-yrsEstimated cases/1000 (95% c.i.)
2.010.03.7 2.7-5.320.05.1 2.7-10.440.09.4 2.7-39.290.043.6 2.7-679.8
1.05.03.2 2.7-3.810.03.7 2.7-5.320.05.1 2.7-10.445.011.0 2.7-54.3
0.52.53.0 2.7-3.25.03.2 2.7-3.810.03.7 2.7-5.322.55.5 2.7-12.3
0.21.02.8 2.7-2.92.02.9 2.7-3.14.03.1 2.7-3.69.03.6 2.7-5.0
0.10.52.8 2.7-2.81.02.8 2.7-2.92.02.9 2.7-3.14.53.1 2.7-3.7
Source: Section VI, Preliminary Risk Assessment.

As shown in Tables 4 and 5, the exposure-response models Dr. Stone developed based on the Cullman data set predict a high risk of both sensitization (about 96-394 cases per 1000 exposed workers) and CBD (about 44-313 cases per 1000) at the current PEL of 2 μg/m3 for an exposure duration of 45 years (90 μg/m3-yr). For a 45-year exposure at the proposed PEL of 0.2 μg/m3, risk estimates for sensitization (about 8-40 cases per 1000 exposed workers) and CBD (about 4-30 per 1000 exposed workers) are substantially reduced. Thus, the model predicts that the risk of sensitization and CBD at a PEL of 0.2 μg/m3 will be about 10 percent of the risk at the current PEL of 2 μg/m3.

OSHA does not believe the risk estimates generated by these exposure-response models to be highly accurate. Limitations of the analysis include the size of the dataset, relatively sparse exposure data from the plant's early years, study size-related constraints on the statistical analysis of the dataset, and limited follow-up time on many workers. The Cullman study population is a relatively small group and can support only limited statistical analysis. For example, its size precludes inclusion of multiple covariates in the exposure-response models or a two-stage exposure-response analysis to model both sensitization and the subsequent development of CBD within the subpopulation of sensitized workers. The limited size of the Cullman dataset is characteristic of studies on beryllium-exposed workers in modern, low-exposure environments, which are typically small-scale processing plants (up to several hundred workers, up to 20-30 cases).

Despite these issues with the statistical analysis, OSHA believes its main policy determinations are well supported by the best available evidence, including the literature review and careful examination of the prevalence of sensitization and CBD among workers with exposure levels comparable to the current and proposed PELs in the NJMRC data set. The previously described literature analysis and prevalence analysis demonstrate that workers with occupational exposure to airborne beryllium at the current PEL face a risk of becoming sensitized to beryllium and progressing to both early and advanced stages of CBD that far exceeds the value of 1 in 1000 used by OSHA as a benchmark of clearly significant risk. Furthermore, OSHA's preliminary risk assessment indicates that risk of beryllium sensitization and CBD can be significantly reduced by reduction of airborne exposure levels, along with respiratory and dermal protection measures, as demonstrated in facilities such as the Tucson ceramics plant, the Elmore beryllium production facility, and the Reading copper beryllium facility described in the literature review.Start Printed Page 47661

OSHA's preliminary risk assessment also indicates that despite the reduction in risk expected with the proposed PEL, the risk to workers with average exposure levels of 0.2 μg/m3 is still clearly significant (see this preamble at section VI). In the prevalence analysis, workers with LTW average or HEJ exposures close to 0.2 μg/m3 experienced high levels of sensitization and CBD. This finding is corroborated by the literature analysis, which showed that workers exposed to mean plant-wide airborne exposures between 0.1 and 0.5 μg/m3 had a similarly high prevalence of sensitization and CBD. Given the significant risk at these levels of exposure, the Agency believes that the proposed action level of 0.1 μg/m3, dermal protection requirements, and other ancillary provisions of the proposed rule are key to reducing the risk of beryllium sensitization and CBD among exposed workers. OSHA preliminarily concludes that the proposed standard, including the PEL of 0.2 μg/m3, the action level of 0.1 μg/m3, and provisions to limit dermal exposure to beryllium, together will significantly reduce workers' risk of beryllium sensitization and CBD from occupational beryllium exposure.

2. Risk of Lung Cancer

OSHA's review of epidemiological studies of lung cancer mortality among beryllium workers found that most did not characterize exposure levels sufficiently to characterize risk of lung cancer at the current and proposed PELs. However, as discussed in this preamble at section V, Health Effects and section VI, Preliminary Risk Assessment, NIOSH recently published a quantitative risk assessment based on beryllium exposure and lung cancer mortality among 5436 male workers employed at beryllium processing plants in Reading, PA; Elmore, OH; and Hazleton, PA, prior to 1970 (Schubauer-Berigan et al., 2010b). This new risk assessment addresses important sources of uncertainty for previous lung cancer analyses, including the sole prior exposure-response analysis for beryllium and lung cancer, conducted by Sanderson et al. (2001) on workers from the Reading plant alone. Workers from the Elmore and Hazleton plants who were added to the analysis by Schubauer-Berigan et al. were, in general, exposed to lower levels of beryllium than those at the Reading plant. The median worker from Hazleton had a mean exposure across his tenure of less than 2 μg/m3, while the median worker from Elmore had a mean exposure of less than 1 μg/m3. The Elmore and Hazleton worker populations also had fewer short-term workers than the Reading population. Finally, the updated cohorts followed the worker populations through 2005, increasing the length of follow-up time compared to the previous exposure-response analysis. For these reasons, OSHA based its preliminary risk assessment for lung cancer on the Schubauer-Berigan risk analysis.

Schubauer-Berigan et al. (2011) analyzed the data set using a variety of exposure-response modeling approaches, described in this preamble at section VI, Preliminary Risk Assessment. The authors found that lung cancer mortality risk was strongly and significantly related to mean, cumulative, and maximum measures of workers' exposure to beryllium (all models reported in Schubauer-Berigan et al., 2011). They selected the best-fitting models to generate risk estimates for male workers with a mean exposure of 0.5 μg/m3 (the current NIOSH Recommended Exposure Limit for beryllium). In addition, they estimated the mean exposure that would be associated with an excess lung cancer mortality risk of one in one thousand. At OSHA's request, the authors also estimated excess risks for workers with mean exposures at each of the other alternate PELs under consideration: 1 μg/m3, 0.2 μg/m3, and 0.1 μg/m3. Table 6 presents the estimated excess risk of lung cancer mortality associated with various levels of beryllium exposure allowed under the current rule, based on the final models presented in Schubauer-Berigan et al' s risk assessment.

Table 6—Excess Risk of Lung Cancer Mortality per 1000 Male Workers at Alternate PELs (NIOSH Models)

Exposure-response modelMean exposure
0.1 µg/m30.2 µg/m30.5 µg/m31 µg/m32 µg/m3
Best monotonic PWL—all workers7.31545120200
Best monotonic PWL—excluding professional and asbestos workers3.16.4173961
Best categorical—all workers4.492559170
Best categorical—excluding professional and asbestos workers1.42.77.11533
Power model—all workers1219304052
Power model—excluding professional and asbestos workers1930496890
Source: Section VI, Preliminary Risk Assessment.

The lowest estimate of excess lung cancer deaths from the six final models presented by Schubauer-Berigan et al. is 33 per 1000 workers exposed at a mean level of 2 μg/m3, the current PEL. Risk estimates as high as 200 lung cancer deaths per 1000 result from the other five models presented. Regardless of the model chosen, the excess risk of about 33 to 200 per 1000 workers is clearly significant, falling well above the level of risk the Supreme Court indicated a reasonable person might consider acceptable (See Benzene, 448 U.S. at 655). The proposed PEL of 0.2 μg/m3 is expected to reduce these risks significantly, to somewhere between 2.7-30 excess lung cancer deaths per 1000 workers. These risk estimates still fall above the threshold of 1 in 1000 that OSHA considers clearly significant. However, the Agency believes the lung cancer risks should be regarded with a greater degree of uncertainty than the risk estimates for CBD discussed previously. While the risk estimates for CBD at the proposed PEL were determined from exposure levels observed in occupational studies, the lung cancer risks are extrapolated from much higher exposure levels.

C. Conclusions

As discussed above, OSHA used the best available scientific evidence to identify adverse health effects of Start Printed Page 47662occupational beryllium exposure, and to evaluate exposed workers' risk of these impairments. The Agency reviewed extensive epidemiological and experimental research pertaining to adverse health effects of occupational beryllium exposure, including lung cancer, immunological sensitization to beryllium, and CBD, and has evaluated the risk of these effects from exposures allowed under the current and proposed standards. The Agency has, additionally, reviewed previous policy determinations and case law regarding material impairment of health, and has preliminarily determined that CBD, in all stages, and lung cancer constitute material health impairments. Furthermore, OSHA has preliminarily determined that long-term exposure to beryllium at the current PEL would pose a risk of CBD and lung cancer greater than the risk of 1 per 1000 exposed workers the Agency considers clearly significant. OSHA's risk assessment for beryllium indicates that adoption of the new PEL, action level, and dermal protection provisions of the proposed rule will significantly reduce this risk. OSHA therefore believes it has met the statutory requirements pertaining to significance of risk, consistent with the OSH Act, Supreme Court precedent, and the Agency's previous policy decisions.

IX. Summary of the Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis

A. Introduction and Summary

OSHA's Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis (PEA) addresses issues related to the costs, benefits, technological and economic feasibility, and the economic impacts (including impacts on small entities) of this proposed respirable beryllium rule and evaluates regulatory alternatives to the proposed rule. Executive Orders 13563 and 12866 direct agencies to assess all costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, and public health and safety effects; distributive impacts; and equity), unless a statute requires another regulatory approach. Executive Order 13563 emphasized the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules, and of promoting flexibility. The full PEA has been placed in OSHA rulemaking docket OSHA-H005C-2006-0870. This rule is an economically significant regulatory action under Sec. 3(f)(1) of Executive Order 12866 and has been reviewed by the Office of Information and Regulatory Affairs in the Office of Management and Budget, as required by executive order.

The purpose of the PEA is to:

  • Identify the establishments and industries potentially affected by the proposed rule;
  • Estimate current exposures and the technologically feasible methods of controlling these exposures;
  • Estimate the benefits resulting from employers coming into compliance with the proposed rule in terms of reductions in cases of lung cancer and chronic beryllium disease;
  • Evaluate the costs and economic impacts that establishments in the regulated community will incur to achieve compliance with the proposed rule;
  • Assess the economic feasibility of the proposed rule for affected industries; and
  • Assess the impact of the proposed rule on small entities through an Initial Regulatory Flexibility Analysis (IRFA), to include an evaluation of significant regulatory alternatives to the proposed rule that OSHA has considered.

The PEA contains the following chapters:

Chapter I. Introduction

Chapter II. Assessing the Need for Regulation

Chapter III. Profile of Affected Industries

Chapter IV. Technological Feasibility

Chapter V. Costs of Compliance

Chapter VI. Economic Feasibility Analysis and Regulatory Flexibility Determination

Chapter VII. Benefits and Net Benefits

Chapter VIII. Regulatory Alternatives

Chapter IX. Initial Regulatory Flexibility Analysis

The PEA includes all of the economic analyses OSHA is required to perform, including the findings of technological and economic feasibility and their supporting materials required by the OSH Act as interpreted by the courts (in Chapters III, IV, V, and VI); those required by EO 12866 and EO 13563 (primarily in Chapters III, V, and VII, though these depend on material in other chapters); and those required by the Regulatory Flexibility Act (in Chapters VI, VIII, and IX, though these depend, in part, on materials presented in other chapters).

Key findings of these chapters are summarized below and in sections IX.B through IX.I of this PEA summary.

Profile of Affected Industries

This proposed rule would affect employers and employees in many different industries across the economy. As described in Section IX.C and reported in Table IX-2 of this preamble, OSHA estimates that a total of 35,051 employees in 4,088 establishments are potentially at risk from exposure to beryllium.

Technological Feasibility

As described in more detail in Section IX.D of this preamble and in Chap