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Occupational Safety and Health Administration (OSHA), Department of Labor.
The Occupational Safety and Health Administration (OSHA) is amending its existing standards for occupational exposure to beryllium and beryllium compounds. OSHA has determined that employees exposed to beryllium at the previous permissible exposure limits face a significant risk of material impairment to their health. The evidence in the record for this rulemaking indicates that workers exposed to beryllium are at increased risk of developing chronic beryllium disease and lung cancer. This final rule establishes new permissible exposure limits of 0.2 micrograms of beryllium per cubic meter of air (0.2 μg/m3) as an 8-hour time-weighted average and 2.0 μg/m3 as a short-term exposure limit determined over a sampling period of 15 minutes. It also includes other provisions to protect employees, such as requirements for exposure assessment, methods for controlling exposure, respiratory protection, personal protective clothing and equipment, housekeeping, medical surveillance, hazard communication, and recordkeeping.
OSHA is issuing three separate standards—for general industry, for shipyards, and for construction—in order to tailor requirements to the circumstances found in these sectors.
Effective date: The final rule becomes effective on March 10, 2017.
Compliance dates: Compliance dates for specific provisions are set in § 1910.1024(o) for general industry, § 1915.1024(o) for shipyards, and § 1926.1124(o) for construction. There are a number of collections of information contained in this final rule (see Section IX, OMB Review under the Paperwork Reduction Act of 1995). Notwithstanding the general date of applicability that applies to all other requirements contained in the final rule, affected parties do not have to comply with the collections of information until the Department of Labor publishes a separate document in the Federal Register announcing the Office of Management and Budget has approved them under the Paperwork Reduction Act.
In accordance with 28 U.S.C. 2112(a), the Agency designates Ann Rosenthal, Associate Solicitor of Labor for Occupational Safety and Health, Office of the Solicitor of Labor, Room S-4004, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210, to receive petitions for review of the final rule.
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FOR FURTHER INFORMATION CONTACT:
For general information and press inquiries, contact Frank Meilinger, Director, Office of Communications, Room N-3647, OSHA, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210; telephone (202) 693-1999; email firstname.lastname@example.org.
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) 693-1950.
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The preamble to the rule on occupational exposure to beryllium follows this outline:
I. Executive Summary
II. Pertinent Legal Authority
III. Events Leading to the Final Standards
IV. Chemical Properties and Industrial Uses
V. Health Effects
VI. Risk Assessment
VII. Significance of Risk
VIII. Summary of the Final Economic Analysis and Final Regulatory Flexibility Analysis
IX. OMB Review Under the Paperwork Reduction Act of 1995
XI. State-Plan States
XII. Unfunded Mandates Reform Act
XIII. Protecting Children From Environmental Health and Safety Risks
XIV. Environmental Impacts
XV. Consultation and Coordination With Indian Tribal Governments
XVI. Summary and Explanation of the Standards
(a) Scope and Application
(c) Permissible Exposure Limits (PELs)
(d) Exposure Assessment
(e) Beryllium Work Areas and Regulated Areas (General Industry); Regulated Areas (Maritime); and Competent Person (Construction)
(f) Methods of Compliance
(g) Respiratory Protection
(h) Personal Protective Clothing and Equipment
(i) Hygiene Areas and Practices
(k) Medical Surveillance
(l) Medical Removal
(m) Communication of Hazards
(p) Appendix A (General Industry)
Authority and Signature
Amendments to Standards
In the docket for the beryllium rulemaking, found at http://www.regulations.gov, every submission was assigned a document identification (ID) number that consists of the docket number (OSHA-H005C-2006-0870) followed by an additional four-digit number. For example, the document ID number for OSHA's Preliminary Economic Analysis and Initial Regulatory Flexibility Analysis is OSHA-H005C-2006-0870-0426. Some document ID numbers include one or more attachments, such as the National Institute for Occupational Safety and Health (NIOSH) prehearing submission (see Document ID OSHA-H005C-2006-0870-1671).
When citing exhibits in the docket, OSHA includes the term “Document ID” followed by the last four digits of the document ID number, the attachment number or other attachment identifier, if applicable, page numbers (designated “p.” or “Tr.” for pages from a hearing transcript). In a citation that contains two or more document ID numbers, the document ID numbers are separated by semi-colons. In some sections, such as Section V, Health Effects, author names and year of study publication are included before the document ID number in a citation, for example: (Deubner et al., 2011, Document ID 0527). Where multiple exhibits are listed with author names and year of study publication, document ID numbers after the first are in parentheses, for example: (Elder et al., 2005, Document ID 1537; Carter et al., 2006 (1556); Refsnes et al., 2006 (1428)).
I. Executive Summary
This final rule establishes new permissible exposure limits (PELs) for beryllium of 0.2 micrograms of beryllium per cubic meter of air (0.2 μg/m3) as an 8-hour time-weighted average (TWA) and 2.0 μg/m3 as a short-term exposure limit (STEL) determined over a sampling period of 15 minutes. In addition to the PELs, the rule includes provisions to protect employees such as requirements for exposure assessment, methods for controlling exposure, respiratory protection, personal protective clothing and equipment, housekeeping, medical surveillance, hazard communication, and recordkeeping. OSHA is issuing three separate standards—for general Start Printed Page 2471industry, for shipyards, and for construction—in order to tailor requirements to the circumstances found in these sectors. There are, however, numerous common elements in the three standards.
The final rule 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, Pertinent Legal Authority, for a full discussion of OSH Act legal requirements.
OSHA has conducted an extensive review of the literature on adverse health effects associated with exposure to beryllium. OSHA has also developed estimates of the risk of beryllium-related diseases, assuming exposure over a working lifetime, at the preceding PELs as well as at the revised PELs and action level. Comments received on OSHA's preliminary analysis, and the Agency's final findings, are discussed in Section V, Health Effects, Section VI, Risk Assessment, and Section VII, Significance of Risk. OSHA finds that employees exposed to beryllium at the preceding PELs are at an increased risk of developing chronic beryllium disease (CBD) and lung cancer. As discussed in Section VII, OSHA concludes that exposure to beryllium constitutes a significant risk of material impairment to health and that the final rule will substantially lower that risk. The Agency considers the level of risk remaining at the new TWA PEL to still be significant. However, OSHA did not adopt a lower TWA PEL because the Agency could not demonstrate technological feasibility of a lower TWA PEL. The Agency has adopted the STEL and ancillary provisions of the rule to further reduce the remaining significant risk.
OSHA's examination of the technological and economic feasibility of the rule is presented in the Final Economic Analysis and Regulatory Flexibility Analysis (FEA), and is summarized in Section VIII of this preamble. OSHA concludes that the final PELs are technologically feasible for all affected industries and application groups. Thus, OSHA concludes that engineering and work practice controls will be sufficient to reduce and maintain beryllium exposures to the new PELs 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 PELs cannot be achieved even when employers implement all feasible engineering and work practice controls, use of respirators will be required.
OSHA developed quantitative estimates of the compliance costs of the 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 rule and an evaluation of the 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 finds that compliance with the requirements of the rule is economically feasible in every affected industry sector.
The final rule includes several major changes from the proposed rule as a result of OSHA's analysis of comments and evidence received during the comment periods and public hearings. The major changes are summarized below and are fully discussed in Section XVI, Summary and Explanation of the Standards. OSHA also presented a number of regulatory alternatives in the Notice of Proposed Rulemaking (80 FR 47566, 47729-47748 (8/7/2015). Where the Agency received substantive comments on a regulatory alternative, those comments are also discussed in Section XVI. A full discussion of all regulatory alternatives can be found in Chapter VIII of the Final Economic Analysis (FEA).
Scope. OSHA proposed to cover occupational exposures to beryllium in general industry, with an exemption for articles and an exemption for materials containing less than 0.1% beryllium by weight. OSHA has made a final determination to cover exposures to beryllium in general industry, shipyards, and construction under the final rule, and to issue separate standards for each sector. The final rule also provides an exemption for materials containing less than 0.1% beryllium by weight only where the employer has objective data demonstrating that employee exposure to beryllium will remain below the action level of 0.1 μg/m3 as an 8-hour TWA under any foreseeable conditions.
Exposure Assessment. The proposed rule would have required periodic exposure monitoring annually where employee exposures are at or above the action level but at or below the TWA PEL; no periodic monitoring would have been required where employee exposures exceeded the TWA PEL. The final rule specifies that exposure monitoring must be repeated within six months where employee exposures are at or above the action level but at or below the TWA PEL, and within three months where employee exposures are above the TWA PEL or STEL. The final rule also includes provisions allowing the employer to discontinue exposure monitoring where employee exposures fall below the action level and STEL. In addition, the final rule includes a new provision that allows employers to assess employee exposures using any combination of air monitoring data and objective data sufficient to accurately characterize airborne exposure to beryllium (i.e., the “performance option”).
Beryllium Work Areas. The proposed rule would have required the employer to establish and maintain a beryllium work area wherever employees are, or can reasonably be expected to be, exposed to airborne beryllium, regardless of the level of exposure. As discussed in the Summary and Explanation section of this preamble, OSHA has narrowed the definition of beryllium work area in the final rule from the proposal. The final rule now limits the requirement to work areas containing a process or operation that can release beryllium where employees are, or can reasonably be expected to be, exposed to airborne beryllium at any level. The final rule expands the exposure requirement to include work areas containing a process or operation where there is potential dermal contact with beryllium based on comments from public health experts that relying solely on airborne exposure omits the potential contribution of dermal exposure to total exposure. See the Summary and Explanation section of this preamble for a full discussion of the relevant comments and reasons for changes from the proposed standard. Beryllium work areas are not required under the standards for shipyards and construction.
Respiratory Protection. OSHA has added a provision in the final rule requiring the employer to provide a powered air-purifying respirator (PAPR) instead of a negative pressure respirator where respiratory protection is required by the rule and the employee requests a PAPR, provided that the PAPR provides adequate protection.
Personal Protective Clothing and Equipment. The proposed rule would have required use of protective clothing and equipment where employee exposure exceeds, or can reasonably be expected to exceed the TWA PEL or STEL; where employees' clothing or skin may become visibly contaminated with beryllium; and where employees' Start Printed Page 2472skin can reasonably be expected to be exposed to soluble beryllium compounds. The final rule requires use of protective clothing and equipment where employee exposure exceeds, or can reasonably be expected to exceed the TWA PEL or STEL; or where there is a reasonable expectation of dermal contact with beryllium.
Medical Surveillance. The exposure trigger for medical examinations has been revised from the proposal. The proposed rule would have required that medical examinations be offered to each employee who has worked in a regulated area (i.e., an area where an employee's exposure exceeds, or can reasonably be expected to exceed, the TWA PEL or STEL) for more than 30 days in the last 12 months. The final rule requires that medical examinations be offered to each employee who is or is reasonably expected to be exposed at or above the action level for more than 30 days per year. A trigger to offer periodic medical surveillance when recommended by the most recent written medical opinion was also added the final rule. Under the final rule, the licensed physician recommends continued periodic medical surveillance for employees who are confirmed positive for sensitization or diagnosed with CBD. The proposed rule also would have required that medical examinations be offered annually; the final rule requires that medical examinations be offered at least every two years.
The final medical surveillance provisions have been revised to provide enhanced privacy for employees. The rule requires the employer to obtain a written medical opinion from a licensed physician for medical examinations provided under the rule but limits the information provided to the employer to the date of the examination, a statement that the examination has met the requirements of the standard, any recommended limitations on the employee's use of respirators, protective clothing, and equipment, and a statement that the results of the exam have been explained to the employee. The proposed rule would have required that such opinions contain additional information, without requiring employee authorization, such as the physician's opinion as to whether the employee has any detected medical condition that would place the employee at increased risk of CBD from further exposure, and any recommended limitations upon the employee's exposure to beryllium. In the final rule, the written opinion provided to the employer will only include recommended limitations on the employee's exposure to beryllium, referral to a CBD diagnostic center, a recommendation for continued periodic medical surveillance, or a recommendation for medical removal if the employee provides written authorization. The final rule requires a separate written medical report provided to the employee to include this additional information, as well as detailed information related to the employee's health.
The proposed rule would have required that the licensed physician provide the employer with a written medical opinion within 30 days of the examination. The final rule requires that the licensed physician provide the employee with a written medical report and the employer with a written medical opinion within 45 days of the examination, including any follow-up beryllium lymphocyte proliferation test (BeLPTs).
The final rule also adds requirements for the employer to provide the CBD diagnostic center with the same information provided to the physician or other licensed health care professional who administers the medical examination, and for the CBD diagnostic center to provide the employee with a written medical report and the employer with a written medical opinion. Under the final standard, employees referred to a CBD diagnostic center can choose to have future evaluations performed there. A requirement that laboratories performing BeLPTs be certified was also added to the final rule.
The proposed rule would have required that employers provide low dose computed tomography (LDCT) scans to employees who met certain exposure criteria. The final rule requires LDCT scans when recommended by the physician or other licensed healthcare professional administering the medical exam, after considering the employee's history of exposure to beryllium along with other risk factors.
Dates. OSHA proposed an effective date 60 days after publication of the rule; a date for compliance with all provisions except change rooms and engineering controls of 90 days after the effective date; a date for compliance with change room requirements, which was one year after the effective date; and a date for compliance with engineering control requirements of two years after the effective date.
OSHA has revised the proposed compliance dates. The final rule is effective 60 days after publication. All obligations for compliance commence one year after the effective date, with two exceptions: The obligation for change rooms and showers commences two years after the effective date; and the obligation for engineering controls commences three years after the effective date.
Under the OSH Act's legal standard directing OSHA to set health standards based on findings of significant risk of material impairment and technological and economic feasibility, OSHA does not use cost-benefit analysis to determine the PEL or other aspects of the rule. It does, however, determine and analyze costs and benefits for its own informational purposes and to meet certain Executive Order requirements, as discussed in Section VIII, Summary of the Final Economic Analysis and Final Regulatory Flexibility Analysis and in the FEA. Table I-1—which is derived from material presented in Section VIII of this preamble—provides a summary of OSHA's best estimate of the costs and benefits of the rule using a discount rate of 3 percent. As shown, the rule is estimated to prevent 90 fatalities and 46 new cases of CBD annually once the full effects are realized, and the estimated cost of the rule is $73.9 million annually. Also as shown in Table I-1, the discounted monetized benefits of the rule are estimated to be $560.9 annually, and the rule is estimated to generate net benefits of approximately $487 annually; however, there is a great deal of uncertainty in those benefits due to assumptions made about dental workers' exposures and reductions; see Section VIII of this preamble. As that section shows, benefits significantly exceed costs regardless of how dental workers' exposures are treated.
Table I-1—Annualized Benefits, Costs and Net Benefits of OSHA's Final Beryllium Standard
[3 Percent discount rate, 2015 dollars]
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|Beryllium Work Areas||129,648|
|Written Exposure Control Plan||2,339,058|
|Protective Work Clothing & Equipment||1,985,782|
|Hygiene Areas and Practices||2,420,584|
|Total Annualized Costs (Point Estimate)||$73,868,230|
|Annual Benefits: Number of Cases Prevented:|
|Fatal Lung Cancers (Midpoint Estimate)||4|
|Fatal Chronic Beryllium Disease||86|
|Monetized Annual Benefits (Midpoint Estimate)||$560,873,424|
|Sources: US DOL, OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis.|
II. Pertinent Legal Authority
The purpose of the Occupational Safety and Health Act (29 U.S.C. 651 et seq.) (“the Act” or “the OSH 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 set mandatory occupational safety and health standards applicable to businesses affecting interstate commerce” (29 U.S.C. 651(b)(3); see 29 U.S.C. 654(a) (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 primary statutory provision relied upon by the Agency in promulgating health standards is section 6(b)(5) of the Act; other sections of the OSH Act, however, authorize the Occupational Safety and Health Administration (“OSHA”) to require labeling and other appropriate forms of warning, exposure assessment, medical examinations, and recordkeeping in its standards (29 U.S.C. 655(b)(5), 655(b)(7), 657(c)).
The Act provides that in promulgating standards dealing with toxic materials or harmful physical agents, such as 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” (29 U.S.C. 655(b)(5)). Thus, “[w]hen Congress passed the Occupational Safety and Health Act in 1970, it chose to place pre-eminent value on assuring employees a safe and healthful working environment, limited only by the feasibility of achieving such an environment” (American Textile Mfrs. Institute, Inc. v. Donovan, 452 US 490, 541 (1981) (“Cotton Dust”)).
OSHA proposed this new standard for beryllium and beryllium compounds and conducted its rulemaking pursuant to section 6(b)(5) of the Act ((29 U.S.C. 655(b)(5)). The preceding beryllium standard, however, was adopted under the Secretary's authority in section 6(a) of the OSH Act (29 U.S.C. 655(a)), to adopt national consensus and established Federal standards within two years of the Act's enactment (see 29 CFR 1910.1000 Table Z-1). Any rule that “differs substantially from an existing national consensus standard” must “better effectuate the purposes of this Act than the national consensus standard” (29 U.S.C. 655(b)(8)). Several additional legal requirements arise from the statutory language in sections 3(8) and 6(b)(5) of the Act (29 U.S.C. 652(8), 655(b)(5)). The remainder of this section discusses these requirements, which OSHA must consider and meet before it may promulgate this occupational health standard regulating exposure to beryllium and beryllium compounds.
Material Impairment of Health
Subject to the limitations discussed below, when setting standards regulating exposure to toxic materials or harmful physical agents, the Secretary is required to set health standards that ensure that “no employee will suffer material impairment of health or functional capacity. . .” (29 U.S.C. 655(b)(5)). “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 (AFL-CIO, 965 F.2d at 975). Thus the Agency has taken the position that “subclinical” health effects, which may be precursors to more serious disease, can be material impairments of health that OSHA should address when feasible (43 FR 52952, 52954 (11/14/78) (Lead Preamble)).
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 its decision on OSHA's benzene standard, interpreted section 3(8) to mean that before promulgating any standard, the Secretary must evaluate whether “significant risk[ ]” exists under current conditions and to then determine whether that risk can be “eliminated or lessened” through regulation (Indus. Union Dep't, AFL-CIO v. Am. Petroleum Inst., 448 U.S. 607, 642 (1980) (plurality opinion) (“Benzene”)). The Court's holding is consistent with evidence in the legislative record, with regard to section 6(b)(5) of the Act (29 U.S.C. 655(b)(5)), that Congress intended the Agency to regulate unacceptably severe occupational hazards, and not “to establish a utopia free from any hazards” or to address risks comparable to those that exist in virtually any occupation or workplace (116 Cong. Rec. 37614 (1970), Leg. Hist. 480-82). It is also consistent with Section 6(g) of the OSH Act, which states that, in determining regulatory priorities, “the Secretary shall give due regard to the urgency of the need for mandatory safety and health standards for particular industries, trades, crafts, occupations, businesses, workplaces or work environments” (29 U.S.C. 655(g)).
The Supreme Court in Benzene clarified that “[i]t is the Agency's responsibility to determine, in the first instance, what it considers to be a `significant' risk” (Benzene, 448 U.S. at 655), and that it was not the Court's responsibility to “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” (Benzene, 448 U.S. at 659). The Court stated, however, that the section 6(f) (29 U.S.C. 655(b)(f)) substantial evidence standard applicable to OSHA's significant risk determination does not require the Agency “to support its finding that a significant risk exists with anything approaching scientific certainty” (Benzene, 448 U.S. at 656). Rather, OSHA may rely on “a body of reputable scientific thought” to which “conservative assumptions in interpreting the data . . . ” may be applied, “risking error on the side of Start Printed Page 2474overprotection” (Benzene, 448 U.S. at 656; see also
United Steelworkers of Am., AFL-CIO-CLC v. Marshall, 647 F.2d 1189, 1248 (D.C. Cir. 1980) (“Lead I”) (noting the Benzene court's application of this principle to carcinogens and applying it to the lead standard, which was not based on carcinogenic effects)). OSHA may thus act with a “pronounced bias towards worker safety” in making its risk determinations (Bldg & Constr. Trades Dep't v. Brock, 838 F.2d 1258, 1266 (D.C. Cir. 1988) (“Asbestos II”).
The Supreme Court further recognized that what constitutes “significant risk” is “not a mathematical straitjacket” (Benzene, 448 U.S. at 655) and will be “based largely on policy considerations” (Benzene, 448 U.S. at 655 n. 62). The Court gave the following example:
If . . . 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% benzene will be fatal, a reasonable person might well consider the risk significant . . . (Benzene, 448 U.S. at 655).
Following Benzene, OSHA has, in many of its health standards, considered the one-in-a-thousand metric when determining whether a significant risk exists. Moreover, as “a prerequisite to more stringent regulation” in all subsequent health standards, OSHA has, consistent with the Benzene plurality decision, based each standard on a finding of significant risk at the “then prevailing standard” of exposure to the relevant hazardous substance (Asbestos II, 838 F.2d at 1263). The Agency's final risk assessment is derived from existing scientific and enforcement data and its final conclusions are made only after considering all evidence in the rulemaking record. Courts reviewing the validity of these standards have uniformly held the Secretary to the significant risk standard first articulated by the Benzene plurality and have generally upheld the Secretary's significant risk determinations as supported by substantial evidence and “a reasoned explanation for his policy assumptions and conclusions” (Asbestos II, 838 F.2d at 1266).
Once OSHA makes its significant risk finding, the “more stringent regulation” (Asbestos II, 838 F.2d at 1263) it promulgates must be “reasonably necessary or appropriate” to reduce or eliminate that risk, within the meaning of section 3(8) of the Act (29 U.S.C. 652(8)) and Benzene (448 U.S. at 642) (see Asbestos II, 838 F.2d at 1269). The courts have interpreted section 6(b)(5) of the OSH Act as requiring OSHA to set the standard that eliminates or reduces risk to the lowest feasible level; as discussed below, the limits of technological and economic feasibility usually determine where the new standard is set (see UAW v. Pendergrass, 878 F.2d 389, 390 (D.C. Cir. 1989)). In choosing among regulatory alternatives, however, “[t]he determination that [one standard] is appropriate, as opposed to a marginally [more or less protective] standard, is a technical decision entrusted to the expertise of the agency . . . ” (Nat'l Mining Ass'n v. Mine Safety and Health Admin., 116 F.3d 520, 528 (D.C. Cir. 1997)) (analyzing a Mine Safety and Health Administration standard under the Benzene significant risk standard). In making its choice, OSHA may incorporate a margin of safety even if it theoretically regulates below the lower limit of significant risk (Nat'l Mining Ass'n, 116 F.3d at 528 (citing American Petroleum Inst. v. Costle, 665 F.2d 1176, 1186 (D.C. Cir. 1982))).
Working Life Assumption
The OSH Act requires OSHA to set the standard that most adequately protects employees against harmful workplace exposures for the period of their “working life” (29 U.S.C. 655(b)(5)). OSHA's longstanding policy is to define “working life” as constituting 45 years; thus, it assumes 45 years of exposure when evaluating the risk of material impairment to health caused by a toxic or hazardous substance. This policy is not based on empirical data that most employees are exposed to a particular hazard for 45 years. Instead, OSHA has adopted the practice to be consistent with the statutory directive that “no employee” suffer material impairment of health “even if” such employee is exposed to the hazard for the period of his or her working life (see 74 FR 44796 (8/31/09)). OSHA's policy was given judicial approval in a challenge to an OSHA standard that lowered the permissible exposure limit (PEL) for asbestos (Asbestos II, 838 F.2d at 1264-1265). In that case, the petitioners claimed that the median duration of employment in the affected industry sectors was only five years. Therefore, according to petitioners, OSHA erred in assuming a 45-year working life in calculating the risk of health effects caused by asbestos exposure. The D.C. Circuit disagreed, stating “[e]ven if it is only the rare worker who stays with asbestos-related tasks for 45 years, that worker would face a 64/1000 excess risk of contracting cancer; Congress clearly authorized OSHA to protect such a worker” (Asbestos II, 838 F.2d at 1264-1265). OSHA might calculate the health risks of exposure, and the related benefits of lowering the exposure limit, based on an assumption of a shorter working life, such as 25 years, but such estimates are for informational purposes only.
Best Available Evidence
Section 6(b)(5) of the Act requires OSHA to set standards “on the basis of the best available evidence” and to consider the “latest available scientific data in the field” (29 U.S.C. 655(b)(5)). As noted above, the Supreme Court, in its Benzene decision, explained that OSHA must look to “a body of reputable scientific thought” in making its material harm and significant risk determinations, while noting that a reviewing court must “give OSHA some leeway where its findings must be made on the frontiers of scientific knowledge” (Benzene, 448 U.S. at 656).
The courts of appeals have afforded OSHA similar latitude to issue health standards in the face of scientific uncertainty. The Second Circuit, in upholding the vinyl chloride standard, stated: “[T]he ultimate facts here in dispute are `on the frontiers of scientific knowledge', and, though the factual finger points, it does not conclude. Under the command of OSHA, it remains the duty of the Secretary to act to protect the workingman, and to act even in circumstances where existing methodology or research is deficient” (Society of the Plastics Industry, Inc. v. OSHA, 509 F.2d 1301, 1308 (2d Cir. 1975) (quoting Indus. Union Dep't, AFL-CIO v. Hodgson, 499 F.2d 467, 474 (D.C. Cir. 1974) (“Asbestos I”))). The D.C. Circuit, in upholding the cotton dust standard, stated: “OSHA's mandate necessarily requires it to act even if information is incomplete when the best available evidence indicates a serious threat to the health of workers” (Am. Fed'n of Labor & Cong. of Indus. Orgs. v. Marshall, 617 F.2d 636, 651 (D.C. Cir. 1979), aff'd in part and vacated in part on other grounds, American Textile Mfrs. Inst., Inc. v. Donovan, 452 U.S. 490 (1981)). When there is disputed scientific evidence in the record, OSHA must review the evidence on both sides and “reasonably resolve” the dispute (Pub. Citizen Health Research Grp. v. Tyson, 796 F.2d 1479, 1500 (D.C. Cir. 1986)). The Court in Public Citizen further noted that, where “OSHA has the expertise we lack and it has exercised that expertise by carefully reviewing the scientific data,” a dispute within the scientific community is not occasion for the reviewing court to take sides about which view is correct (Pub. Citizen Health Research Grp., 796 F.2d Start Printed Page 2475at 1500) or for OSHA or the courts to “ `be paralyzed by debate surrounding diverse medical opinions' ” (Pub. Citizen Health Research Grp., 796 F.2d at 1497 (quoting H.R. Rep. No. 91-1291, 91st Cong., 2d Sess. 18 (1970), reprinted in Legislative History of the Occupational Safety and Health Act of 1970 at 848 (1971))). Provided the Agency gave adequate notice in the proposal's preamble discussion of potential regulatory alternatives that the Secretary would be considering one or more stated options for regulation, OSHA is not required to prefer the option in the text of the proposal over a given regulatory alternative that was addressed in the rulemaking if substantial evidence in the record supports inclusion of the alternative in the final standard. See Owner-Operator Independent Drivers Ass'n, Inc. v. Federal Motor Carrier Safety Admin., 494 F.3d 188, 209 (D.C. Cir. 2007) (notice by agency concerning modification of sleeper-berth requirements for truck drivers was sufficient because proposal listed several options and asked a question regarding the details of the one option that ultimately appeared in final rule); Kooritzky v. Reich, 17 F.3d 1509, 1513 (D.C. Cir. 1994) (noting that a final rule need not match a proposed rule, as long as “the agency has alerted interested parties to the possibility of the agency's adopting a rule different than the one proposed” and holding that agency failed to comply with notice and comment requirements when “preamble in July offered no clues of what was to come in October”).
The OSH Act requires that, in setting a standard, OSHA must eliminate the risk of material health impairment “to the extent feasible” (29 U.S.C. 655(b)(5)). The statutory mandate to consider the feasibility of the standard encompasses both technological and economic feasibility; these analyses have been done primarily on an industry-by-industry basis (Lead I, 647 F.2d at 1264, 1301). The Agency has also used application groups, defined by common tasks, as the structure for its feasibility analyses (Pub. Citizen Health Research Grp. v. OSHA, 557 F.3d 165, 177-179 (3d Cir. 2009)). The Supreme Court has broadly defined feasible as “capable of being done” (Cotton Dust, 452 U.S. at 509-510).
Although OSHA must set the most protective PEL that the Agency finds to be technologically and economically feasible, it retains discretion to set a uniform PEL even when the evidence demonstrates that certain industries or operations could reasonably be expected to meet a lower PEL. OSHA health standards generally set a single PEL for all affected employers; OSHA exercised this discretion most recently in its final rules on occupational exposure to Chromium (VI) (71 FR 10100, 10337-10338 (2/28/2006) and Respirable Crystalline Silica (81 FR 16285, 16576-16575 (3/25/2016); see also 62 FR 1494, 1575 (1/10/97) (methylene chloride)). In its decision upholding the chromium (VI) standard, including the uniform PEL, the Court of Appeals for the Third Circuit addressed this issue as one of deference, stating “OSHA's decision to select a uniform exposure limit is a legislative policy decision that we will uphold as long as it was reasonably drawn from the record” (Chromium (VI), 557 F.3d at 183 (3d Cir. 2009)); see also Am. Iron & Steel Inst. v. OSHA, 577 F.2d 825, 833 (3d Cir. 1978)). OSHA's reasons for choosing one chromium (VI) PEL, rather than imposing different PELs on different application groups or industries, included: Multiple PELs would create enforcement and compliance problems because many workplaces, and even workers, were affected by multiple categories of chromium (VI) exposure; discerning individual PELs for different groups of establishments would impose a huge evidentiary burden on the Agency and unnecessarily delay implementation of the standard; and a uniform PEL would, by eliminating confusion and simplifying compliance, enhance worker protection (Chromium (VI), 557 F.3d at 173, 183-184). The Court held that OSHA's rationale for choosing a uniform PEL, despite evidence that some application groups or industries could meet a lower PEL, was reasonably drawn from the record and that the Agency's decision was within its discretion and supported by past practice (Chromium (VI), 557 F.3d at 183-184).
A standard is technologically feasible if the protective measures it requires already exist, can be brought into existence with available technology, or can be created with technology that can reasonably be expected to be developed (Lead I, 647 F.2d at 1272; Amer. Iron & Steel Inst. v. OSHA, 939 F.2d 975, 980 (D.C. Cir. 1991) (“Lead II”)). OSHA's standards may be “technology forcing,” i.e., where the Agency gives an industry a reasonable amount of time to develop new technologies, OSHA is not bound by the “technological status quo” (Lead I, 647 F.2d at 1264). While the test for technological feasibility is normally articulated in terms of the ability of employers to decrease exposures to the PEL, provisions such as exposure measurement requirements must also be technologically feasible (see Forging Indus. Ass'n v. Sec'y of Labor, 773 F.2d 1436, 1453 (4th Cir. 1985)).
In its Lead decisions, the D.C. Circuit described OSHA's obligation to demonstrate the technological feasibility of reducing occupational exposure to a hazardous substance.
[W]ithin the limits of the best available evidence . . . OSHA must prove a reasonable possibility 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 . . . The effect of such proof is to establish a presumption that industry can meet the PEL without relying on respirators . . . Insufficient proof of technological feasibility for a few isolated operations within an industry, or even OSHA's concession that respirators will be necessary in a few such operations, will not undermine this general presumption in favor of feasibility. Rather, in such operations firms will remain responsible for installing engineering and work practice controls to the extent feasible, and for using them to reduce . . . exposure as far as these controls can do so (Lead I, 647 F.2d at 1272).
Additionally, the D.C. Circuit explained that “[f]easibility of compliance turns on whether exposure levels at or below [the PEL] can be met in most operations most of the time . . .” (Lead II, 939 F.2d at 990).
Courts have given OSHA significant deference in reviewing its technological feasibility findings. “So long as we require OSHA to show that any required means of compliance, even if it carries no guarantee of meeting the PEL, will substantially lower . . . exposure, we can uphold OSHA's determination that every firm must exploit all possible means to meet the standard” (Lead I, 647 F.2d at 1273). Even in the face of significant uncertainty about technological feasibility in a given industry, OSHA has been granted broad discretion in making its findings (Lead I, 647 F.2d at 1285). “OSHA cannot let workers suffer while it awaits . . . scientific certainty. It can and must make reasonable [technological feasibility] predictions on the basis of `credible sources of information,' whether data from existing plants or expert testimony” (Lead I, 647 F.2d at 1266 (quoting Am. Fed'n of Labor & Cong. of Indus. Orgs., 617 F.2d at 658)). For example, in Lead I, the D.C. Circuit allowed OSHA to use, as best available evidence, information about new and expensive industrial smelting processes that had not yet been adopted in the U.S. and would require the rebuilding of plants (Lead I, 647 F.2d at 1283-1284). Even under circumstances where Start Printed Page 2476OSHA's feasibility findings were less certain and the Agency was relying on its “legitimate policy of technology forcing,” the D.C. Circuit approved of OSHA's feasibility findings when the Agency granted lengthy phase-in periods to allow particular industries time to comply (Lead I, 647 F.2d at 1279-1281, 1285).
OSHA is permitted to adopt a standard that some employers will not be able to meet some of the time, with employers limited to challenging feasibility at the enforcement stage (Lead I, 647 F.2d at 1273 & n. 125; Asbestos II, 838 F.2d at 1268). Even when the Agency recognized that it might have to balance its general feasibility findings with flexible enforcement of the standard in individual cases, the courts of appeals have generally upheld OSHA's technological feasibility findings (Lead II, 939 F.2d at 980; see Lead I, 647 F.2d at 1266-1273; Asbestos II, 838 F.2d at 1268). Flexible enforcement policies have been approved where there is variability in measurement of the regulated hazardous substance or where exposures can fluctuate uncontrollably (Asbestos II, 838 F.2d at 1267-1268; Lead II, 939 F.2d at 991). A common means of dealing with the measurement variability inherent in sampling and analysis is for the Agency to add the standard sampling error to its exposure measurements before determining whether to issue a citation (e.g., 51 FR 22612, 22654 (06/20/86) (Asbestos Preamble)).
In addition to technological feasibility, OSHA is required to demonstrate that its standards are economically feasible. A reviewing court will 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 . . .” (Lead I, 647 F.2d at 1265 (omitting citation)). As articulated by the D.C. Circuit in Lead I, “OSHA must construct a reasonable estimate of compliance costs and demonstrate a reasonable likelihood that these costs will not threaten the existence or competitive structure of an industry, even if it does portend disaster for some marginal firms” (Lead I, 647 F.2d at 1272). A reasonable estimate entails assessing “the likely range of costs and the likely effects of those costs on the industry” (Lead I, 647 F.2d at 1266). As with OSHA's consideration of scientific data and control technology, however, the estimates need not be precise (Cotton Dust, 452 U.S. at 528-29 & n. 54) as long as they are adequately explained. Thus, as the D.C. Circuit further explained:
Standards may be economically feasible even though, from the standpoint of employers, they are financially burdensome and affect profit margins adversely. Nor does the concept of economic feasibility necessarily guarantee the continued existence of individual employers. It would appear to be consistent with the purposes of the Act to envisage the economic demise of an employer who has lagged behind the rest of the industry in protecting the health and safety of employees and is consequently financially unable to comply with new standards as quickly as other employers. As the effect becomes more widespread within an industry, the problem of economic feasibility becomes more pressing (Asbestos I, 499 F.2d. at 478).
OSHA standards therefore satisfy the economic feasibility criterion even if they impose significant costs on regulated industries so long as they do not cause massive economic dislocations within a particular industry or imperil the very existence of the industry (Lead II, 939 F.2d at 980; Lead I, 647 F.2d at 1272; Asbestos I, 499 F.2d. at 478). As with its other legal findings, OSHA “is not required to prove economic feasibility with certainty, but is required to use the best available evidence and to support its conclusions with substantial evidence” ((Lead II, 939 F.2d at 980-981) (citing Lead I, 647 F.2d at 1267)).
Because section 6(b)(5) of the Act explicitly imposes the “to the extent feasible” limitation on the setting of health standards, OSHA is not permitted to use cost-benefit analysis to make its standards-setting decisions (29 U.S.C. 655(b)(5)).
Congress itself defined the basic relationship between costs and benefits, by placing the “benefit” of worker health above all other considerations save those making attainment of this “benefit” unachievable. Any standard based on a balancing of costs and benefits by the Secretary that strikes a different balance than that struck by Congress would be inconsistent with the command set forth in § 6(b)(5) (Cotton Dust, 452 U.S. at 509).
Thus, while OSHA estimates the costs and benefits of its proposed and final rules, these calculations do not form the basis for the Agency's regulatory decisions; rather, they are performed to ensure compliance with requirements such as those in Executive Orders 12866 and 13563.
Structure of OSHA Health Standards
OSHA's health standards traditionally incorporate a comprehensive approach to reducing occupational disease. OSHA substance-specific health standards generally include the “hierarchy of controls,” which, as a matter of OSHA's preferred policy, mandates that employers install and implement all feasible engineering and work practice controls before respirators may be used. The Agency's adherence to the hierarchy of controls has been upheld by the courts (ASARCO, Inc. v. OSHA, 746 F.2d 483, 496-498 (9th Cir. 1984); Am. Iron & Steel Inst. v. OSHA, 182 F.3d 1261, 1271 (11th Cir. 1999)). In fact, courts view the legal standard for proving technological feasibility as incorporating the hierarchy: “OSHA must prove a reasonable possibility 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. . . . The effect of such proof is to establish a presumption that industry can meet the PEL without relying on respirators” (Lead I, 647 F.2d at 1272).
The reasons supporting OSHA's continued reliance on the hierarchy of controls, as well as its reasons for limiting the use of respirators, are numerous and grounded in good industrial hygiene principles (see discussion in Section XVI. Summary and Explanation of the Standards, Methods of Compliance). The hierarchy of controls focuses on removing harmful airborne materials at their source “to prevent atmospheric contamination” to which the employee would be exposed, rather than relying on the proper functioning of a respirator as the primary means of protecting the employee (see 29 CFR 1910.134, 1910.1000(e), 1926.55(b)).
In health standards such as this one, the hierarchy of controls is augmented by ancillary provisions. These provisions work with the hierarchy of controls and personal protective equipment requirements to provide comprehensive protection to employees in affected workplaces. Such provisions typically include exposure assessment, medical surveillance, hazard communication, and recordkeeping.
The OSH Act compels OSHA to require all feasible measures for reducing significant health risks (29 U.S.C. 655(b)(5); Pub. Citizen Health Research Grp., 796 F.2d at 1505 (“if in fact a STEL [short-term exposure limit] would further reduce a significant health risk and is feasible to implement, then the OSH Act compels the agency to adopt it (barring alternative avenues to the same result)”). When there is significant risk below the PEL, the D.C. Circuit indicated that OSHA should use its regulatory authority to impose additional requirements on employers when those requirements will result in Start Printed Page 2477a greater than de minimis incremental benefit to workers' health (Asbestos II, 838 F.2d at 1274). The Supreme Court alluded to a similar issue in Benzene, pointing out that “in setting a permissible exposure level in reliance on less-than-perfect methods, OSHA would have the benefit of a backstop in the form of monitoring and medical testing” (Benzene, 448 U.S. at 657). OSHA concludes that the ancillary provisions in this final standard provide significant benefits to worker health by providing additional layers and types of protection to employees exposed to beryllium and beryllium compounds.
III. Events Leading to the Final 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 (Document ID 1323). 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 1970, ANSI issued a national consensus standard for beryllium and beryllium compounds (ANSI Z37.29-1970). 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 (Document ID 1303) .
In 1971, OSHA adopted, under Section 6(a) of the Occupational Safety and Health Act of 1970, and made applicable to general industry, the ANSI standard (Document ID 1303). Section 6(a) provided 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 as well as several from United States of America Standards Institute (USASI) [later the American National Standards Institute (ANSI)].
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 with Recommended Exposure Limits (RELs) of 2 µg/m3 as an 8-hour TWA 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 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 from studies finding that beryllium caused cancer in animals (40 FR 48814 (10/17/75)). 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. Then in 2009, ACGIH adopted a revised TLV for beryllium that lowered the TWA to 0.05 μg/m3 (inhalable) (see Document ID 1755, Tr. 136).
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 (Document ID 1323). 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 (10 CFR 850.22; 64 FR 68873 and 68906, Dec. 8, 1999).
Also in 1999, OSHA was petitioned by the Paper, Allied-Industrial, Chemical and Energy Workers International Union (PACE) (Document ID 0069) and by Dr. Lee Newman and Ms. Margaret Mroz, from the National Jewish Health (NJH) (Document ID 0069), 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 (Document ID 0069). 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) [6(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 ordinary notice and comment [section 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 in preparation for possible section 6(b) rulemaking.
On November 26, 2002, OSHA published a Request for Information (RFI) for “Occupational Exposure to Beryllium” (Document ID 1242). 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 chronic beryllium disease (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, Start Printed Page 2478OSHA 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 draft rule and submitted them to the panel.
The SBREFA Panel issued a report on January 15, 2008 which included the SERs' comments. 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.”
OSHA then developed a draft preliminary beryllium health effects evaluation (Document ID 1271) and a draft preliminary beryllium risk assessment (Document ID 1272), and in 2010, OSHA hired a contractor to oversee an independent scientific peer review of these documents. 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 Beryllium Lymphocyte Proliferation Test (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 preliminary 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 (Document ID 1210). 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 (Document ID 1210). 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, Document ID 0754). This draft standard 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. They 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 (NPRM) for beryllium. As described in greater detail in the Introduction to the Summary and Explanation of the final rule, there was substantial agreement between the submitted joint standard and the OSHA proposed standard.
On August 7, 2015, OSHA published its NPRM in the Federal Register (80 FR 47565 (8/7/15)). In the NPRM, the Agency made a preliminary determination that employees exposed to beryllium and beryllium compounds at the preceding PEL face a significant risk to their health and that promulgating the proposed standard would substantially reduce that risk. The NPRM (Section XVIII) also responded to the SBREFA Panel recommendations, which OSHA carefully considered, and clarified the requirements about which SERs expressed confusion. OSHA also discussed the regulatory alternatives recommended by the SBREFA Panel in NPRM, Section XVIII, and in the PEA (Document ID 0426).
The NPRM invited interested stakeholders to submit comments on a variety of issues and indicated that OSHA would schedule a public hearing upon request. Commenters submitted information and suggestions on a variety of topics. In addition, in response to a request from the Non-Ferrous Founders' Society, OSHA scheduled an informal public hearing on the proposed rule. The Agency invited interested persons to participate by providing oral testimony and documentary evidence at the hearing. OSHA also welcomed presentation of data and documentary evidence that would provide the Agency with the best available evidence to use in determining whether to develop a final rule.
The public hearing was held in Washington, DC on March 21 and 22, 2016. Administrative Law Judge William Colwell presided over the hearing. The Agency heard testimony from several organizations, such as public health groups, the Non-Ferrous Founders' Society, other industry representatives, and labor unions. Following the hearing, participants who had filed notices of intent to appear were allowed 30 days—until April 21, 2016—to submit additional evidence and data, and an additional 15 days—until May 6, 2016—to submit final briefs, arguments, and summations (Document ID 1756, Tr. 326).
In 2016, in an action parallel to OSHA's rulemaking, DOE proposed to update its action level to 0.05 μg/m3 (81 FR 36704-36759, June 7, 2016). The DOE action level triggers workplace precautions and control measures such as periodic monitoring, exposure Start Printed Page 2479reduction or minimization, regulated areas, hygiene facilities and practices, respiratory protection, protective clothing and equipment, and warning signs (Document ID 1323; 10 CFR 850.23(b)). Unlike OSHA's PEL, however, DOE's selection of an action level is not required to meet statutory requirements of technological and economic feasibility.
In all, the OSHA rulemaking record contains over 1,900 documents, including all the studies OSHA relied on in its preliminary health effects and risk assessment analyses, the hearing transcript and submitted testimonies, the joint Materion-USW draft proposed standard, and the pre- and post-hearing comments and briefs. The final rule on occupational exposure to beryllium and beryllium compounds is thus based on consideration of the entire record of this rulemaking proceeding, including materials discussed or relied upon in the proposal, the record of the hearing, and all written comments and exhibits timely received. Based on this comprehensive record, OSHA concludes that employees exposed to beryllium and beryllium compounds are at significant risk of material impairment of health, including chronic beryllium disease and lung cancer. The Agency concludes that the PEL of 0.2 μg/m3 reduces the significant risks of material impairments of health posed to workers by occupational exposure to beryllium and beryllium compounds to the maximum extent that is technologically and economically feasible. OSHA's substantive determinations with regard to the comments, testimony, and other information in the record, the legal standards governing the decision-making process, and the Agency's analysis of the data resulting in its assessments of risks, benefits, technological and economic feasibility, and compliance costs are discussed elsewhere in this preamble. More technical or complex issues are discussed in greater detail in the background documents referenced in this preamble.
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 (Document ID 0389, p. 1). It occurs naturally in rocks, soil, coal, and volcanic dust (Document ID 1567, p. 1). 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.
Start Printed Page 2480
Table IV-1—Properties of Beryllium and Beryllium Compounds
|Chemical name||CAS No.||Synonyms and trade
names||Molecular weight||Melting point (°C)||Description||Density (g/cm3)||Solubility|
|Beryllium metal||7440-41-7||Beryllium; beryllium-9, beryllium element; beryllium metallic||9.0122||1287||Grey, close-packed, hexagonal, brittle metal||1.85 (20 °C)||Soluble in most dilute acids and alkali; decomposes in hot water; insoluble in mercury and cold water.|
|Beryllium chloride||7787-47-5||Beryllium dichloride||79.92||399.2||Colorless to slightly yellow; orthorhombic, deliques-cent crystal||1.899 (25 °C)||Soluble in water, ethanol, diethyl ether and pyridine; slightly soluble in benzene, carbon disulfide and chloroform; insoluble in acetone, ammonia, and toluene.|
|Beryllium fluoride||7787-49-7 (12323-05-6)||Beryllium difluoride||47.01||555||Colorless or white, amorphous, hygroscopic solid||1.986||Soluble in water, sulfuric acid, mixture of ethanol and diethyl ether; slightly soluble in ethanol; insoluble in hydrofluoric acid.|
|Beryllium hydroxide||13327-32-7 (1304-49-0)||Beryllium dihydroxide||43.3||138 (decomposes to beryllium oxide)||White, amorphous, amphoteric powder||1.92||Soluble in hot concentrated acids and alkali; slightly soluble in dilute alkali; insoluble in water.|
|Beryllium sulfate||13510-49-1||Sulfuric acid, beryllium salt (1:1)||105.07||550-600 °C (decomposes to beryllium oxide)||Colorless crystal||2.443||Forms soluble tetrahydrate in hot water; insoluble in cold water.|
|Beryllium sulfate tetrhydrate||7787-56-6||Sulfuric acid; beryllium salt (1:1), tetrahydrate||177.14||100 °C||Colorless, tetragonal crystal||1.713||Soluble in water; slightly soluble in concentrated sulfuric acid; insoluble in ethanol.|
|Beryllium Oxide||1304-56-9||Beryllia; beryllium monoxide thermalox TM||25.01||2508-2547 °C||Colorless to white, hexagonal crystal or amorphous, amphoteric powder||3.01 (20 °C)||Soluble in concentrated acids and alkali; insoluble in water.|
|Beryllium carbonate||1319-43-3||Carbonic acid, beryllium salt, mixture with beryllium hydroxide||112.05||No data||White powder||No data||Soluble in acids and alkali; insoluble in cold water; decomposes in hot water.|
|Beryllium nitrate trihydrate||7787-55-5||Nitric acid, beryllium salt, trihydrate||187.97||60||White to faintly yellowish, deliquescent mass||1.56||Very soluble in water and ethanol.|
|Beryllium phosphate||13598-15-7||Phosphoric acid, beryllium salt (1:1)||104.99||No data||Not reported||Not reported||Slightly soluble in water.|
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 (Document ID 0389, p. 1). 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 (Document ID 1342, pp. 45, 48).
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 (Document ID 1342, p. 48). Imported beryl is also converted into beryllium hydroxide as the United States has very little beryl that can be economically mined (Document ID 0616, p. 28).
Materion Corporation (Materion), 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 (Document ID 0389, p. 1). Beryllium oxide is used in components such as ceramics, electrical insulators, microwave oven components, military vehicle armor, laser structural components, and automotive ignition systems (Document ID 1567, p. 147). 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 (Document ID 0389, p. 2; 1278, p. 182; 1280, pp. 1-2; 1281, pp. 816, 818). Electrical components and conductors are stamped and formed from beryllium alloys. Beryllium-copper alloys are used to make switches in automobiles (Document ID 1280, p. 2; 1281, p. 818) and connectors, relays, and switches in computers, radar, satellite, and telecommunications equipment (Document ID 1278, p. 183). Beryllium-aluminum alloys are used in the construction of aircraft, high resolution medical and industrial X-ray equipment, and mirrors to measure weather patterns (Document ID 1278, p. 183). 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 (Document ID 0385, 0426).
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
Overview of Findings and Supportive Comments
As discussed in detail throughout this section (section V, Final Health Effects) and in Section VI, Final Quantitative Risk Assessment and Significance of Risk, OSHA finds, based upon the best available evidence in the record, that exposure to soluble and poorly soluble forms of beryllium are associated with several adverse health outcomes including sensitization, chronic beryllium disease, acute beryllium disease and lung cancer.
The findings and conclusions in this section are consistent with those of the National Academies of Sciences (NAS), the World Health Organization's International Agency for Research on Cancer (IARC), the U.S. Department of Health and Human Services' (HHS) National Toxicology Program (NTP), the National Institute for Occupational Safety and Health (NIOSH), the Agency for Toxic Substance and Disease Registry (ATSDR), the European Commission on Health, Safety and Hygiene at Work, and many other organizations and individuals, as evidenced in the rulemaking record and further discussed below. Other scientific organizations and governments have recognized the strong body of scientific evidence pointing to the health risks of exposure to beryllium and have deemed it necessary to take action to reduce those risks. In 1999, the Department of Energy (DOE) updated its airborne beryllium concentration action level to 0.2 μg/m3 (Document ID 1323). In 2009, the American Conference of Governmental Industrial Hygienists (ACGIH), a professional society that has been recommending workplace exposure limits for six decades, revised its Threshold Limit Value (TLV) for beryllium and beryllium-containing compounds to 0.05 μg/m3 (Document ID 1304).
In finalizing this Health Effects preamble section for the final rule, OSHA updated the preliminary Health Effects section published in the NPRM based on the stakeholder response received by the Agency during the public comment period and public hearing. OSHA also corrected several non-substantive errors that were published in the NPRM as well as those identified by NIOSH and Materion including several minor organizational changes made to sections V.D.3 and V.E.2.b (Document ID 1671, pp. 10-11; 1662, pp. 3-5). A section titled “Dermal Effects” was added to V.F.5 based on comments received by the American Thoracic Society (ATS), National Jewish Health, and the National Supplemental Screening Program (Document ID 1688, p. 2; 1664, p. 5; 1677, p. 3). Additionally, the Agency responded to relevant stakeholder comments contained in specific sections.
In developing its review of the preliminary health effects from beryllium exposure and assessment of risk for the NPRM, OSHA prepared a Start Printed Page 2481pair of draft documents, entitled “Occupation Exposure to Beryllium: Preliminary Health Effects Evaluation” (OSHA, 2010, Document ID 1271) and “Preliminary Beryllium Risk Assessment” (OSHA, 2010, Document ID 1272), that underwent independent scientific peer review in accordance with the Office of Management and Budget's (OMB) Information Quality Bulletin for Peer Review. Eastern Research Group, Inc. (ERG), under contract with OSHA, selected five highly qualified experts with collective expertise in occupational epidemiology, occupational medicine, toxicology, immunology, industrial hygiene, and risk assessment methodology.
The peer reviewers responded to 27 questions that covered the accuracy, completeness, and understandability of key studies and adverse health endpoints as well as questions regarding the adequacy, clarity and reasonableness of the risk analysis (ERG, 2010; Document ID 1270).
Overall, the peer reviewers found that the OSHA draft health effects evaluation described the studies in sufficient detail, appropriately addressed their strengths and limitations, and drew scientifically sound conclusions. The peer reviewers were also supportive of the Agency's preliminary risk assessment approach and the major conclusions. OSHA provided detailed responses to reviewer comments in its publication of the NPRM (80 FR 47646-47652, 8/7/2015). Revisions to the draft health effects evaluation and preliminary risk assessment in response to the peer review comments were reflected in sections V and VI of the same publication (80 FR 47581-47646, 8/7/2015). OSHA received public comment and testimony on the Health Effects and Preliminary Risk Assessment sections published in the NPRM, which are discussed in this preamble.
The Agency received a wide variety of stakeholder comments and testimony for this rulemaking on issues related to the health effects and risk of beryllium exposure. Statements supportive of OSHA's Health Effects section include comments from NIOSH, the National Safety Council, the American Thoracic Society (ATS), Representative Robert C. “Bobby” Scott, Ranking Member of Committee on Education and the Workforce, the U.S. House of Representatives, national labor organizations (American Federation of Labor—Congress of Industrial Organizations (AFL-CIO), North American Building Trades Unions (NABTU), United Steelworkers (USW), Public Citizen, ORCHSE, experts from National Jewish Health (Lisa Maier, MD and Margaret Mroz, MSPH), the American Association for Justice, and the National Council for Occupational Safety and Health.
For example, NIOSH commented in its prepared written hearing testimony:
OSHA has appropriately identified and documented all critical health effects associated with occupational exposure to beryllium and has appropriately focused its greatest attention on beryllium sensitization (BeS), chronic beryllium disease (CBD) and lung cancer . . .
NIOSH went on to say that sensitization was more than a test result with little meaning. It relates to a condition in which the immune system is able to recognize and adversely react to beryllium in a way that increases the risk of developing CBD. NIOSH agrees with OSHA that sensitization is a functional change that is necessary in order to proceed along the pathogenesis to serious lung disease.
The National Safety Council, a congressionally chartered nonprofit safety organization, also stated that “beryllium represents a serious health threat resulting from acute or chronic exposures.” (Document ID 1612, p. 5). Representative Robert C. “Bobby” Scott, Ranking Member of Committee on Education and the Workforce, the U.S. House of Representatives, submitted a statement recognizing that the evidence strongly supports the conclusion that sensitization can occur from exposure to soluble and poorly soluble forms of beryllium (Document ID 1672, p. 3).
OSHA also received supporting statements from ATS and ORCHSE on the inclusion of beryllium sensitization, CBD, skin disease, and lung cancer as major adverse health effects associated with beryllium exposure (Document ID 1688, p. 7; 1691, p. 14). ATS specifically stated:
. . . the ATS supports the inclusion of beryllium sensitization, CBD, and skin disease as the major adverse health effects associated with exposure to beryllium at or below 0.1 μg/m3 and acute beryllium disease at higher exposures based on the currently available epidemiologic and experimental studies. (Document ID 1688, p. 2)
In addition, OSHA received supporting comments from labor organizations representing workers exposed to beryllium. The AFL-CIO, NABTU, and USW submitted comments supporting the inclusion of beryllium sensitization, CBD and lung cancer as health effects from beryllium exposure (Document ID 1689, pp. 1, 3; 1679, p. 6; 1681, p. 19). AFL-CIO commented that “[t]he proposal is based on extensive scientific and medical evidence . . .” and “[b]eryllium exposure causes immunological sensitivity, CBD and lung cancer. These health effects are debilitating, progressive and irreversible. Workers are exposed to beryllium through respiratory, dermal and gastrointestinal routes.” (Document ID 1689, pp. 1, 3). Comments submitted by USW state that “OSHA has correctly identified, and comprehensively documented the material impairments of health resulting from beryllium exposure.” (Document ID 1681, p. 19).
Dr. Lisa Maier and Ms. Margaret Mroz of National Jewish Health testified about the health effects of beryllium in support of the beryllium standard:
We know that chronic beryllium disease often will not manifest clinically until irreversible lung scarring has occurred, often years after exposure, with a latency of 20 to 30 years as discussed yesterday. Much too late to make changes in the work place. We need to look for early markers of health effects, cast the net widely to identify cases of sensitization and disease, and use screening results in concert with exposure sampling to identify areas of increased risk that can be modified in the work place. (Document ID 1756, Tr. 102; 1806).
American Association for Justice noted that:
Unlike many toxins, there is no threshold below which no worker will become sensitized to beryllium. Worker sensitization to beryllium is a precursor to CBD, but not cancer. The symptoms of chronic beryllium disease (CBD) are part of a continuum of disease that is progressive in nature. Early recognition of and treatment for CBD may lead to a lessening of symptoms and may prevent the disease from progressing further. Symptoms of CBD may occur at exposure levels well below the proposed permissible exposure limit of .2 µg/m3 and even below the action level of .1 µg/m3. OSHA has clear authority to regulate health effects across the entire continuum of disease to protect workers. We applaud OSHA for proposing to do so. (Document ID 1683, pp. 1-2).
National Committee for Occupational Safety and Health support OSHA findings of health effects due to beryllium exposure (1690, p. 1). Comments from Public Citizen also support OSHA findings: “Beryllium is toxic at extremely low levels and exposure can result in BeS, an immune response that eventually can lead to an autoimmune granulomatous lung disease known as CBD. BeS is a necessary prerequisite to the development of CBD, with OSHA's Start Printed Page 2482NPRM citing studies showing that 31-49 percent of all sensitized workers were diagnosed with CBD after clinical evaluations. Beryllium also is a recognized carcinogen that can cause lung cancer.” (Document ID 1670, p.2).
In addition to the comments above and those noted throughout this Health Effects section, Materion submitted their correspondence to the National Academies (NAS) regarding the company's assessment of the NAS beryllium studies and their correspondence to NIOSH regarding the Cummings 2009 study (Document 1662, Attachments) to OSHA. For the NAS study, Materion included a series of comments regarding studies included in the NAS report. OSHA has reviewed these comments and found that the comments submitted to the NAS critiquing their review of the health effects of beryllium were considered and incorporated where appropriate. For the NIOSH study Materion included comments regarding 2 cases of acute beryllium disease evaluated in a study published by Cummings et al., 2009. NIOSH also dealt with the comments from Materion as they found appropriate. However, none of the changes recommended by Materion to the NAS or NIOSH altered the overall findings or conclusions from either study. OSHA has taken the Materion comments into account in the review of these documents. OSHA found them not to be sufficient to discount either the findings of the NAS or NIOSH.
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, Document ID 1324, 1325, 1326, 1327, 1328; NIOSH, 2011 (0544)).
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—Particle Characterization
1. Particle Physical/Chemical Properties
Beryllium has two oxidative states: Be(0) and Be(2+) (Agency for Toxic Substance and Disease Registry (ATSDR) 2002, Document ID 1371). 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) as discussed in more detail in the Beryllium Sensitization section below. Beryllium has a high charge-to-radius ratio, forming various types of ionic bonds. In addition, 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, Document ID 1371; Greene et al., 1998 (1519)). However, it appears that few, if any, toxicity studies exist for the organometallic compounds. Additional physical/chemical properties, such as solubility, for beryllium compounds that may be important in their biological response are summarized in Table 1 below. Solubility (as discussed in biological fluids in Section V.A.2.A below) is an important factor in evaluating the biological response to beryllium. For comparative purposes, water solubility is used in Table 1. The International Chemical Safety Cards lists water solubility as a way to standardize solubility values among particles and fibers. The information contained within Table 1 was obtained from the International Chemical Safety Cards (ICSC) for beryllium metal (ICSC 0226, Document ID 0438), beryllium oxide (ICSC 1325, Document ID 0444), beryllium sulfate (ICSC 1351, Document ID 0443), beryllium nitrate (ICSC 1352, Document ID 0442), beryllium carbonate (ICSC 1353, Document ID 0441), beryllium chloride (ICSC 1354, Document ID 0440), beryllium fluoride (ICSC 1355, Document ID 0439) and from the hazardous substance data bank (HSDB) for beryllium hydroxide (CASRN: 13327-32-7), and beryllium phosphate (CASRN: 13598-15-7, Document ID 0533). 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.
Start Printed Page 2483
Table 1—Beryllium Characteristics and Properties
|Compound name||Chemical formula||Molecular mass||Acute physical hazards||Solubility in water at 20 °C|
|Beryllium Metal||Be||9.0||Combustible; Finely dispersed particles—Explosive||None.|
|Beryllium Oxide||BeO||25.0||Not combustible or explosive||Very sparingly soluble.|
|Beryllium Carbonate||Be2 CO3 (OH)/Be2 CO5 H2||181.07||Not combustible or explosive||None.|
|Beryllium Sulfate||BeSO4||105.1||Not combustible or explosive||Slightly soluble.|
|Beryllium Nitrate||BeN2 O6/Be(NO3)2||133.0||Enhances combustion of other substances||Very soluble (1.66 × 106 mg/L).|
|Beryllium Hydroxide||Be(OH)2||43.0||Not reported||Slightly soluble 0.8 × 10−4 mol/L (3.44 mg/L).|
|Beryllium Chloride||BeCl2||79.9||Not combustible or explosive||Soluble.|
|Beryllium Fluoride||BeF2||47.0||Not combustible or explosive||Very soluble.|
|Beryllium Phosphate||Be3 (PO4)2||271.0||Not reported||Soluble.|
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 and cause respiratory tract exposure or dermal exposure (also referred to as dermal contact). The physical properties of 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, solubility 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. 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.
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 contact or exposure, the physical characteristics of the particle are also important since they can influence skin absorption and bioavailability. This section addresses certain physical characteristics (i.e., solubility, particle size, particle surface area) that influence the toxicity of beryllium materials in occupational settings.
Solubility has been shown to 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, Document ID 1560; Mandervelt et al., 1997 (1451)). Similar to inhaled agents, the ability of materials to penetrate the skin is also influenced by solubility because dermal absorption may occur at a greater rate for soluble materials than poorly soluble materials (Kimber et al., 2011, Document ID 0534). In post-hearing comments, NIOSH explained:
In biological systems, solubility is used to describe the rate at which a material will undergo chemical clearance and dissolve in a fluid (airway lining, inside phagolysomes) relative to the rate of mechanical clearance. For example, in the lung a “poorly soluble” material is one that dissolves at a rate slower than the rate of mechanical removal via the mucociliary escalator. Examples of poorly soluble forms of beryllium are beryllium silicates, beryllium oxide, and beryllium metal and alloys (Deubner et al. 2011; Huang et al. 2011; Duling et al. 2012; Stefaniak et al. 2006, 201la, 2012). A highly soluble material is one that dissolves at a rate faster than mechanical clearance. Examples of highly soluble forms of beryllium are beryllium fluoride, beryllium sulfate, and beryllium chloride. (Document ID 1660-A2, p. 9).
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 poorly 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, Document ID 1309). According to an EPA report, 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 poorly soluble hydroxides or hydrated complexes within the general physiological range of pH values (between 5 and 8) (EPA, 1998, Document ID 1322). This may be an important factor in the development of CBD since lower-soluble 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, Document ID 1355).
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 or poorly soluble (almost insoluble or having an extremely slow rate of dissolution and most often referred to as poorly soluble in more recent literature). 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, Document 1547). 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, Document ID 1510). 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, Document ID 0527).
Investigators have also attempted to determine how biological fluids can dissolve beryllium materials. In two studies, poorly soluble beryllium, taken up by activated phagocytes, was shown to be ionized by myeloperoxidases (Leonard and Lauwerys, 1987, Document ID 1293; Lansdown, 1995 (1469)). 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, Document ID 1355). 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, Document ID 1398), and the rate of dissolution of the multi-constituent (mixed) particles Start Printed Page 2484was 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) and therefore dissolve at a higher rate. A follow-up study by the same investigational team (Duling et al., 2012, Document ID 0539) 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, Document ID 0539).
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 smelter 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, Document ID 0537).
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, and rose more 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, Document ID 0531).
In an in vitro skin model, Sutton et al. (2003) demonstrated the dissolution of beryllium compounds (poorly soluble beryllium hydroxide, soluble beryllium phosphate) in a simulated sweat fluid (Document ID 1393). 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) (Document ID 0539).
In summary, studies have shown that soluble forms of beryllium readily dissolve into ionic components making them biologically available for dermal penetration and activation of immune cells (Stefaniak et al., 2011; Document ID 0537). Soluble forms can also be converted to less soluble forms in the lung (Reeves and Vorwald, 1967, Document ID 1309) making persistence in the lung a possibility and increasing the potential for development of CBD (see section V.D.2). Studies by Stefaniak et al. (2003, 2006, 2011, 2012) (Document ID 1347; 1398; 0537; 0469), Huang et al. (2011), Duling et al. (2012), and Deubner et al. (2011) have demonstrated poorly soluble forms can be readily dissolved in biological fluids such as sweat, lung fluid, and cellular fluids. The dissolution of beryllium ions into biological fluids increases the likelihood of beryllium presentation to immune cells, thus increasing the potential for sensitization through dermal contact or lung exposure (Document ID 0531; 0539; 0527) (see section V.D.1).
OSHA received comments from the Non-Ferrous Founders' Society (NFFS) contending that the scientific evidence does not support insoluble beryllium as a causative agent for sensitization and CBD (Document ID 1678, p. 6). The NFFS contends that insoluble beryllium is not carcinogenic or a sensitizer to humans, and argues that based on this information, OSHA should consider a bifurcated standard with separate PELs for soluble and poorly soluble beryllium and beryllium compounds and insoluble beryllium metallics (Document ID 1678, p. 7). As evidence supporting its conclusion, the NFFS cited a 2010 statement written by Dr. Christian Strupp commissioned by the beryllium industry (Document ID 1785, 1814), which reviewed selected studies to evaluate the toxic potential of beryllium metal and alloys (Document ID 1678, pp. 7). The Strupp and Furnes statement (2010) cited by the NFFS is the background material and basis of the Strupp (2011a and 2011b) studies in the docket (Document ID 1794; 1795). In response to Strupp 2011 (a and b), Aleks Stefaniak of NIOSH published a letter to the editor refuting some of the evidence presented by Strupp (2011a and b, Document ID 1794; 1795). The first study by Strupp (2011a) evaluated selected animal studies and concluded that beryllium metal was not a sensitizer. Stefaniak (2011) evaluated the validity of the Strupp (2011a) study of beryllium toxicity and noted numerous deficiencies, including deficiencies in the study design, improper administration of beryllium test compounds, and lack of proper controls (Document ID 1793). In addition, Strupp (2011a) omitted numerous key animal and epidemiological studies demonstrating the potential of poorly soluble beryllium and beryllium metal as a sensitizing agent. One such study, Tinkle et al. (2003), demonstrated that topical application of poorly soluble beryllium induced skin sensitization in mice (Document ID 1483). Comments from NIOSH and National Jewish Medical Center state that poorly soluble beryllium materials are capable of dissolving in sweat (Document ID 1755; 1756). After evaluating the scientific evidence from epidemiological and animal studies, OSHA finds, based on the best available evidence, that soluble and poorly soluble forms of beryllium and beryllium compounds are causative agents of sensitization and CBD.
b. Particle Size
The toxicity of beryllium as exemplified by beryllium oxide is dependent, in part, on the particle size, with smaller particles (less than 10 μm in diameter) able to penetrate beyond the larynx (Stefaniak et al., 2008, Document ID 1397). Most inhalation studies and occupational exposures involve quite small (less than 1-2 μm in diameter) beryllium oxide particles that can penetrate to the pulmonary regions of the lung (Stefaniak et al., 2008, Document ID 1397). In inhalation studies with beryllium ores, particle sizes are generally much larger, with deposition occurring in several areas throughout the respiratory tract for particles less than 10 μm in diameter.
The temperature at which beryllium oxide is calcined influences its particle size, surface area, solubility, and ultimately its toxicity (Delic, 1992, Document ID 1547). 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, Document ID 1547).
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 Start Printed Page 2485and 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 (Document ID 0540). 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 across different operations (Document ID 1314). 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 (Document ID 1053). 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 those smaller particles being 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 (Document ID 1389). Kent et al. (2001) measured airborne beryllium using size-selective samplers in five furnace areas at a beryllium processing facility (Document ID 1361). A statistically significant linear trend was reported between the 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 (Document ID 0465). 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 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 poorly soluble forms of beryllium. Analysis of particle size revealed most process areas had particles ranging from 5 to 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 by considering more relevant aspects of exposure such as particle size distribution, chemical form, and solubility could potentially improve exposure assessments (Virji et al., 2011, Document ID 0465).
To summarize, particle size influences deposition of beryllium particles in the lung, thereby influencing toxicity. Studies by Stefaniak et al. (2008) demonstrated that the majority of particles generated by beryllium processing operations were in the respirable range (less than 1-2 μm) (Document ID 1397). However, studies by Virji et al. (2011) (Document ID 0465), Cohen et al. (1983) (Document ID 0540) and Hoover et al. (1990) (Document ID 1314) showed that some operations could generate particle sizes ranging from 3 to 16 μm.
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, Document ID 1539; Miller, 1995 (0523); Oberdorster et al., 1996 (1434)). 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, pro- and anti-oxidant defenses and apoptosis, which has been shown to increase the tumorigenic potential of poorly-soluble particles (Elder et al., 2005, Document ID 1537; Carter et al., 2006 (1556); Refsnes et al., 2006 (1428)).
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 (Document ID 1317). 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 (Document ID 1547).
Several studies have investigated the lung toxicity of beryllium oxide calcined at different temperatures and generally have 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, Document ID 1495; Polák et al., 1968 (1431); Haley et al., 1989 (1366); Haley et al., 1992 (1365); Hall et al., 1950 (1494)). 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, Document ID 1495). 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 Start Printed Page 2486area did not entirely predict cytotoxicity (Finch et al., 1991, Document ID 1535).
Stefaniak et al. (2003) investigated the particle structure and surface area of beryllium metal, beryllium oxide, and copper-beryllium alloy particles (Document ID 1347). 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. (2003) found lesser variation in SSA for the alloys or oxides (Document ID 1347). 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 beryllium sensitization 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, absorption through the skin, or ingestion. 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. Disposition (deposition and clearance) of the particle or droplet along the respiratory tract influences the biological response to the toxicant (Schlesinger et al., 1997, Document ID 1290). Inhaled beryllium particles are deposited along the respiratory tract in a size dependent manner as described by the International Commission for radiological Protection (ICRP) model (Figure 1). 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 in particle diameter, 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). However, due to the hygroscopic nature of soluble particles, deposition patterns may be slightly different with an enhanced preference for the tracheobronchial or bronchial region of the lung. Nonetheless, soluble particles are still capable of depositing in the pulmonary region (Schlesinger et al., 1997, Document ID 1290).
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.
Beryllium is removed from the respiratory tract by various clearance mechanisms. Soluble beryllium is removed from the respiratory tract via absorption or chemical clearance (Schlesinger, 1997, Document ID 1290). Sparingly soluble or poorly soluble beryllium is removed via mechanical mechanisms and may remain in the Start Printed Page 2487lungs for many years after exposure, as has been observed in workers (Schepers, 1962, Document ID 1414). Clearance mechanisms for sparingly soluble or poorly soluble 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, Document ID 1290). Mechanical clearance mechanisms may occur slowly in humans, which is consistent with some animal and human 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, Document ID 1405).
Due to physiological differences, clearance rates can vary between humans and animal species (Schlesinger, 1997, Document ID 1290; Miller, 2000 (1831)). However, clearance rates are also dependent upon the solubility, dose, and size of the inhaled beryllium compound. As reviewed in a WHO Report (2001) (Document ID 1282), 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, Document ID 1287; Hart et al., 1980 (1493); Finch et al., 1990 (1318)). Animal inhalation or intratracheal instillation studies administering soluble beryllium salts demonstrated significant absorption of approximately 20 percent of the initial lung burden with rapid dissolution of soluble compounds from the lung (Delic, 1992, Document ID 1547). Absorption of poorly soluble compounds such as beryllium oxide administered via inhalation or intratracheal instillation was slower and less significant (Delic, 1992, Document ID 1547). Additional animal studies have demonstrated that clearance of poorly 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, Document ID 1558; Sanders et al., 1978 (1485); Delic, 1992 (1547); WHO, 2001 (1282)). Confirmatory studies in rats have shown the half-time for the rapid phase to be between 1 and 60 days, while the slow phase ranged from 0.6 to 2.3 years. Studies have also shown that this process was influenced by the solubility of the beryllium compounds: Weeks/months for soluble compounds, months/years for poorly soluble compounds (Reeves and Vorwald, 1967; Reeves et al., 1967; 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 poorly soluble beryllium compounds or metal administered by this exposure route. (WHO, 2001, Document ID 1282; ATSDR, 2002 (1371).)
Evidence from animal studies suggests that greater amounts of beryllium deposited in the lung may result in slower clearance times. Acute inhalation studies performed in rats and mice using a single dose of inhaled aerosolized beryllium metal showed that exposure to beryllium metal can slow particle clearance and induce lung damage in rats and mice (Finch et al., 1998, Document ID 1317; Haley et al., 1990 (1314)). 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 from 250 to 380 days for the three concentrations. For mice (Finch et al., 1998, Document ID 1317), 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 was shown to distribute primarily to the tracheobronchial lymph nodes via the lymph system, bloodstream, and skeleton (Stokinger et al., 1953, Document ID 1277; Clary et al., 1975 (1320); Sanders et al., 1975 (1486); Finch et al., 1990 (1318)). Studies in rats demonstrated accumulation of beryllium chloride in the skeletal system following intraperitoneal injection (Crowley et al., 1949, Document ID 1551; Scott et al., 1950 (1413)) and accumulation of beryllium phosphate and beryllium sulfate in both non-parenchymal and parenchymal cells of the liver after intravenous administration in rats (Skilleter and Price, 1978, Document ID 1408). Studies have also demonstrated intracellular accumulation of beryllium oxide in bone marrow throughout the skeletal system after intravenous administration to rabbits (Fodor, 1977, Document ID 1532; WHO, 2001 (1282)). Trace amounts of beryllium have also been shown to be distributed throughout the body (WHO, 2001, Document ID 1282).
Systemic distribution of the more soluble compounds was shown to be greater than that of the poorly soluble compounds (Stokinger et al., 1953, Document ID 1277). 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, Document ID 1342). A half-life of 450 days has been estimated for beryllium in the human skeleton (ICRP, 1960, Document ID 0248). 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 (WHO, 2001, Document ID 1282). In a recent review of the information, the American Conference of Governmental Industrial Hygienists (ACGIH, 2010) was not able to confirm the association between occupational inhalation and urinary excretion (Document ID 1662, p. 4). However, IARC (2012) noted that an accidental exposure of 25 people to beryllium dust reported in a study by Zorn et al. (1986) resulted in a mean serum concentration of 3.5 μg/L one day after the exposure, which decreased to 2.4 μg/L by day six. The IARC report concluded that beryllium from beryllium metal was biologically available for systemic distribution from the lung (IARC, 2012, Document ID 0650).
Based on these studies, OSHA finds that the respiratory tract is a primary pathway for beryllium exposure. While particle size and surface area may contribute to the toxicity of beryllium, there is not sufficient evidence for OSHA to regulate based on size and surface area. However, the Agency finds that both soluble and poorly soluble forms of beryllium and beryllium compounds can contribute to exposure via the respiratory system and therefore can be causative agents of sensitization and CBD.Start Printed Page 2488
2. Dermal Exposure
Beryllium compounds have been shown to cause skin irritation and sensitization in humans and certain animal models (Van Ordstrand et al., 1945, Document ID 1383; de Nardi et al., 1953 (1545); Nishimura, 1966 (1435); Epstein, 1991 (0526); Belman, 1969 (1562); Tinkle et al., 2003 (1483); Delic, 1992 (1547)). 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, Document ID 1371). However, even minute contact and absorption across the skin may directly elicit an immunological response resulting in sensitization (Deubner et al., 2001, Document ID 1543; Toledo et al., 2011 (0522)). 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 less than or equal to 1μm in diameter, as confirmed by scanning electron microscopy (Document ID 1483). 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, Document ID 1391) suggesting the flexing and stretching motion as a plausible mechanism for dermal penetration of beryllium as well. As earlier summarized, poorly soluble forms of beryllium can be solubilized in biological fluids (e.g., sweat) making them available for absorption through intact skin (Sutton et al., 2003, Document ID 1393; Stefaniak et al., 2011 (0537) and 2014 (0517); Duling et al., 2012 (0539)).
Although its precise role remains to be elucidated, there is evidence 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, Document ID 1383). Further investigation by McCord in 1951 (Document ID 1448) 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 poorly soluble 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, Document ID 1273). 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, Document ID 1383). Contamination of cuts and scrapes with beryllium can result in the beryllium becoming embedded within the skin causing an ulcerating granuloma to develop in the skin (Epstein, 1991, Document ID 0526). Soluble and poorly soluble beryllium-compounds that penetrate the skin as a result of abrasions or cuts have been shown to result in chronic ulcerations and skin granulomas (Van Ordstrand et al., 1945, Document ID 1383; Lederer and Savage, 1954 (1467)). Beryllium absorption through bruises and cuts has been demonstrated as well (Rossman et al., 1991, Document ID 1332).
In a study by Ivannikov et al. (1982) (as cited in Deubner et al., 2001, Document ID 0023), beryllium chloride was applied directly to three different types of wounded skin: abrasions (superficial skin trauma), cuts (skin and superficial muscle trauma), and penetration wounds (deep muscle trauma). According to Deubner et al. (2001) the percentage of the applied dose systemically absorbed 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 (Deubner et al., 2001, Document ID 0023).
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, Document ID 1543). 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, Document ID 0474), multiplied by a factor of 10 to approximate the workplace concentrations and the very low absorption rate of beryllium into skin of 0.001 percent (taken from EPA estimates). As cited by Deubner et al. (2001), the EPA 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 (Deubner et al., 2001, Document ID 1543).
A study conducted by Day et al. (2007) evaluated the effectiveness of a dermal protection program implemented in a beryllium alloy facility in 2002 (Document ID 1548). 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 strong correlation between air concentrations determined from sampling data 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 promoted 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) demonstrating the importance of dermal protection measures since sensitization can occur via dermal exposure as well as respiratory exposure. The investigators demonstrated multiple pathways of exposure which could lead to sensitization, increasing risk for developing CBD (Day et al., 2007, Document ID 1548).
The same group of investigators extended their work on investigating multiple exposure pathways contributing to sensitization and CBD (Armstrong et al., 2014, Document ID 0502). 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 and surface concentrations; glove and surface concentrations; and air and glove concentrations at this facility. This work supports findings from Day et al. (2007) (Document ID 1548) demonstrating the importance of airborne beryllium concentrations to surface contamination and dermal exposure even at exposures below the Start Printed Page 2489preceding OSHA PEL (Armstrong et al., 2014, Document ID 0502).
OSHA received comments regarding the potential for dermal penetration of poorly soluble particles. Materion contended there is no supporting evidence to suggest that insoluble or poorly soluble particles penetrate skin and stated:
. . . we were aware that, a hypothesis has been put forth which suggests that being sensitized to beryllium either through a skin wound or via penetration of small beryllium particles through intact skin could result in sensitization to beryllium which upon receiving a subsequent inhalation dose of airborne beryllium could result in CBD. However, there are no studies that skin absorption of insoluble beryllium results in a systemic effect. The study by Curtis, the only human study looking for evidence of a beryllium sensitization reaction occurring through intact human skin, found no sensitization reaction using insoluble forms of beryllium. (Document ID 1661, p. 12).
OSHA disagrees with the assertion that no studies are available indicating skin absorption of poorly soluble (insoluble) beryllium. In addition to the study cited by Materion (Curtis, 1951, Document ID 1273), OSHA reviewed numerous studies on the effects of beryllium solubility and dermal penetration (see section V. B. 2) including the Tinkle et al. (2003) (Document ID 1483) study which demonstrated the potential for poorly soluble beryllium particles to penetration skin using an ex vivo human skin model. While OSHA believes that these studies demonstrate poorly soluble beryllium can in fact penetrate intact skin, penetration through intact skin is not the only means for a person to become sensitized through skin contact with poorly soluble beryllium. During the informal hearing proceedings, NIOSH was asked about the role of poorly soluble beryllium in sensitizing workers to beryllium. Aleks Stefaniak, Ph.D., NIOSH, stated that “intact skin naturally has a barrier that prevents moisture from seeping out of the body and things from getting into the body. Very few people actually have fully intact skin, especially in an industrial environment. So the skin barrier is often compromised, which would make penetration of particles much easier.” (Document ID 1755, Tr. 36).
As summarized above, poorly soluble beryllium particles have been shown to solubilize in biological fluids (e.g., sweat) releasing beryllium ions and making them available for absorption through intact skin (Sutton et al., 2003, Document ID 1393; Stefaniak et al. 2014 (0517); Duling et al., 2012 (0539)). Epidemiological studies evaluating the effectiveness of PPE in facilities working with beryllium (with special emphasis on skin protection) have demonstrated a reduced rate of beryllium sensitization after implementation of this type of control (Day et al., 2007, Document ID 1548; Armstrong et al., 2014 (0502)). Dr. Stefaniak confirmed these findings:
[T]he particles can actually dissolve when they're in contact with liquids on the skin, like sweat. So we've actually done a series of studies, using a simulant of sweat, but it had characteristics that very closely matched human sweat. We see in those studies that, in fact, beryllium particles, beryllium oxide, beryllium metal, beryllium alloys, all these sort of what we call insoluble forms actually do in fact dissolve very readily in analog of human sweat. And once beryllium is in an ionic form on the skin, it's actually very easy for it to cross the skin barrier. And that's been shown many, many times in studies that beryllium ions can cross the skin and induce sensitization. (Document ID 1755, Tr. 36-37).
Based on information from various studies demonstrating that poorly soluble particles have the potential to penetrate skin, that skin as a barrier is rarely intact (especially in industrial settings), and that beryllium particles can readily dissolve in sweat and other biological fluids, OSHA finds that dermal exposure to poorly soluble beryllium can cause sensitization (Rossman, et al., 1991, Document ID 1332; Deubner et al., 2001 (1542); Tinkle et al., 2003 (1483); Sutton et al., 2003 (1393); Stefaniak et al., 2011 (0537) and 2014 (0517); Duling et al., 2012 (0539); Document ID 1755, Tr. 36-37).
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 (Document ID 1282). 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 poorly soluble material deposited in the upper respiratory tract (Schlesinger, 1997, Document ID 1290). Animal studies have shown oral administration of beryllium compounds to result in very limited absorption and storage (as reviewed by U.S. EPA, 1998, Document ID 0661). Oral studies utilizing radio-labeled beryllium chloride in rats, mice, dogs, and monkeys, found the majority of the beryllium was unabsorbed by the gastrointestinal tract and was eliminated in the feces. In most studies, less than 1 percent of the administered radioactivity was absorbed into the bloodstream and subsequently excreted in the urine (Crowley et al., 1949, Document ID 1551; Furchner et al., 1973 (1523); LeFevre and Joel, 1986 (1464)). 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 poorly soluble phosphate and is not absorbed (Reeves, 1965, Document ID 1430; WHO, 2001 (1282)).
Further studies suggested that beryllium absorbed into the bloodstream is primarily excreted via urine (Crowley et al., 1949, Document ID 1551; Furchner et al., 1973 (1523); Scott et al., 1950 (1413); Stiefel et al., 1980 (1288)). Unabsorbed beryllium is primarily excreted via the fecal route (Finch et al., 1990, Document ID 1318; Hart et al., 1980 (1493)). Parenteral administration in a variety of animal species demonstrated that beryllium was eliminated at much higher percentages in the urine than in the feces (Crowley et al., 1949, Document ID 1551; Furchner et al., 1973 (1523); Scott et al., 1950 (1413)). A study using percutaneous administration of soluble beryllium nitrate in rats demonstrated that more than 90 percent of the beryllium in the bloodstream was eliminated via urine (WHO, 2001, Document ID 1282). Greater than 99 percent of ingested beryllium chloride was excreted in the feces (Mullen et al., 1972, Document ID 1442). A study of mice, rats, monkeys, and dogs given intravenously dosed with beryllium chloride determined elimination half-times to be between 890 to 1,770 days (2.4 to 4.8 years) (Furchner et al., 1973, Document ID 1523). In a comparison study, baboons and rats were instilled intratracheally with beryllium metal. Mean daily excretion rates were calculated as 4.6 × 10−5 percent of the dose administered in baboons and 3.1 × 10−5 percent in rats (Andre et al., 1987, Document ID 0351).
In summary, animal studies evaluating the absorption, distribution and excretion of beryllium compounds found that, in general, poorly soluble beryllium compounds were not readily absorbed in the gastrointestinal tract and was mostly excreted via feces (Hart et al., 1980, Document ID 1493; Finch et al., 1990 (1318); Mullen et al., 1972 (1442)). Soluble beryllium compounds orally administered were partially cleared via urine; however, some soluble forms are precipitated in the gastrointestinal tract due to different pH values between the intestine and the stomach (Reeves, 1965, Document ID 1430). Intravenous administration of Start Printed Page 2490poorly soluble beryllium compounds were distributed systemically through the lymphatics and stored in the skeleton for potential later release (Furchner et al., 1973, Document ID 1523). Therefore, while intravenous administration can lead to uptake, OSHA does not consider oral and gastrointestinal exposure to be a major route for the uptake of beryllium because poorly soluble beryllium is not readily absorbed in the gastrointestinal tract.
Beryllium and its compounds may not be metabolized or biotransformed, but soluble beryllium salts may be converted to less soluble forms in the lung (Reeves and Vorwald, 1967, Document ID 1309). As stated earlier, solubility is an important factor for persistence of beryllium in the lung. Poorly soluble phagocytized beryllium particles can be dissolved into an ionic form by an acidic cellular environment and by myeloperoxidases or macrophage phagolysomal fluids (Leonard and Lauwerys, 1987, Document ID 1293; Lansdown, 1995 (1469); WHO, 2001 (1282); Stefaniak et al., 2006 (1398)). The positive charge of the beryllium ion 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, Document ID 1531).
5. Conclusion For Particle Characterization and Kinetics and Metabolism of Beryllium
The forms and concentrations of beryllium across the workplace vary substantially based upon location, process, production and work task. Many factors may influence the potency of beryllium including concentration, composition, structure, size, solubility 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, Document ID 1355), 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 to release beryllium ions (Sutton et al., 2003, Document ID 1393; Stefaniak et al., 2011(0537) and 2014(0517)). For beryllium to persist in the lung it needs to be poorly soluble. However, soluble beryllium has been shown to precipitate in the lung to form poorly soluble beryllium (Reeves and Vorwald, 1967, Document ID 1309).
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 poorly soluble particles or mist) can deposit in the respiratory tract and interact with immune cells located along the entire respiratory tract (Scheslinger, 1997, Document ID 1290). Interaction and presentation of beryllium (either in ionic or particulate form) is discussed further in Section V.D.1.
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, Document ID 1383) and later reported by Eisenbud (1948) and Aub (1949) (as cited in Document ID 1662, p. 2). Since the Atomic Energy Commission's adoption of a maximum permissible peak occupational exposure limit of 25 μg/m3 for beryllium beginning in 1949, cases of ABD have been much rarer. 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 (Document ID 1282). However, cases of ABD have been reported with beryllium exposures below 100 µg/m3 (Cummings et al., 2009, Document ID 1550). The Cummings et al. (2009) study examined two cases of workers exposed to soluble and poorly soluble beryllium below 100 µg/m3 using data obtained from company records. Cummings et al. (2009) also examined the possibility that an immune-mediated mechanism may exist for ABD as well as CBD and that ABD and CBD are on a pathological continuum since some patients would later develop CBD after recovering from ABD (ACCP, 1965, Document ID 1286; Hall, 1950 (1494); Cummings et al., 2009 (1550)).
ABD involves an inflammatory or immune-mediated 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 ABD 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, Document ID 1527).
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, Document ID 1494; DeNardi et al., 1953 (1545); Newman and Kreiss, 1992 (1440)). Evidence of a dose-response relationship to the concentration of beryllium is limited (Eisenbud et al., 1948, Document ID 0490; Stokinger, 1950 (1484); Sterner and Eisenbud, 1951 (1396)). Recovery from either type of ABD is generally complete after a period of several weeks or months (DeNardi et al., 1953, Document ID 1545). However, deaths have been reported in more severe cases (Freiman and Hardy, 1970, Document ID 1527). 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, 1982, Document ID 1254; Middleton, 1998 (1445)). ABD is extremely rare in the workplace today due to more stringent exposure controls implemented following occupational and environmental standards set in 1970-1971 (ACGIH, 1971, Document ID 0543; ANSI, 1970 (1303); OSHA, 1971, see 39 FR 23513; EPA, 1973 (38 FR 8820)).
Materion submitted post-hearing comments regarding ABD (Document ID 1662, p. 2; Attachment A, p. 1). Materion contended that only soluble forms of beryllium have been demonstrated to produce ABD at exposures above 100 µg/m3 because cases of ABD were only found in workers exposed to beryllium during beryllium extraction processes which always contain soluble beryllium (Document ID 1662, pp. 2, 3). Citing communications between Marc Kolanz (Materion) and Dr. Eisenbud, Materion noted that when Mr. Kolanz asked Dr. Eisenbud if he ever “observed an acute reaction to beryllium that did not involve the beryllium extraction process and exposure to soluble salts of beryllium,” Dr. Eisenbud responded that “he did not know of a case that was not either directly associated with Start Printed Page 2491exposure to soluble compounds or where the work task or operation would have been free from exposure to soluble beryllium compounds from adjacent operations.” (Document ID 1662, p. 3). OSHA acknowledges that workers with ABD may have been exposed to a combination of soluble and poorly soluble beryllium. This alone, however, cannot completely exclude poorly soluble beryllium as a causative or contributing agent of ABD. The WHO (2001) has concluded that both ABD and CBD results from exposure to both soluble and insoluble forms of beryllium. In addition, the European Commission has classified poorly soluble beryllium and beryllium oxide as acute toxicity categories 2 and 3 (Document ID 1669, p. 2).
Additional comments from Materion regarding ABD criticized the study by Cummings et al. (2009), stating that it “incompletely explained the source of the workers exposures, which resulted in the use of a misleading statement that, `None of the measured air samples exceeded 100 μg/m3 and most were less than 10 μg/m3.' ” (Document ID 1662, p. 3). Materion argues that the Cummings et al. study is not valid because workers in that study “had been involved with high exposures to soluble beryllium salts caused by upsets during the chemical extraction of beryllium.” (Document ID 1662, pp. 3-4). In response, NIOSH written testimony explained that the measurements in the study “were collected in areas most likely to be sources of high beryllium exposures in processes, but were not personal breathing zone measurements in the usual sense.” (Document ID 1725, p. 3). “Cummings et al. (2009) made every effort to overestimate (rather than underestimate) exposure,” including “select[ing] the highest time weighted average (TWA) value from the work areas or activities associated with a worker's job and tenure” and not adjusting for “potential protective effects of respirators, which were reportedly used for some tasks and during workplace events potentially associated with uncontrolled higher exposures.” Even so, “the available TWA data did not exceed 100 μg/m3 even on days with evacuations.” (Document ID 1725, p. 3). Furthermore, OSHA notes that, the discussion in Cummings et al. (2009) stated, “we cannot rule out the possibility of unusually elevated airborne concentrations of beryllium that went unmeasured.” (Document ID 1550, p. 5).
In response to Materion's contention that OSHA should eliminate the section on ABD because this disease is no longer a concern today (Document ID 1661, p. 2), OSHA notes that the discussion on ABD is included for thoroughness in review of the health effects caused by exposure to beryllium. As indicated above, the Agency acknowledges that ABD is extremely rare, but not non-existent, in workplaces today due to the more stringent exposure controls implemented since OSHA's inception (OSHA, 1971, see 39 FR 23513).
D. Beryllium Sensitization and 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 (Document ID 1516). It was proposed as early as 1951 that CBD could be a chronic disease resulting from sensitization to beryllium (Sterner and Eisenbud, 1951, Document ID 1396; Curtis, 1959 (1273); Nishimura, 1966 (1435)). 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, Document ID 1355). 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, Document ID 0436; Rossman et al., 1988 (0476); Saltini et al., 1989 (1351)).
CBD shares many clinical and histopathological features with pulmonary sarcoidosis, a granulomatous lung disease of unknown etiology. These similarities include 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, Document ID 1533; Rossman and Kreider, 2003 (1423)). 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., 2005, Document ID 1262; Cherry et al., 2015 (0463)).
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 (Pappas and Newman, 1993, Document ID 1433; Rossman, 1996 (1283); NAS, 2008 (1355)). These symptoms are consistent with the CBD symptoms described during the public hearing by Dr. Kristin Cummings of NIOSH and Dr. Lisa Maier of National Jewish Health (Document ID 1755, Tr. 70-71; 1756, Tr. 105-107).
Besides these listed symptoms from CBD patients, there have been reported cases of CBD that remained asymptomatic (Pappas and Newman, 1993, Document ID 1433; Muller-Querheim, 2005 (1262); NAS, 2008 (1355); NIOSH, 2011 (0544)). Asymptomatic CBD refers to those patients that have physiological changes upon clinical evaluation yet exhibit no outward signs or symptoms (also referred to as subclinical CBD).
Unlike ABD, CBD can result from inhalation exposure to beryllium at levels below the preceding OSHA PEL, can take months to years after initial beryllium exposure before signs and symptoms of CBD occur (Newman 1996, Document ID 1283, 2005 (1437) and 2007 (1335); Henneberger, 2001 (1313); Seidler et al., 2012 (0457); Schuler et al., 2012 (0473)), and may continue to progress following removal from beryllium exposure (Newman, 2005, Document ID 1437; Sawyer et al., 2005 (1415); Seidler et al., 2012 (0457)). 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, Document ID 1425; Newman et al., 2005 (1437)). The National Academy of Sciences (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, Document ID 1355). The report emphasized that risk factors and Start Printed Page 2492time course for clinical disease have not been fully delineated. However, for people now under surveillance, clinical progression from 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, Document ID 1355). A study by Newman (1996) emphasized the need for prospective studies to determine the natural history and time course from beryllium sensitization and asymptomatic CBD to full-blown disease (Newman, 1996, Document ID 1283). Drawing from his own clinical experience, Dr. 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, Document ID 1355; Newman, 1996 (1283)).
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 et al., 2008, Document ID 0370; NAS, 2008 (1355)). 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.
A study by Pappas and Newman (1993) observed that patients with known prior beryllium exposure and identified as confirmed positive for beryllium sensitization through the beryllium lymphocyte proliferation test (BeLPT) screening were evaluated for physiological changes in the lung. Pappas and Newman categorized the patients as being either “clinically identified,” meaning they had known physiological abnormalities (e.g., abnormal chest radiogram, respiratory symptoms) or “surveillance-identified,” meaning they had BeLPT positive results with no reported symptoms, to differentiate state of disease progression. Physiological changes were identified by three factors: (1) Reduced tolerance to exercise; (2) abnormal pulmonary function test during exercise; (3) abnormal arterial blood gases during exercise. Of the patients identified as “surveillance identified,” 52 percent had abnormal exercise physiologies while 87 percent of the “clinically identified” patients had abnormal physiologies (Pappas and Newman, 1993, Document ID 1433). During the public hearing, Dr. Newman noted that:
. . . one of the sometimes overlooked points is that in that study . . . the majority of people who were found to have early stage disease already had physiologic impairment. So before the x-ray or the CAT scan could find it the BeLPT had picked it up, we had made a diagnosis of pathology in those people, and their lung function tests—their measures of gas exchange, were already abnormal. Which put them on our watch list for early and more frequent monitoring so that we could observe their worsening and then jump in with treatment at the earliest appropriate time. So there is advantage of having that early diagnosis in terms of the appropriate tracking and appropriate timing of treatment. (Document ID 1756, p. 112).
OSHA was unable to find any controlled studies to determine the optimal treatment for CBD (see Rossman, 1996, Document ID 1425; NAS 2008 (1355); Sood, 2009 (0456)), and none were added to the record during the public comment period. Management of CBD is generally modeled after sarcoidosis treatment. Oral corticosteroid treatment can be initiated in patients with evidence 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. Document ID 1355; Maier et al., 2012 (0461); Salvator et al., 2013 (0459)) 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, Document ID 1521; Zaki et al., 1987 (1374)). Alternative treatments such as azathioprine and infliximab, while successful at treating symptoms of CBD, have been demonstrated to have side effects as well (Pallavicino et al., 2013, Document ID 0630; Freeman, 2012 (0655)).
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, Document ID 1437; NAS, 2008 (1355)), as well as from skin exposure to beryllium (Curtis, 1951, Document ID 1273; Newman et al., 1996 (1439); Tinkle et al., 2003 (1483); Rossman, et al., 1991, (1332); Deubner et al., 2001 (1542); Tinkle et al., 2003 (1483); Sutton et al., 2003 (1393); Stefaniak et al., 2011 (0537) and 2014 (0517); Duling et al., 2012 (0539); Document ID 1755, Tr. 36-37). Representative Robert C. “Bobby” Scott, Ranking Member of Committee on Education and the Workforce, the U.S. House of Representatives, provided comments to the record stating that “studies have demonstrated that beryllium sensitization, an indicator of immune response to beryllium, can occur from both soluble and poorly soluble beryllium particles.” (Document ID 1672, p. 3).
Sensitization is currently detected using the BeLPT (a laboratory blood test) described in section V.D.5. Although there may be no clinical symptoms associated with beryllium sensitization, 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, Document ID 1477; Newman et al., 1996 (1439); Kreiss et al., 1997 (1360); Kelleher et al., 2001 (1363); Rossman, 2001 (1424); Newman et al., 2005 (1437)). Since the pathogenesis of CBD involves a beryllium-specific, cell-mediated immune response, CBD cannot occur in the absence of sensitization (NAS, 2008, Document ID 1355). The expert peer reviewers agreed that the scientific evidence supported sensitization as a necessary condition and an early endpoint in the development of CBD (ERG, 2010, Document ID 1270, pp. 19-21). Dr. John Balmes remarked that the “scientific evidence reviewed in the [Health Effects] document supports consideration of beryllium sensitization as an early endpoint and as a necessary condition in the development of CBD.” Dr. Patrick Breysee stated that “there is strong scientific consensus that sensitization is a key first step in the progression of CBD.” Dr. Terry Gordon stated that “[a]s discussed in the draft [Health Effects] document, beryllium sensitization should be considered as an early endpoint in the development of CBD.” Finally, Dr. Milton Rossman agreed “that sensitization is necessary for someone to develop CBD and should be considered a condition/risk factor for the development of CBD.” Various factors, including genetic susceptibility, have been shown to influence risk of developing sensitization and CBD (NAS 2008, Document ID 1355) and will be discussed later in this section.Start Printed Page 2493
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, Document ID 1363; Henneberger et al., 2001 (1313)). 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, Document ID 1354; Henneberger et al., 2001 (1313); Rossman, 2001 (1424); Schuler et al., 2005 (0919); Donovan et al., 2007 (0491), Schuler et al., 2012 (0473)) 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, Document ID 1477; Kreiss et al., 1997 (1360)). While only very limited evidence has described humoral changes in certain patients with CBD (Cianciara et al., 1980, Document ID 1553), clear evidence exists for an immune cell-mediated response, specifically the T-cell (NAS, 2008, Document ID 1355). Figure 2 delineates the major steps required for progression from beryllium contact to sensitization to CBD.
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, Document ID 1475). Some soluble forms of beryllium are readily presented, since the soluble beryllium form disassociates into its ionic components. However, for poorly soluble 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 Start Printed Page 2494low-level beryllium presentation to the immune system (Document ID 1257). Stefaniak et al. (2006 and 2012) reported that poorly soluble beryllium particles phagocytized by macrophages were dissolved in phagolysomal fluid (Stefaniak et al., 2006, Document ID 1398; Stefaniak et al., 2012 (0469)) and that the dissolution rate stimulated by phagolysomal fluid was different for various forms of beryllium (Stefaniak et al., 2006, Document ID 1398; Duling et al., 2012 (0539)). 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, Document ID 1417; Sawyer et al., 2004 (1416); Kittle et al., 2002 (0485)). 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, Document ID 1355).
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., HLA-DP, HLA-DR, HLA-DQ) associated with the progression to CBD (NAS, 2008, Document ID 1355; Yucesoy and Johnson, 2011 (0464); Petukh et al., 2014 (0397)). Several studies have also demonstrated that the electrostatic charge of HLA may be a factor in binding beryllium (Snyder et al., 2003, Document ID 0524; Bill et al., 2005 (0499); Dai et al., 2010 (0494)). 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, Document ID 0471; Dai et al., 2010 (0494); Petukh et al., 2014 (0397)). 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, Document ID 0455). The direct binding of BeO may eliminate the biological requirement for antigen processing or dissolution of beryllium oxide to activate an immune response.
Once the beryllium-MHC-APC complex is established, the complex binds 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, Document ID 1351 and 1990 (1420); Martin et al., 2011 (0483)) 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, Document ID 0489). This may also indicate a pathogenic potential for subsets of T-cell clones expressing this homologous TCR (NAS, 2008, Document ID 1355). Fontenot et al. (2006) (Document ID 0487) reported beryllium self-presentation by HLA-DP expressing BAL CD4+ T-cells. According the NAS report, BAL T-cell self-presentation in the lung granuloma may result in cell death, leading to oligoclonality (only a few clones) of the T-cell population characteristic of CBD (NAS, 2008, Document ID 1355).
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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, Document ID 1416; Kimber et al., 2011 (0534)).
In summary, OSHA concludes that sensitization is a necessary and early functional change in the immune system that leads to the development of CBD.
2. Development of CBD
The continued presence 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, Document ID 1529). This change in phenotype correlated with lung inflammation (Fontenot et al., 2003, Document ID 1529). While these CD4+ independent cells continued to secrete cytokines necessary for additional recruitment of inflammatory and immunological cells, they were less proliferative and less susceptible to cell death compared to the CD28 dependent cells (Fontenot et al., 2005, Document ID 1528; Mack et al., 2008 (1460)). These beryllium-specific CD4+ independent cells are considered to be mature memory effector cells (Ndejembi et al., 2006, Document ID 0479; Bian et al., 2005 (0500)). 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, Document ID 1528).
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., 1997, Document ID 1387; Tinkle et al., 1997 (1388); Fontenot et al., 2002 (1530)) and MIP-1α and GRO-1 (Hong-Geller, 2006, Document ID 1511). This also results in the accumulation of various types of inflammatory cells including mononuclear cells (mostly CD4+ T cells) in the BAL fluid (Saltini et al., 1989, Document ID 1351, 1990 (1420)).
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, Document ID 1355). 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, Document ID 1415; Tinkle et al., 1996 (0468); Hong-Geller et al., 2006 (1511); NAS, 2008 (1355)).
The cascade of events described above results in the formation of a noncaseating granulomatous lesion. Release 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, Document ID 1351, 1990 (1420)).
Over time, the granulomas spread and can lead to lung fibrosis and abnormal Start Printed Page 2496pulmonary function, with symptoms including a persistent dry cough and shortness of breath (Saber and Dweik, 2000, Document ID 1421). 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, Document ID 1319; ACCP, 1965 (1286); Kriebel et al., 1988, Document ID 1292; Kriebel et al., 1988 (1473)). While CBD primarily affects the lungs, it can also involve other organs such as the liver, skin, spleen, and kidneys (ATSDR, 2002, Document ID 1371).
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, Document ID 1417; Kittle et al., 2002 (0485); Sawyer et al., 2004 (1416)). 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, Document ID 0478; Rana, 2008 (0477)). Macrophages and neutrophils can phagocytize beryllium particles in an attempt to remove the beryllium from the lung (Ding, et al., 2009, Document ID 0492)). Multiple studies (Sawyer et al., 2004, Document ID 1416; Kittle et al., 2002 (0485)) 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, Document ID 1299; Dai et al., 1999 (0495)). The stimulation of CBD-derived macrophages by beryllium sulfate 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, Document ID 1417). However, other factors, such as genetic factors and duration or level of exposure leading to a continued presence of beryllium in the lung, may influence the development of CBD and are outlined in the following sections V.D.3 and V.D.4.
In summary, the persistent presence of beryllium in the lung of a sensitized individual creates a progressive inflammatory response that can culminate in the granulomatous lung disease, CBD.
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, Document ID 1396). 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, Document ID 1531; Amicosante et al., 2005 (1564); Tinkle et al., 1996 (0468); Gaede et al., 2005 (0486); Van Dyke et al., 2011 (1696); Silveira et al., 2012 (0472)).
Potential sources of variation associated with genetic susceptibility have been investigated. 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, beryllium sensitization, and CBD (McClesky et al., 2009, as cited in Document ID 1808, p. 3). Specific SNPs have been evaluated as a factor in the Glu69 variant from the HLA-DPB1 locus (Richeldi et al., 1993, Document ID 1353; Cai et al., 2000 (0445); Saltini et al., 2001 (0448); Silviera et al., 2012 (0472); Dai et al., 2013 (0493)). Other SNPs lacking the Glu69 variant, such as HLA-DRPheβ47, have also been evaluated for an association with CBD (Amicosante et al., 2005, Document ID 1564).
HLA-DPB1 (one of 2 subtypes of HLA-DP) with a glutamic acid at amino position 69 (Glu69) has been shown to confer increased risk of beryllium sensitization and CBD (Richeldi et al., 1993, Document ID 1353; Saltini et al., 2001 (0448); Amicosante et al., 2005 (1564); Van Dyke et al., 2011 (1696); Silveira et al., 2012 (0472)). In vitro human research has identified genes coding for specific protein molecules on the surface of the immune cells of sensitized individuals from a cohort of beryllium workers (McCanlies et al., 2004, Document ID 1449). The research identified the HLA-DPB1 (Glu69) allele that place carriers at greater risk of becoming sensitized to beryllium and developing CBD than those not carrying this allele (McCanlies et al., 2004, Document ID 1449). 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 (Document ID 1531). Richeldi et al. (1993) reported a strong association between the MHC class II allele HLA-DPB 1 and the development of CBD in beryllium-exposed workers from a Tucson, AZ facility (Document ID 1353). 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 alleles of the HLA-DPB 1 containing a variant of Glu69 are negatively charged at this site and could directly interact with the positively charged beryllium ion. Additional studies by Amicosante et al. (2005) (Document ID 1564) 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) (Document ID 1394) also found a relationship between the HLA-DP 1 allele and beryllium sensitization. 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 sensitization 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 yielded an approximately 10-fold increase (Weston et al., 2005, Document ID 1345; Snyder et al., 2008 (0471)). Specifically, Snyder et al. (2008) found that variants of the Glu69 allele with the greatest negative charge may confer greater risk for developing CBD (Document ID 0471). The study by Weston et al. (2005) assigned odds ratios for specific alleles on the basis of previous studies discussed above (Document ID 1345). The researchers found a strong Start Printed Page 2497correlation (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 (Weston et al., 2005, Document ID 1345). This confirms the importance of beryllium charge as a key factor in its ability to induce an immune response.
In contrast, the HLA-DRB1 allele, which lacks Glu69, has also been shown to increase the risk of developing sensitization and CBD (Amicosante et al., 2005, Document ID 1564; Maier et al., 2003 (0484)). Bill et al. (2005) found that HLA-DR has a glutamic acid at position 71 of the β chain, functionally equivalent to the Glu69 of HLA-DP (Bill et al., 2005, Document ID 0499). Associations with BeS and CBD have also been reported with the HLA-DQ markers (Amicosante et al., 2005, Document ID 1564; Maier et al., 2003 (0484)). 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 presentation of beryllium to T lymphocytes (Amicosante et al., 2002, Document ID 1370). 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, Document ID 0497). 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 non-proliferating BAL CD4 T cells may still contribute to inflammation leading to the progression of CBD (Chou et al., 2005, Document ID 0497).
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 that may be associated with a more progressive form of CBD (NAS, 2008). Beryllium exposure has been shown to upregulate transcription factors AP-1 and NF-κB (Sawyer et al., 2007, as cited in Document ID 1355) 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, Document ID 1456; Saltini et al., 2001 (0448); Dotti et al., 2004 (1540)). While a study by McCanlies et al. (2007) (Document ID 0482) of 886 beryllium workers (including 64 sensitized for beryllium and 92 with CBD) found no relationship between TNF-α polymorphism and sensitization or CBD, the National Academies of Sciences noted that “discrepancies between past studies showing associations and the more recent studies may be due to misclassification, exposure differences, linkage disequilibrium between HLA-DRB1 and TNF-α genes, or statistical power.” (NAS, 2008, Document ID 1355).
Other genetic variations have been shown to be associated with increased risk of beryllium sensitization and CBD (NAS, 2008, Document ID 1355). These include TGF-β (Gaede et al., 2005, Document ID 0486), angiotensin-1 converting enzyme (ACE) (Newman et al., 1992, Document ID 1440; Maier et al., 1999 (1458)) and an enzyme involved in glutathione synthesis (glutamate cysteine ligase) (Bekris et al., 2006, as cited in Document ID 1355). 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 (Document ID 0481). 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 between those variants and beryllium sensitization.
In addition to the genetic factors which may contribute to the susceptibility and severity of disease, other factors such as smoking and sex may play a role in the development of CBD (NAS, 2008, Document ID 1355). 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, Document ID 1356).
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 BeLTT (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, Document ID 1552; Maier, 2001 (1456)). 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 to 49 percent of them were diagnosed with CBD (Kreiss et al., 1993, Document ID 1479; Newman et al., 1996 (1283), 2005 (1437), 2007 (1335); Mroz, 2009 (1356)), although some estimate that with increased surveillance that percentage could be much higher (Newman, 2005, Document ID 1437; Mroz, 2009 (1356)). It has been estimated from ongoing surveillance studies of sensitized individuals with an average follow-up time of 4.5 years that Start Printed Page 249831 percent of beryllium-sensitized employees were estimated to progress to CBD (Newman et al., 2005, Document ID 1437). The study by Newman et al. (2005) was the first longitudinal study to assess the progression from beryllium sensitization to CBD in individuals undergoing clinical evaluation at National Jewish Medical and Research Center from 1988 through 1998. Approximately 50 percent of sensitized individuals (as identified by BeLPT) had CBD at their initial clinical evaluation. The remaining 50 percent, or 76 individuals, without evidence of CBD were monitored at approximately two year intervals for indication of disease progression by pulmonary function testing, chest radiography (with International Labour Organization B reading), fiberoptic bronchoscopy with bronchoalveolar lavage, and transbronchial lung biopsy. Fifty-five of the 76 individuals were monitored with a range of two to five clinical evaluations each. The Newman et al. (2005) study found that CBD developed in 31 percent of individuals (17 of the 55) in a period ranging from 1.0 to 9.5 years (average 3.8 years). After an average of 4.8 years (range 1.7 to 11.6 years) the remaining individuals showed no signs of progression to CBD. A study of nuclear weapons facility employees enrolled in an ongoing medical surveillance program found that the sensitization rate in exposed workers increased rapidly over the first 10 years of beryllium exposure and then more gradually in succeeding years. On the other hand, the rate of CBD pathology increased slowly over the first 15 years of exposure and then climbed more steeply following 15 to 30 years of beryllium exposure (Stange et al., 2001, Document ID 1403). The findings from these longitudinal studies of sensitized workers provide evidence of CBD progression over time from asymptomatic to symptomatic disease. One limitation for all these studies is lack of long-term follow-up. Newman suggested that it may be necessary to continue to monitor these workers in order to determine whether all sensitized workers will develop CBD (Newman et al., 2005, Document ID 1437).
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, Document ID 1355). OSHA requested additional information in the NPRM, but no additional studies were added during the public comment period. 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, Document ID 1355). In advanced cases of CBD, corticosteroids are the standard treatment (NAS, 2008, Document ID 1355). No comprehensive studies have been published measuring the overall effect of removal of workers from beryllium exposure on sensitization and CBD (NAS, 2008, Document ID 1355) although this has been suggested as part of an overall treatment regime for CBD (Mapel et al., 2002, as cited in Document ID 1850; Sood et al., 2004 (1331); Sood, 2009 (0456); Maier et al., 2012 (0461)). Expert testimony from Dr. Lee Newman and Dr. Lisa Maier agreed that while no studies exist on the efficacy of removal from beryllium exposure, it is medically prudent to reduce beryllium exposure once someone is sensitized (Document ID 1756, Tr. 142). Sood et al. reported that cessation of exposure can sometimes have beneficial effects on lung function (Sood et al., 2004, Document ID 1331). However, this was based on anecdotal evidence from six patients with CBD, while this indicates a benefit of removal of patients from exposure, more research is needed to better determine the relationship between exposure duration and disease progression.
Materion commented that sensitization should be defined as a test result indicating an immunological sensitivity to beryllium without identifiable adverse health effects or other signs of illness or disability. It went on to say that, for these reasons, sensitization is not on a pathological continuum with CBD (Document ID 1661, pp. 4-7). Other commenters disagreed. NIOSH addressed whether sensitization should be considered an adverse health effect and said the following in their written hearing testimony:
Some have questioned whether BeS should be considered an adverse health effect. NIOSH views it as such, since it is a biological change in people exposed to beryllium that is associated with increased risk for developing CBD. BeS refers to the immune system's ability to recognize and react to beryllium. BeS is an antigen-specific cell mediated immunity to beryllium, in which CD4+ T cells recognize a complex composed of beryllium ion, self-peptide, and major histocompatibility complex (MHC) Class II molecule on an antigen-presenting cell [Falta et al. (2013); Fontenot et al. (2016)]. BeS necessarily precedes CBD. Pathogenesis depends on the immune system's recognition of and reaction to beryllium in the lung, resulting in granulomatous lung disease. BeS can be detected with tests that assess the immune response, such as the beryllium lymphocyte proliferation test (BeLPT), which measures T cell activity in the presence of beryllium salts [Balmes et al. (2014)]. Furthermore, after the presence of BeS has been confirmed, periodic medical evaluation at 1-3 year intervals thereafter is required to assess whether BeS has progressed to CBD [Balmes et al. (2014)]. Thus, BeS is not just a test result, but an adverse health effect that poses risk of the irreversible lung disease CBD. (Document ID 1725, p. 2)
The American College of Occupational and Environmental Medicine (ACOEM) also commented that the term pathological “continuum” should only refer to signs and symptoms associated with CBD because some sensitized workers never develop CBD (Document ID 1685, p. 6). However, Dr. Newman, testifying on behalf of ACOEM, clarified that not all members of the ACOEM task force agreed:
So I hope I'm reflecting to you the range and variety of outcomes relating to this. My own view is that it's on a continuum. I do want to reflect back that the divided opinion among people on the ACOEM task force was that we should call it a spectrum because not everybody is necessarily lock step into a continuum that goes from sensitization to fatality. (Document ID 1756, Tr. 133).
Lisa Maier, MD of National Jewish Health agreed with Dr. Newman (Document ID 1756, Tr. 133-134). Additionally, Dr. Weissman of NIOSH testified that sensitization is “a biological change in people exposed to beryllium that is associated with increased risk for developing CBD” and should be considered an adverse health effect (Document ID 1755, Tr. 13).
OSHA agrees that not every sensitized worker develops CBD, and that other factors such as extent of exposure, particulate characteristics, and genetic susceptibility influence the development and progression of disease. The mechanisms by which beryllium sensitization leads to CBD are described in earlier sections and are supported by numerous studies (Newman et al., 1996a, Document ID 1439; Newman et al., 2005 (1437); Saltini et al., 1989 (1351); Amicosante et al., 2005a (1564); Amicosante et al., 2006 (1465); Fontenot et al., 1999 (0489); Fontenot et al., 2005 (1528)). OSHA concludes that sensitization is an immunological condition that increases one's likelihood Start Printed Page 2499of developing CBD. As such, sensitization is a necessary step along a continuum to clinical lung disease.
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 Supplemental Information for the Beryllium Health Effects Section summarizes the prevalence of beryllium sensitization and CBD, range of exposure measurements, and other salient information from the key epidemiological studies (Document ID 1965).
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 preceding 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, Document ID 1313), case-control studies of workers at the Rocky Flats nuclear weapons facility (Viet et al., 2000, Document ID 1344), and workers from a beryllium machining plant in Cullman, AL (Kelleher et al., 2001, Document ID 1363). 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, Document ID 1368; Johnson et al., 2001 (1505); Schuler et al., 2005 (0919)). 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 (0590); Bailey et al., 2010 (0676); Schuler et al., 2012(0473)).
Some of the epidemiological studies presented in this section 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 preceding PEL of 2 μg/m3. The available literature also indicates that the rate of beryllium sensitization 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) (Document ID 1516). 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, Document ID 1355). 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, Document ID 1514). 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, Document ID 1461). 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, Document ID 1284; Lieben and Metzner, 1959 (1343)). 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, Document ID 1355).
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, Document ID 1515); or any three of the six criteria listed below (Hasan and Kazemi, 1974, Document ID 0451). Patients identified using the above criteria were registered and added to the BCR from 1952 through 1983 (Eisenbud and Lisson, 1983, Document ID 1296).
The BCR listed the following criteria for diagnosing CBD (Eisenbud and Lisson, 1983, Document ID 1296):
(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, Document ID 1296). 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 (Document ID 0447). This study also presented a 28 percent mortality rate from complications of CBD at the time of publication. However, even with the improved Start Printed Page 2500methodology 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 diagnostic 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, Document ID 0196; Pappas and Newman, 1993 (1433); Maier et al., 1999 (1458)):
(1) History of beryllium exposure;
(2) Histopathological evidence of non-caseating granulomas or mononuclear cell infiltrates in the absence of infection; and
(3) Positive blood or BAL BeLPT (Newman et al., 1989, Document ID 0196).
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, Document ID 1283). 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 that 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, Document ID 0068; Frome, 2003 (0462)). 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, 0435; Rossman et al., 2001 (1424)). 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, Document ID 1478; Pappas and Newman, 1993 (1433)). 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, Document ID 1478). 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, Document ID 1364).
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, Document ID 1344; Stange et al., 2001 (1403); DOE/HSS Report, 2006 (0664)), a beryllium ceramics plant in Arizona (Kreiss et al., 1996, Document ID 1477; Henneberger et al., 2001 (1313); Cummings et al., 2007 (1369)), a beryllium production plant in Ohio (Kreiss et al., 1997, Document ID 1476; Kent et al., 2001 (1112)), a beryllium machining facility in Alabama (Kelleher et al., 2001, Document ID 1363; Madl et al., 2007 (1056)), a beryllium alloy plant (Schuler et al., 2005, Document ID 0473; Thomas et al., 2009 (0590)), and another beryllium processing plant (Rosenman et al., 2005, Document ID 1352) 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.
In order to investigate the reliability and laboratory variability of the BeLPT, Stange et al. (2004, Document ID 1402) studied 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, Document ID 1402). Borak et al. (2006) contended that the positive predictive value (PPV) 
is not high enough to meet the criteria of a good screening tool (Document ID 0498). 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, Document ID 0480). In April 2006, the Agency for Toxic Substances and Disease Registry (ATSDR) convened an expert panel of seven physicians and scientists to discuss the BeLPT and to consider what algorithm should be used to interpret BeLPT results to establish beryllium sensitization (Middleton et al., 2008, Document ID 0480). The three criteria proposed by panel members were Criterion A (one abnormal BeLPT result establishes sensitization); Criterion B (one abnormal and one borderline result establish sensitization); and Criterion C (two abnormal results establish sensitization). Using the single-test outcome probabilities developed by Stange et al., the panel convened by ATSDR calculated and compared the sensitivity, specificity, and positive predictive values (PPVs) for each algorithm. The characteristics for each algorithm were as follows:
Table 2—Characteristics of BeLPT Algorithms (Adapted from Middleton et al., (2008)
[Adapted from Middleton et al., 2008, Document ID 0480]
| ||Criterion A (1 abnormal)||Criterion B (1 abnormal + 1 borderline)||Criterion C (2 abnormal)|
|PPV at 1% prevalence||38.3%||89.3%||96.8%|
|PPV at 10% prevalence||87.2%||98.9%||99.7%|
|Start Printed Page 2501|
|False positives per 10,000||111||8||2|
The Middleton et al. (2008) study demonstrated that confirmation of BeLPT results, whether as one abnormal and one borderline abnormal or as two abnormals, enhances the test's PPV and protects the persons tested from unnecessary and invasive medical procedures. In populations with a high prevalence of beryllium sensitization (i.e., 10 percent or more), however, a single test may be adequate to predict sensitization (Middleton et al., 2008, Document ID 0480).
Still, there has been criticism regarding the reliability and specificity of the BeLPT as a screening tool and that the BeLPT has not been validated appropriately (Cher et al., 2006, as cited in Document ID 1678; Borak et al., 2006 (0498); Donovan et al., 2007 (0491); Document ID 1678, Attachment 1, p. 6). Even when a confirmational second test is performed, an apparent false positive can occur in people not occupationally exposed to beryllium (NAS, 2008, Document ID 1355). 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, Document ID 0491). 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. However, this should not be considered unusual because there have been reported incidences of non-occupational and community-based beryllium sensitization (Eisenbud et al., 1949, Document ID 1284; Leiben and Metzner, 1959 (1343); Newman and Kreiss, 1992 (1440); Maier and Rossman, 2008 (0598); NAS, 2008 (1355); Harber et al., 2014 (0415), Harber et al., 2014 (0421)).
Materion objected to OSHA treating “two or three uninterpretable or borderline abnormal BeLPT test results as confirmation of BeS for the purposes of the standard” (Document ID 1808, p. 4). In order to address some criticism regarding the PPV of the BeLPT, Middleton et al. (2011) conducted another study to evaluate borderline results from BeLPT testing (Document ID 0399). Utilizing the common clinical algorithm with a criterion that accepted one abnormal result and one borderline result as establishing beryllium sensitization resulted in a PPV of 94.4 percent. This study also found that three borderline results resulted in a PPV of 91 percent. Both of these PPVs were based on a population prevalence of 2 percent. This study further demonstrates the value of borderline results in predicting beryllium sensitization using the BeLPT. OSHA finds that multiple, consistent borderline BeLPT results (as found with three borderline results) recognize a change in a person's immune system to beryllium exposure. In addition, a study by Harber et al. (2014) reexamined the algorithms to determine sensitization and CBD data using the BioBank data.
The study suggested that changing the algorithm could potentially help distinguish sensitization from progression to CBD (Harber et al., 2014, Document ID 0363).
Materion further contended that “[w]hile some refer to BeLPT testing as a `gold' standard for BeS, it is hardly `golden,' as numerous commentators have noted.” (Document ID 1808, p. 4). NIOSH submitted testimony to OSHA comparing the use of the BeLPT for determining beryllium sensitization to other common medical screening tools such as mammography for breast cancer, tuberculin skin test for latent tuberculosis infection, prostate-specific antigen (PSA) for prostate cancer, and fecal occult blood testing for colon cancer. NIOSH stated that “[a]lthough there is no gold standard test to identify beryllium sensitization, BeLPT has been estimated to have a sensitivity of 66-86% and a specificity of >99% for sensitization [Middleton et al. (2006)]. These values are comparable or superior to those of other common medical screening tests.” (Document ID 1725, pp. 32-33). In addition, Dr. Maier of National Jewish Health stated during the public hearing that “medical surveillance should rely on the BeLPT or a similar test if validated in the future, as it detects early and late beryllium health effects. It has been validated in many population-based studies.” (Document ID 1756, Tr. 103).
Since there are currently no alternatives to the BeLPT in a beryllium sensitization screening program, many programs rely on a second test to confirm a positive result (NAS, 2008). Various expert organizations support the use of the BeLPT (with a second confirmational test) as a screening tool for beryllium sensitization and CBD. The American Thoracic Society (ATS), based on a systematic review of the literature, noted that “the BeLPT is the cornerstone of medical surveillance” (Balmes et al., 2014; Document ID 0364, pp. 1-2). The use of the BeLPT in medical surveillance has been endorsed by the National Academies in their review of beryllium-related diseases and disease prevention programs for the U. S. Air Force (NAS, 2008, Document ID 1355). In 2011, NIOSH issued an alert “Preventing Sensitization and Disease from Beryllium Exposure” where the BeLPT is recommended as part of a medical screening and surveillance program (NIOSH, 2011, Document ID 0544). OSHA finds that the BeLPT is a useful and reliable test method that has been utilized in numerous studies and validated and improved through multiple studies.
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, Document ID 1354; Stange et al., 2001 (1403)). Based on the studies above, as well as comments from NIOSH, ATS, and National Jewish Health, OSHA regards Start Printed Page 2502the BeLPT as a reliable medical surveillance tool.
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, Document ID 1282). 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, Document ID 1282). Most exposures from mining and extraction come in the form of beryllium ore, beryllium salts, beryllium hydroxide (NAS, 2008, Document ID 1355) or beryllium oxide (Stefaniak et al., 2008, Document ID 1397).
Deubner et al. published a study of 75 workers employed at a beryllium mining and extraction facility in Delta, UT (Deubner et al., 2001b, Document ID 1543). 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 were higher than either LP or GA concentrations. 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 (Document ID 1397).
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 (Document ID 1360). 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 μg/m3, with 18.5 percent of samples exceeding OSHA's preceding permissible ceiling concentration 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 preceding OSHA permissible ceiling concentration 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 result upon initial testing and at least one of two subsequent test results for each of those workers confirmed the worker 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 workers 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, Document ID 1360). After including five workers who had been diagnosed prior to the study, a total of 29 (4.6 percent of the 627 workers who underwent BeLPT screening) workers still employed at the time of the study 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, Document ID 1360). Preliminary follow-up investigations of particle size-specific sampling at five furnace sites within the plant determined that the highest respirable (i.e., particles <10 μm in diameter as defined by the authors) and alveolar-deposited (i.e., 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, Document ID 1361; McCawley et al., 2001 (1357)). 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 Start Printed Page 2503than the total mass concentration of airborne beryllium.
Bailey et al. (2010) (Document ID 0610) evaluated the effectiveness of a workplace preventive program in lowering incidences of sensitization at the beryllium metal, oxide, and alloy production plant studied by Kreiss et al. (1997) (Document ID 1360). 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 and administrative 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 program 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, Document ID 0610).
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 (Document ID 1352). Of 715 former workers located, 577 were screened for beryllium sensitization with the BLPT and 544 underwent chest radiography to identify cases of beryllium sensitization 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 (Document ID 1352). 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 poorly soluble beryllium (metal and oxide), soluble beryllium (fluoride and hydroxide), mixed soluble and poorly soluble 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 μg/m3 to 84 μg/m3 in the 1960s, falling to a range of 0.5-16.7 μg/m3 in the 1970s. A large number of workers' mean DWA estimates (25 percent) were above the preceding OSHA PEL of 2.0 μg/m3, while most workers had mean DWA exposures between 0.2 and 2.0 μg/m3 (74 percent) or below 0.02 μg/m3 (1 percent) (Rosenman et al., Table 11; revised erratum April, 2006, Document ID 1352).
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 (Document ID 1352).
Of the 577 workers who were evaluated for CBD, 32 (5.5 percent) with evidence of granulomas were classified as “definite” CBD cases (as identified by bronchoscopy). 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 those 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 (Document ID 1352).
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 preceding OSHA PEL of 2 μg/m3. Of those, seven (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 (Document ID 1352).
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 μg/m3 (Rosenman et al., Table 11, erratum 2006, Document ID 1352). Ten cases of sensitization and five cases of Start Printed Page 2504CBD 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 poorly soluble 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 poorly soluble beryllium than those classified as sensitized without disease, while exposure to soluble beryllium was higher among sensitized individuals than those with CBD (Document ID 1352).
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 could 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 (Document ID 1352).
A follow-up was conducted of the cross-sectional study of a population of workers first evaluated by Kreiss et al. (1997) (Document ID 1360) and Rosenman et al. (2005) (Document ID 1352) by Schuler et al. (2012) (Document ID 0473), and in a companion study by Virji et al. (2012) (Document ID 0466). 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, Document ID 0473).
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) (Document ID 0466). 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.
e. Beryllium Machining Operations
Newman et al. (2001) (Document ID 1354) and Kelleher et al. (2001) (Document ID 1363) 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, Document ID 1354; Madl et al., 2007 (1056)). 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 controls, rather than PPE, were primarily used to control beryllium exposures at the plant (Madl et al., 2007, Document ID 1056). 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, Document ID 1056). Throughout the plant's history, respiratory protection was used mainly for “unusually large, anticipated exposures” to beryllium (Kelleher et al., 2001, Document ID 1363), and was not routinely used otherwise (Newman et al., 2001, Document ID 1354).
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 Start Printed Page 2505on 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 BAL and transbronchial lung biopsy, if the repeat test was abnormal. CBD was diagnosed upon evidence of sensitization with granulomas or mononuclear cell infiltrates in the lung tissue (Newman et al., 2001, Document ID 1354). 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, Document ID 1056).
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, Document ID 1363). 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 μm in diameter, particles less than 1 μm in diameter, and total mass. The great majority of workers' exposures were below the preceding OSHA PEL of 2 μg/m3. However, a few higher exposure 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 included in the study parameters (1981 to 1984, 1995 to 1997, and 1998 to 1999) 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. Of the 20 workers composing the case group, 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). The other seven were evaluated for CBD and found to be sensitized only. Nine of the remaining 215 workers first identified in original study (Newman et al., 2001, Document ID 1354) were excluded 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 less than 6 μm in diameter, and particles less than 1 μm in diameter 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 preceding PEL of 2 μg/m3, and no cases of sensitization or CBD were observed among workers with LTW exposure less than 0.02 μg/m3. Twelve (60 percent) of the 20 sensitized workers had LTW exposures >0.20 μg/m3.
In 2007, Madl et al. 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 (Madl et al., 2007, Document ID 1056). 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, Document ID 1056). 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 sensitized workers or workers with 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. Madl et al. also concluded that most sensitization and CBD cases were likely to have been exposed to levels greater than 0.4 μg/m3
Start Printed Page 2506at some point in their work at the plant. Madl et al. did not reconstruct exposures for workers at the plant who were not sensitized and did not develop 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, Document ID 1056). 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, Document ID 1056).
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 (Document ID 1478). 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 of the 9 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 exposed to beryllium dust. Particularly high CBD rates of 11.1 to 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, Document ID 1477), 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/m3, 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/m3, 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 as a DWA.
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 (Document ID 1477). 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, Document ID 1477). The overall prevalence of sensitization in the plant was 5.9 percent, with a 4.4 percent prevalence of CBD.
Kreiss et al. (1996) (Document ID 1477) 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 (Document ID 1478), one case of CBD was diagnosed in a worker who had never been employed in a production job. This worker was employed in office administration, a job with a median DWA of 0.1 μg/m3 (range 0.1-0.3 μg/m3).
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, Document ID 1313). All current plant employees were eligible for the study unless they had previously been diagnosed with CBD. The study tracked two sets of workers in presenting prevalence outcomes and exposure characterization. “Short-term workers” were those hired since the last plant survey in 1992. “Long-term workers” Start Printed Page 2507were those hired before 1992 and had a longer history of beryllium exposures. There were 74 short-term and 77 long-term workers in the survey (Henneberger et al., 2001, Document ID 1313).
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—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 in the 151 study participants (15/151; 9.9%), including seven among short-term (7/74; 9.5%) and eight among long-term workers (8/77; 10.4%). There were eight cases of CBD (8/151; 5.3%) identified in the study. One sensitized short-term worker developed CBD (1/74; 1.4%). Seven of the eight sensitized long-term workers developed CBD (7/77; 9.1%). The other sensitized long-term worker declined to participate in the clinical evaluation.
Henneberger et al. (2001) 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 (Document ID 1313). No association was observed for average or cumulative exposures. The authors reported higher (but not statistically significant) prevalence of sensitization 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. Document ID 1291). 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 2002-2003. 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 exposures and risk of sensitization and CBD by implementing additional engineering, administrative, and PPE measures (Cummings et al., 2007, Document ID 1369). 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 in production, similar to the 1994-1999 samples. However, respiratory protection requirements to control workers' airborne beryllium exposures were instituted prior to the 2000 sample collections, so actual exposure to the production workers may have been lower than the airborne beryllium levels indicate.
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 of 126 workers). 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. (2007) 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 (Document ID 1369). 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 particle migration control (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 who processed copper-beryllium alloys and small quantities of nickel-beryllium alloys and converted semi-finished alloy Start Printed Page 2508strip 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, it also performed salt baths, cadmium plating, welding and deburring. Since the late 1980s, rod and wire production processes have been 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, Document ID 0919). 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 the laboratory was experiencing technical problems with the test (Schuler et al., 2005, Document ID 0919). 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. (2005) 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 (Document ID 0919). Occupational exposures to airborne beryllium were generally low. Ninety-nine percent of all LP measurements were below the preceding OSHA PEL of 2.0 μg/m3 (8-hr TWA); 93 percent were below the new final OSHA PEL 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 preceding OSHA ceiling limit of 5.0 μg/m3. The highest levels of beryllium exposure 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 μg/m3, range 0.01-0.72 μg/m3), in production support jobs (median 0.02 μg/m3, range <0.01-0.33 μg/m3), plant administration (median 0.02 μg/m3, range <0.01-0.11 μg/m3), and office administration jobs (median 0.01 μg/m3, 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 significantly 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 workers who had never worked in strip metal (p > 0.1). Based on these results, together with the higher exposure levels reported for the rod and wire production area, Schuler et al. (2005) 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. (2001) among beryllium ceramics workers exposed for one year or less (16 percent) (Henneberger et al., 2001, Document ID 1313). All four workers who were sensitized without disease had been exposed for 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., 2005, Table 2, Document ID 0919).
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 as a DWA. 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 preceding 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, Document ID 0919). 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, Document ID 1061). Measures 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 protection 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 2000-2001 samples in areas other than the RAZ. Within the RAZ, required use of powered air-purifying respirators indicates that actual respiratory exposure was negligible (Thomas et al., 2009, Document ID 1061).
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; Start Printed Page 2509and 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 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., 2009, Document ID 1061).
Thomas et al. (2009) 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, Document ID 1061). 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, Document ID 1061).
Stanton et al. (2006) (Document ID 1070) conducted a study of workers in three different copper-beryllium alloy distribution centers in the United States. The distribution centers, consisting of 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.
Stanton et al. (2006) estimated workers' beryllium exposures using IH data from company records and job history information collected through interviews conducted by a company occupational health nurse (Document ID 1090). 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 values for specific jobs ranged from 0.01-0.07 µg/m3 while geometric mean values for specific jobs ranged from 0.02-0.07 µg/m3. All measurements were below the preceding OSHA PEL of 2.0 μg/m3 and 97 percent were below the new final OSHA PEL of 0.2 μg/m3. The study does not report use of respiratory or skin protection.
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 µg/m3, 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, Document ID 1090).
h. Nuclear Weapons Production Facilities and 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) (Document ID 1480) 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. Six workers had abnormal BeLPT readings, and four were diagnosed with CBD. This study classified workers as sensitized after one abnormal BeLPT reading, so this resulted in an estimated 11.8 percent prevalence of sensitization.
Kreiss et al. (1993) expanded the work of Kreiss et al. (1989) (Document ID 1480) by performing a cross-sectional study of 895 current and former beryllium workers in the same nuclear weapons plant (Document ID 1479). Participants were placed in qualitative exposure groups (“no exposure,” “minimal exposure,” “intermittent Start Printed Page 2510exposure,” and “consistent exposure”) based on questionnaire responses. Eighteen workers had abnormal BeLPT test results, with 12 being diagnosed with CBD. Three additional sensitized workers (those with abnormal BeLPT results) 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 both individual susceptibility to sensitization and exposure circumstance affect the development of beryllium sensitization and CBD.
In 1991, the Beryllium Health Surveillance Program (BHSP) was established at the Rocky Flats Nuclear Weapons Facility to offer BeLPT screening to current and former employees who may have been exposed to beryllium (Stange et al., 1996, Document ID 0206). 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 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 (Document ID 1403). 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 test results. 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, based on a 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. In order to determine beryllium exposure for all participants in the study, personal beryllium air monitoring results were used, when available, from employees with the same job title or similar job. However, no quantitative exposure information was presented in the study. The authors conclude that for some individuals, exposure to beryllium at levels below the preceding OSHA PEL appears to cause sensitization and CBD.
Viet et al. (2000) conducted a case-control study of the Rocky Flats worker population studied by Stange et al. (1996 and 2001, Document ID 0206 and 1403) to examine the relationship between estimated beryllium 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 fixed airhead samples from Building 444, the beryllium machine shop, where machine operators were considered to have the highest exposures at the Rocky Flats facility. These fixed air samples were collected away from the breathing zone 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., 2000, Document ID 1344).
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 but 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 (Document ID 1505). 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 from 1981-1997. The authors estimated that over the 17 years of measurement data analyzed, airborne beryllium concentrations did exceed 2.0 µg/m3, but 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 had not been routinely conducted among any of the workers at this facility.
Arjomandi et al. (2010) (Document ID 1275) 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 (Document ID 1275). Of the 1,875 current or former workers at the R&D facility, 59 were determined to be Start Printed Page 2511sensitized 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 and 2005. Arjomandi 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 authors believed beryllium levels were 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 across exposure categories 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 (Arjomandi et al., 2010, Document ID 1275).
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 (Document ID 0621).
Of the 3,185 workers determined to be potentially exposed to beryllium, 1,932 (60 percent) agreed to participate in a medical surveillance program between 2000 and 2006. The medical surveillance program included BeLPT analysis, confirmation of an abnormal BeLPT with a second BeLPT, and follow-up of all confirmed positive BeLPT results by a pulmonary physician to evaluate for progression to CBD.
Eight-hour TWA exposures 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 TWA with an arithmetic mean of 0.25 μg/m3 and geometric mean of 0.06 μg/m3. Based on a survey of published studies, the investigators concluded that exposure levels to beryllium observed in aluminum smelters were 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 the consistent use of respiratory protection. However, the authors also speculated that the low participation rate of 60 percent 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 exposures estimated in this plant were 0.1 µg/m3 to 0.31 µg/m3 (Nilsen et al., 2010, Document ID 0460).
6. Animal Models of CBD
This section reviews the relevant animal studies supporting the biological mechanisms outlined above. In order for an animal model to be useful for investigating the mechanisms underlying the development of CBD, the model should include: The demonstration of a beryllium-specific immune response; the formation of immune granulomas following inhalation exposure to beryllium; and progression of disease as observed in 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 not immune-induced reactions (which would predominantly consist of T-cells or lymphocytes), but were foreign-body-induced reactions, which predominantly consist of macrophages and monocytes, with only a small numbers of lymphocytes. Although no single model has completely mimicked the disease process as it progresses in humans, 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, such as sensitization and CBD. However, there is no dependable animal model that mimics all facets of the human response, and studies thus far have been limited by single dose experiments, too few animals, or abbreviated observation periods. Therefore, the utility of this data is limited. 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 Supplemental Information for the Beryllium Health Effects Section summarizes species, route, chemical form of beryllium, dose levels, and pathological findings of the key studies (Document ID 1965).
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, Document ID 1257). One group of dogs served as an air inhalation control group 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.
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BAL content was collected at 30, 60, 90, 180, and 210 days after exposure, and lavage fluid and cellular content was evaluated for neutrophilic and lymphocytic infiltration. In addition, BAL cells were evaluated at the 210 day period to determine activation potential by phytohemagglutinin (PHA) or beryllium sulfate as mitogen. BAL neutrophils were significantly elevated only at 30 days with exposure to either dose of 500 °C beryllium oxide. BAL lymphocytes were significantly elevated at all time points of the high dose of beryllium oxide. 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. Only the BAL lymphocytes from animals exposed to the 500 °C beryllium oxide responded to stimulation by either PHA or beryllium sulfate.
In a series of studies, Haley et al. also found that the beagle dog models certain aspects of human CBD (Haley et al., 1989, 1991 and 1992; Document ID 1366, 1315, 1365. Briefly, dogs were exposed by inhalation to a single exposure to beryllium aerosol generated from beryllium oxide calcined at 500 °C or 1,000 °C for initial lung burdens of 17 or 50 μg beryllium/kg body weight (Haley et al., 1989, Document ID 1366; 1991 (1315)). The dogs were monitored for lung pathologic effects, particle clearance, and immune sensitization of peripheral blood leukocytes. Lung retention was higher in the 1,000 °C treated beryllium oxide group (Haley et al., 1989, Document ID 1366).
Haley et al. (1989) described the bronchoalveolar lavage (BAL) and histopathological changes in dogs exposed as described above. One group of dogs underwent BAL for lung lymphocyte analysis at 3, 6, 7, 11, 15, 18, and 22 months post exposure. The investigators 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 and 1,000 °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 at 3 and 6 month post exposure. Another group underwent histopathological examination at days 8, 32, 64, 180, and 365 (Haley et al., 1989, Document ID 1366; 1991 (1315)). Histopathologic examination revealed peribronchiolar and perivascular lymphocytic histiocytic inflammation, 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. Although there was considerable inter-animal variation, lesions were generally more severe in the dogs exposed to material calcined at 500 °C. The investigators observed granulomatous lesions and lung lymphocyte responses consistent with those observed in humans with CBD, including perivascular and peribronchiolar infiltrates of lymphocytes and macrophages, progressing to microgranulomas with areas of granulomatous pneumonia and interstitial fibrosis. However, lesions declined in severity after 64 days post-exposure. 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 CBD 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 (cases) for an initial lung burden target of 50 μg beryllium oxide/kg body weight (Haley et al., 1992, Document ID 1365). Immune responses of blood and BAL lymphocytes, as well as 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 in beagle dogs.
In a comparison study of dogs and monkeys, Conradi et al. (1971) exposed animals via inhalation to an average aerosol to either 0, 3,300 or 4,380 μg/m3 of beryllium as beryllium oxide calcined at 1,400 °C for 30 minutes, once per month for 3 months (Document ID 1319). Conradi et al. found no changes in the histological or ultrastructure of the lung of animals exposed to beryllium versus control animals. This was in contrast to previous findings reported in other studies cited by Conradi et al. The investigators speculated that the differences may be due in part to calcination temperature or follow-up time after initial exposure. The findings from Haley et al. (1989, Document ID 1366; 1991 (1915); and 1992 (1365)) as well as Harmsen et al. (1986, Document ID 1257) suggest that the beagle model for sensitization of CBD is more closely related to the human response that other species such as the monkey (and those reviewed in Table A2 of the Supplemental Information for the Beryllium Health Effects Section).
A 1994 study by Haley et al. comparing the potential toxicity of beryllium oxide versus beryllium metal showed that instillation of both beryllium oxide and beryllium metal induced an immune response in monkeys. Briefly, male cynomolgus monkeys were exposed to either beryllium metal or beryllium oxide calcined at 500 °C via intrabronchiolar instillation as a saline suspension. Lymphocyte counts in BAL fluid were observed through bronchoalveolar lavage at 14, 30, 60, 90, and 120 days post exposure, and were found to be significantly increased in monkeys exposed to beryllium metal on post-exposure days 14, 30, 60, and 90, and in monkeys exposed to beryllium oxide on post-exposure day 30 and 60. Histological examination of lung tissue revealed that monkeys exposed to beryllium metal developed interstitial fibrosis, Type II cell hyperplasia with increased lymphocytes infiltration, and lymphocytic mantles accumulating around alveolar macrophages. Similar but much less severe lesions were observed in beryllium-oxide-exposed monkeys. Only monkeys exposed to beryllium metal had positive BAL BeLPT results (Haley et al., 1994, Document ID 1364).
As discussed earlier in this Health Effects section, at the cellular level, beryllium dissolution may be necessary in order for either a dendritic cell or a macrophage to present beryllium as an antigen to induce the cell-mediated CBD immune reactions (NAS, 2008, Document ID 1355). 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 (Stefaniak et al., 2006, Document ID 1398). As discussed previously, Haley et al. (1989, Document ID 1366) 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 Start Printed Page 2513elicited 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., 1989, Document ID 1366 and 1991 (1315)).
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, Document ID 1364). A study by Mueller and Adolphson (1979) observed that an oxide layer can develop on beryllium-metal surfaces after exposure to air (Mueller and Adolphson, 1979, Document ID 1260). According to the NAS report, Harmesen et al (1994) suggested that the presence of beryllium metal could lead to persistent exposures of small amounts beryllium oxide sufficient for presentation to the immune system (NAS, 2008, Document ID 1355).
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, Document ID 1345; Snyder et al., 2008 (0471)): (1) The HLA-DPB1*0401 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*0201 mice, where the transgene codes for glutamic acid residue at the 69th position of the B-chain 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 but coded for a more negatively charged protein to confer higher risk of CBD (Tarantino-Hutchinson et al., 2009, Document ID 0536).
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, Document ID 1345; Snyder et al., 2008 (0471)). 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.
7. Beryllium Sensitization and CBD Conclusions
There is substantial evidence that skin and inhalation exposure to beryllium may lead to sensitization (section V.D.1) and that inhalation exposure, or skin exposure coupled with inhalation exposure, may lead to the onset and progression of CBD (section V.D.2). These conclusions are supported by extensive human studies (section V.D.5). 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 earlier sections (sections V.D.1-5). Sensitization is considered to be a necessary first step to the onset of CBD (NAS, 2008, Document ID 1355; ERG, 2010 (1270)). 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 can progress to CBD (Rosenman et al., 2005, Document ID 1352; NAS, 2008 (1355); Mroz et al., 2009 (1356)). 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, Document ID 1257; Haley et al., 1989 (1366), 1992 (1365), 1994 (1364)). 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, Document ID 1257; Haley et al., 1992 (1365); Tarantino-Hutchison et al., 2009 (0536)). The evidence supports sensitization as an early functional change that allows the immune system to recognize and adversely react to beryllium. As such, OSHA regards beryllium sensitization as a necessary first step along a continuum that can culminate in clinical lung disease.
The epidemiological evidence presented in section V.D.5 demonstrates that sensitization and CBD are continuing to occur from exposures below OSHA's preceding PEL. The prevalence of sensitization among beryllium-exposed workers, as measured by the BeLPT and reported in 16 surveys of occupationally exposed cohorts reviewed by the Agency, ranged from 0.3 to 14.5 percent (Deubner et al., 2001, Document ID 1543; Kreiss et al., 1997 (1360); Rosenman et al., 2005 (1352); Schuler et al., 2012 (0473); Bailey et al., 2010 (0676); Newman et al., 2001 (1354); OSHA, 2014 (1589); Kreiss et al., 1996 (1477); Henneberger et al., 2001 (0589); Cummings et al., 2007 (1369); Schuler et al., 2005 (0919); Thomas et al., 2009 (1061); Kreiss et al., 1989 (1480); Arjomandi et al., 2010 (1275); Taiwo et al., 2011 (0621); Nilson et al., 2010 (0460)). The lower prevalence estimates (0.3 to 3.7 percent) were from facilities known to have implemented respiratory protection programs and have lower personal exposures (Cummings et al., 2007, Document ID 1369; Thomas et al., 2009 (1061); Bailey et al., 2010 (0676); Taiwo et al, 2011 (0621), Nilson et al., 2010 (0460); Arjomandi et al., 2010 (1275)). Thirteen of the surveys also evaluated workers for CBD and reported prevalences of CBD ranging from 0.1 to 7.8 percent. The cohort studies cover workers across many different industries and processes as discussed in section V.D.5. Several studies show that incidence of sensitization among workers can be reduced by reducing inhalation exposure and that minimizing skin exposure may serve to further reduce sensitization (Cummings et al., 2007, Document ID 1369; Thomas et al., 2009 (1061); Bailey et al., 2010 (0676)). The risk assessment further discusses the effectiveness of interventions to reduce beryllium exposures and the risk of sensitization and CBD (see section VI of this preamble, Risk Assessment).
Longitudinal studies of sensitized workers found early signs of asymptomatic CBD that can progress to clinical disease in some individuals. One study found that 31 percent of beryllium-exposed sensitized employees progressed to CBD with an average follow-up time of 3.8 years (Newman, 2005, Document ID 1437). However, Newman (2005) went on to suggest that if follow-up times were much longer, the rate of progression from Start Printed Page 2514sensitization to CBD could be much higher. Mroz et al. (2009) (Document ID 1356) conducted a longitudinal study between 1982 and 2002 in which they followed 171 cases of CBD and 229 cases of sensitization initially evaluated through workforce medical surveillance by National Jewish Health. All study subjects had abnormal BeLPTs upon study entry and were then clinically evaluated and treated for CBD. Over the 20-year study period, 22 sensitized individuals went on to develop CBD which was an incidence of 8.8 percent (i.e., 22 cases out of 251 sensitized, calculated by adding those 22 cases to the 229 initially classified as sensitized). The findings from this study indicated that the average span of time from initial beryllium exposure to CBD diagnosis for those 22 workers was 24 years (Mroz et al., 2009, Document ID 1356).
A study of sensitized workers believed to have been exposed to low levels of airborne beryllium metal (e.g., 0.01 µg/m3 or less) at a nuclear weapons research and development facility were clinically evaluated between 1999 and 2005 (Arjomandi et al., 2010, Document ID 1275). Five of 49 sensitized workers (10.2 percent incidence) were found to have pathology consistent with CBD. The CBD was asymptomatic and had not progressed to clinical disease. The mean duration of employment among workers in the study was 18 years with mean latency of 32 years to time of CBD diagnosis (Arjomandi et al., 2010, Document ID 1275). This suggests that some sensitized individuals can develop CBD even from low levels of beryllium exposure. Another study of nuclear weapons facility employees enrolled in an ongoing medical surveillance program found that sensitization rate among exposed workers was highest over the first 10 years of beryllium exposure while onset of CBD pathology was greatest following 15 to 30 years of exposure (Stange et al., 2001, Document ID 1403). This indicates length of exposure may play a role in further development of the disease. OSHA concludes from the study evidence that the persistent presence of beryllium in the lungs of sensitized workers can lead to a progression of CBD over time from an asymptomatic stage to serious clinical disease.
E. Beryllium Lung Cancer Section
Beryllium exposure is 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, IARC did an extensive evaluation in 1993 (Document ID 1342) and reevaluation in April 2009 (IARC, 2012, Document ID 0650). 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, Document ID 0661), and the National Toxicology Program (NTP) classifies beryllium and its compounds as known carcinogens (NTP, 2014, Document ID 0389). OSHA has conducted an independent evaluation of the carcinogenic potential of beryllium and these compounds. The following is a summary of the studies used to support the Agency's finding 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, Document ID 1355).
Non-mammalian test systems (generally bacterial assays) are often used to identify genotoxicity of a compound. In bacteria studies evaluating beryllium sulfate for mutagenicity, all studies performed utilizing the Ames assay (Simmon, 1979, Document ID 0434; Dunkel et al., 1981 (0432); Arlauskas et al., 1985 (0454); Ashby et al., 1990 (0437)) and other bacterial assays (E. coli pol A (Rosenkranz and Poirer, 1979, Document ID 1426); E. coli WP2 uvrA (Dunkel et al., 1981, Document ID 0432), as well as those utilizing Saccharomyces cerevisiae (Simmon, 1979, Document ID 0434)) were reported as negative, with the exception of results reported for Bacillus subtilis rec assay (Kada et al., 1980, Document ID 0433; Kanematsu et al., 1980 (1503)). Beryllium nitrate was also reported as negative in the Ames assay (Tso and Fung, 1981, Document ID 0446; Kuroda et al., 1991 (1471)) but positive in a Bacillus subtilis rec assay (Kuroda et al., 1991, Document ID 1471). In addition, beryllium chloride was reported as negative using the Ames assay (Ogawa et al., 1987, as cited in Document ID 1341, p. 112; Kuroda et al., 1991 (1471)) and other bacterial assays (E. coli WP2 uvrA (Rossman et al., 1984, Document ID 0431), as well as the Bacillus subtilis rec assay (Nishioka, 1975, Document ID 0449)) and failed to induce SOS DNA repair in E. coli (Rossman et al., 1984, Document ID 0431). Positive results for beryllium chloride were reported for Bacillus subtilis rec assay using spores (Kuroda et al., 1991, Document ID 1471) as well as increased mutations in the lacI gene of E. coli KMBL 3835 (Zakour and Glickman, 1984, Document ID 1373). Beryllium oxide was reported to be negative in the Ames assay and Bacillus subtilis rec assays (Kuroda et al., 1991, Document ID 1471; EPA, 1998 (0661)).
Mutations using in vitro mammalian systems were also evaluated. Beryllium chloride induced mutations in V79 and CHO cultured cells (Miyaki et al., 1979, Document ID 0450; Hsie et al., 1978 (0427); Vegni-Talluri and Guiggiani, 1967 (1382)), and beryllium sulfate induced clastogenic alterations, producing breakage or disrupting chromosomes in mammalian cells (Brooks et al., 1989, Document ID 0233; Larramendy et al., 1981 (1468); Gordon and Bowser, 2003 (1520)). However, beryllium sulfate did not induce unscheduled DNA 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). Positive results were found for beryllium chloride when evaluating the hprt gene in Chinese hamster lung V79 cells (Miyaki et al., 1979, Document ID 0450).
Data from in vivo genotoxicity testing of beryllium are limited. Beryllium metal was found to induce methylation of the p16 gene in the lung tumors of rats exposed to beryllium metal (Swafford et al., 1997, Document ID 1392) (described in more detail in section V.E.3). A study by Nickell-Brady et al., (1994) found that 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 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 (described in more detail in section V. E. 3) (Nickell-Brady et al., 1994, Document ID 1312). On the other hand, beryllium chloride evaluated in a mouse model indicated increased DNA strand breaks and the formation of micronuclei Start Printed Page 2515in bone marrow (Attia et al., 2013, Document ID 0501).
In summary, genetic mutations have been observed in mammalian systems (in vitro and in vivo) with beryllium chloride, beryllium sulfate, and beryllium metal in a number of studies (Miyaki et al., 1979, Document ID 0450; Hsie et al., 1978 (0427); Vegni-Talluri and Guiggiani, 1967 (1382); Brooks et al., 1989 (0233); Larramendy et al., 1981 (1468); Miyaki et al., 1979 (0450); Swafford et al., 1997 (1392); Attia et al., 2013 (0501); EPA, 1998 (0661); Gordon and Bowser, 2003 (1520)). However, most studies utilizing non-mammalian test systems (either with or without metabolic activity) have found that beryllium chloride, beryllium nitrate, beryllium sulfate, and beryllium oxide did not induce gene mutations, with the exception of Kada et al. (1980, Document ID 0433) (Kanematsu et al., 1980, Document ID 1503; Kuroda et al., 1991 (1471)).
2. Human Epidemiological Studies
This section describes the human epidemiological data supporting the mechanistic overview of beryllium-induced lung cancer in workers. It has been divided into reviews of epidemiological studies by industry and beryllium form. The epidemiological studies utilizing data from the BCR, in general, focus on workers mainly exposed to soluble forms of beryllium. Those studies evaluating the epidemiological evidence by industry or process are, in general, focused on exposures to poorly soluble or mixed (soluble and poorly soluble) compounds. Table A.3 in the Supplemental Information for the Beryllium Health Effects Section summarizes the important features and characteristics of each study discussed herein (Document ID 1965).
a. Beryllium Case Registry (BCR)
Two studies evaluated participants in the BCR (Infante et al., 1980, Document ID 1507; Steenland and Ward, 1991 (1400)). 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 from 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) (Document ID 1400) extended the work of Infante et al. (1980) (Document ID 1507) 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 with confirmed beryllium exposure. 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 then diagnosed with beryllium disease (ABD and CBD).
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.
Bayliss et al. (1971) (Document ID 1285) performed a nested cohort study of 7,948 former workers from the beryllium processing industry who were employed from 1942-1967. Information for the workers was collected from the personnel files of participating companies. Of the 7,948 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 the 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, Document ID 1453; 1979, (0529); 1980 (1452)) and Mancuso and El-Attar (1969) (Document ID 1455) performed a series of occupational cohort studies on a group of workers (primarily white males) employed in the beryllium manufacturing industry during 1937-1948. The cohort identified in Mancuso and El-Attar (1969) was a study of 3,685 workers (primarily white males) while Mancuso (1970, 1976, 1980) continued the study follow-up with 3266 workers due to several limitations in identifying specific causes for mortality as identified in Mancuso and El-Attar (1969). 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 (exposure data was taken from a study by Zielinsky et al., 1961 (as cited in Mancuso, 1970)). 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 Start Printed Page 2516viscose 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 initial exposure regardless of the length of employment.
Wagoner et al. (1980) (Document ID 1379) expanded the work of Mancuso (1970, Document ID 1453; 1979 (0529); 1980 (1452)) 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 of employment and a ≥25-year interval since the beginning of employment (p <0.05). The study was criticized by two epidemiologists (MacMahon, 1978, Document ID 0107; Roth, 1983 (0538)), by a CDC Review Committee appointed to evaluate the study (as cited in Document ID 0067), and by one of the study's coauthors (Bayliss, 1980, Document ID 0105) 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 (which may underestimate the expected number of lung cancer deaths for the cohort) and inadequate adjustment for smoking.
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, Document ID 1250). 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 exposures. 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 largest and most comprehensive study investigated the mortality experience of 9,225 workers employed in 7 different beryllium processing plants over a 30-year period (Ward et al., 1992, Document ID 1378). 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. The workers at these two plants were believed to have the highest exposure levels to beryllium. 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) (Document ID 1455), Mancuso (1970, Document ID 1453; 1979 (0529); 1980 (1452)), and Wagoner et al. (1980) (Document ID 1379). The men were employed for no less than 2 days between January 1940 and December 1969. Medical records were followed through 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.
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-exposed employees (Levy et al., 2002, Document ID 1463). Both cohort studies (Levy et al., 2002, Document ID 1463; Ward et al., 1992 (1378)) are limited by a lack of job history and air monitoring data that would allow investigation of mortality trends with different levels and durations of 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.
Levy et al. (2002) (Document ID 1463) questioned the results of Ward et al. (1992) (Document ID 1378) 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) (Document ID 1463) 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) (Document ID 1378) for their smoking adjustment, or (2) results from a smoking/lung cancer study of veterans. Second, Levy et al. (2002) also examined the impact 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 (Document ID 1463). Finally, Levy et al. (2002) considered a meta-analytical approach to combining the results across beryllium facilities (Document ID 1463). For all of the alternatives Levy et al. (2002) (Document ID 1463) considered, except the meta-analysis, the facility-specific and combined SMRs derived were lower than those reported by Ward et al. (1992) (Document ID 1378). 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 Start Printed Page 2517Levy et al. (2002) (Document ID 1463) to conclude that there was little evidence of statistically significant elevated SMRs in those plants. This study was not included in the synthesis of epidemiological studies assessed by IARC due to several methodological limitations (IARC, 2012, Document ID 0650).
The EPA Integrated Risk Information System (IRIS), IARC, and California EPA Office of Environmental Health Hazard Assessment (OEHHA) all based their cancer assessments on the Ward et al. 1992 study, with supporting data concerning exposure concentrations from Eisenbud and Lisson (1983) (Document ID 1296) and NIOSH (1972) (Document ID 0560), 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 increase in lung cancer deaths (EPA, 1987, Document ID 1295). Based on its 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” (EPA, 1998, Document ID 0237). The EPA 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.
Sanderson et al. (2001) (Document ID 1419) estimated the cumulative, average, and maximum beryllium exposure concentration for the 142 known lung cancer cases to be 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 (Sanderson et al., 2001, Document ID 1419). 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 1940s and 1950s and the shape of the dose-response curve for lung cancer (Sanderson et al., 2001, Document ID 1419). 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 preceding 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, Document ID 0650). NIOSH comments in the rulemaking docket support IARC's finding (citing Schubauer-Berigan et al., 2007; Hein et al., 2009, 2011; Langholz and Richardson 2009; Wacholder 2009) (Document ID 1671, Attachment 1, p. 10).
Schubauer-Berigan et al. (2008) (Document ID 1350) reanalyzed data from the Sanderson et al. (2001) nested case-control study of 142 lung cancer cases in the Reading, PA, beryllium processing plant. 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 (Document ID 1419). 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.
Schubauer-Berigan et al. stated that the reanalysis indicated that differences in the hire ages among cases and controls, first noted by Deubner et al. (2001) (Document ID 0109) and Levy et al. (2007) (Document ID 1462), 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, Document ID 1350). 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) (Document ID 1512) re-examined the weight of evidence of beryllium as a lung carcinogen in a recent publication. 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 was not relevant to today's industrial settings. IARC performed a similar re-evaluation in 2009 (IARC, 2012, Document ID 0650) 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 Start Printed Page 2518beryllium should be considered carcinogenic to humans.
Schubauer-Berigan et al. (2011) (Document ID 1266) 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 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 this change represents more than an update of the beryllium cohort. Standardized mortality ratios (SMRs) were estimated based on U.S. 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 U.S. 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) (Schubauer-Berigan et al., 2011, Document ID 1266). Mortality rates for most diseases of interest increased with time since hire. For the category including CBD, rates were substantially elevated compared to the U.S. 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 that 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., 2011, Document ID 1266).
A study by Boffetta et al. (2014, Document ID 0403) and an abstract by Boffetta et al., (2015, Document ID 1661, Attachment 1) were submitted by Materion for Agency consideration (Document ID 1661, p. 3). Briefly, Boffetta et al. investigated lung cancer and other diseases in a cohort of 4,950 workers in four beryllium manufacturing facilities. Based on available process information from the facilities, the cohort of workers included only those working with poorly soluble beryllium. Workers having potential for soluble beryllium exposure were excluded from the study. Boffetta et al. reported a slight increase in lung cancer rates among workers hired prior to 1960, but the increase was reported as not statistically significant. Bofetta et al. (2014) indicated that “[t]his study confirmed the lack of an increase in mortality from lung cancer and nonmalignant respiratory diseases related to [poorly] soluble beryllium compounds” (Document ID 0403, p. 587). OSHA disagrees, and a more detailed analysis of the Boffetta et al. (2014, Document ID 0403) study is provided in the Risk Assessment section (VI) of this preamble. The Boffetta et al. (2015, Document ID 1661, Attachment 1) study cited by Materion was an abstract to the 48th annual Society of Epidemiological Research conference and does not provide sufficient information for OSHA to consider.
To summarize, most of the epidemiological studies reviewed in this section show an elevated lung cancer rate in beryllium-exposed workers compared to control groups. While exposure data was incomplete in many studies inferences can be made based on industry profiles. Specifically, studies reviewing excess lung cancer in workers registered in the BCR found an elevated lung cancer rate in those patients identified as having acute beryllium disease (ABD). ABD patients are most closely associated with exposure to soluble forms of beryllium (Infante et al., 1980, Document ID 1507; Steenland and Ward, 1991 (1348)). Industry profiles in processing and extraction indicate that most exposures would be due to poorly soluble forms of beryllium. Excess lung cancer rates were observed in workers in industries associated with extraction and processing (Schubauer-Berigan et al., 2008, Document ID 1350; Schubauer-Berigan et al. 2011 (1266, 1815 Attachment 105); Ward et al., 1992 (1378); Hollins et al., 2009 (1512); Sanderson et al., 2001 (1419); Mancuso et al., 1980 (1452); Wagoner et al., 1980 (1379)). During the public comment period NIOSH noted that:
. . . in Table 1 of Ward et al. (1992), all three of these beryllium plants were engaged in operations associated with both soluble and [poorly soluble] forms of beryllium. Industrial hygienists from NIOSH [Sanderson et al. (2001); Couch et al. (2011)] and elsewhere [Chen (2001); Rosenman et al. (2005)] created job-exposure matrices (JEMs), which estimated the form of beryllium exposure (soluble, consisting of beryllium salts; [poorly soluble], consisting of beryllium metal, alloys, or beryllium oxide; and mixed forms) associated with each job, department and year combination at each plant. Unpublished evaluations of these JEM estimates linked to the employee work histories in the NIOSH risk assessment study [Schubauer-Berigan et al., 2011b, Document ID 0521] show that the vast majority of beryllium work-time at all three of these facilities was due to either [poorly] soluble or mixed chemical forms. In fact, [poorly] soluble beryllium was the largest single contributor to work-time (for beryllium exposure of known solubility class) at the three facilities across most time periods . . . . Therefore, the strong and consistent exposure-response pattern that was observed in the published NIOSH studies was very likely associated with exposure to [poorly] soluble as well as soluble forms of beryllium. (Document ID 1725, p. 9)
Taken collectively, the Agency finds that the epidemiological data presented in the reviewed studies provides sufficient evidence to demonstrate carcinogenicity in humans of both soluble and poorly soluble forms of beryllium.
3. Animal Cancer Studies
This section reviews the animal literature used to support the findings for beryllium-induced lung cancer. Early animal studies revealed that some beryllium compounds are carcinogenic when inhaled (ATSDR, 2002, Document ID 1371). 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 mice. In addition to lung cancer, Start Printed Page 2519osteosarcomas have been produced in mice and rabbits exposed to various beryllium salts by intravenous injection or implantation into the bone (NTP, 1999, Document ID 1341: IARC, 2012 (0650)). While not completely understood, experimental studies in animals (in vitro and in vivo) have found that a number of mechanisms are likely involved in beryllium-induced carcinogenicity, including chronic inflammation, genotoxicity, mitogenicity, oxidative stress, and epigenetic changes.
In an inhalation study assessing the potential tumorigenicity of beryllium, Schepers et al. (1957) (Document ID 0458) exposed 115 albino Sherman and Wistar rats (male and female) via inhalation to 0.0357 mg beryllium/m (1 γ beryllium/ft ) 
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,
including adenomas, squamous-cell carcinomas, acinous adenocarcinomas, papillary adenocarcinomas, and alveolar-cell adenocarcinomas, were observed in 52 of the rats exposed to the beryllium sulfate aerosol. Adenocarcinomas 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 3:
Table 3—Neoplasm Analysis, Based on Schepers et al. (1957)
Schepers (1962) (Document ID 1414) 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. Ten varieties of tumors were observed, with adenocarcinoma being the most common variety.
In another study, Vorwald and Reeves (1959) (Document ID 1482) 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. (1967) investigated the carcinogenic process in lungs resulting from chronic (up to 72 weeks) beryllium sulfate inhalation (Document ID 1310). 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 exposed 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 were “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 occurred in females.
In the second article, Reeves et al. (1967) (Document ID 1309) described the rate of accumulation and clearance of beryllium sulfate aerosol from the same experiment (Reeves et al., 1967) (Document ID 1310). 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 Start Printed Page 2520decreased 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) (Document ID 1316) 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 4—Summary of Beryllium Dose, Based on Groth et al. (1980)
[Document ID 1316]
|Form of Be||Percent Be||Percent other compounds||Total Number rats autopsied||Compound dose(mg)||Be dose(mg)|
|Be metal||100||None||16 21||2.5 0.5||2.5 0.5|
|Passivated Be metal||99||0.26% Chromium||26 20||2.5 0.5||2.5 0.5|
|BeAl alloy||62||38% Aluminum||24 21||2.5 0.5||1.55 0.3|
|BeCu alloy||4||96% Copper||28 24||2.5 0.5||0.1 0.02|
|BeCuCo alloy||2.4||0.4% Cobalt 96% Copper||33 30||2.5 0.5||0.06 0.012|
|BeNi alloy||2.2||97.8% Nickel||28 27||2.5 0.5||0.056 0.011|
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 beryllium 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. Of 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, Document ID 1316).
Finch et al. (1998b) (Document ID 1367) investigated the carcinogenic effects of inhaled beryllium on heterozygous TSG-p53 knockout (p53+/−) mice and wild-type (p53+/+) mice. Knockout mice can be valuable tools in determining the role played by specific genes in 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 Start Printed Page 2521beryllium 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 5—Summary of Animal Data, Based on Finch et al. (1998)
[Document ID 1367]
|Mouse strain||Mean exposure concentration (μg Be/L)||Target beryllium lung burden (μg)||Number of mice||Mean daily exposure duration (minutes)||Mean ILB (μg)||Number of mice with 1 or more lung tumors/total number examined|
|Knockout (p53+/−)||34 36||15 60||30 30||112 (single) 139||NA NA||0/29 4/28|
|Wild-type (p53+/+)||34 36||15 60||6 36||112 (single) 139||12 ± 4 54 ± 6||NA 0/28|
|Knockout (p53+/−)||NA (air)||Control||30||60-180 (single)||NA||0/30|
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 of which 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., 1998, Document ID 1367).
During the public comment period Materion submitted correspondence from Dr. Finch speculating on the reason for the less-robust lung cancer response observed in mice (versus that observed in rats) (Document ID 1807, Attachment 11, p. 1). Materion contended that this was support for their assertion of evidence that “directly contradicts the claims that beryllium metal causes cancer in animals” (Document ID 1807, p. 6). OSHA reviewed this correspondence and disagrees with Materion's assertion. While Dr. Finch did suggest that the mouse lung cancer response was less robust, it was still present. Dr. Finch went on to suggest that while the rat has a more profound neutrophilic response (typical of a “foreign body response), the mouse has a lung response more typical of humans (neutrophilic and lymphocytic) (Document ID 1807, Attachment 11, p. 1).
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 (Document ID 1312). 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 or 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 Start Printed Page 2522activation 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) (Document ID 1312) 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 concluded 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 p16 INK4a(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 (Document ID 1392). 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) (Document ID 1392), Belinsky et al. (2002) (Document ID 1300) 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) (Document ID 1481) 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 monkeys (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 (Document ID 1319). 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 Start Printed Page 2523and 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.
To summarize, animal studies show that multiple forms of beryllium, when inhaled or instilled in the respiratory tract of rats, mice, and monkeys, lead to increased incidence of lung tumors. Animal studies have demonstrated a consistent scenario of beryllium exposure resulting in chronic pulmonary inflammation and tumor formation at levels below overload conditions (Groth et al., 1980, Document ID 1316; Finch et al., 1998 (1367); Nickel-Brady et al., 1994 (1312)). The animal studies support the human epidemiological evidence and contributed to the findings of the NTP, IARC, and others that beryllium and beryllium-containing material should be regarded as known human carcinogens. The beryllium compounds found to be carcinogenic in animals include both soluble beryllium compounds, such as beryllium sulfate and beryllium hydroxide, as well as poorly soluble beryllium compounds, such as beryllium oxide and beryllium metal. The doses that produce tumors in experimental animal are fairly large and also lead to chronic pulmonary inflammation. The exact tumorigenic mechanism for beryllium is unclear and a number of mechanisms are likely involved, including chronic inflammation, genotoxicity, mitogenicity, oxidative stress, and epigenetic changes.
4. In Vitro Studies
The exact mechanism by which beryllium induces pulmonary neoplasms in animals remains unknown (NAS 2008, Document ID 1355). Keshava et al. (2001) performed studies to determine the carcinogenic potential of beryllium sulfate in cultured mammalian cells (Document ID 1362). Joseph et al. (2001) investigated differential gene expression to understand the possible mechanisms of beryllium-induced cell transformation and tumorigenesis (Document ID 1490). 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 (Document ID 1362). 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 after beryllium sulfate exposure in a mouse cell line (Document ID 1490). 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).
In summary, in vitro studies have been used to evaluate the neoplastic potential of beryllium compounds and the possible underlying mechanisms. Both Keshava et al. (2001) (Document ID 1362) and Joseph et al. (2001) (Document ID 1490) have found that beryllium sulfate induced a number of onco-genes (c-fos, c-jun, c-myc, and R-ras) and down-regulated genes responses for normal cellular function and repair (including those involved in DNA synthesis, repair, and recombination).
5. Lung Cancer Conclusions
OSHA has determined that substantial evidence in the record indicates that beryllium compounds should be regarded as occupational lung carcinogens. Many well-respected scientific organizations, including IARC, NTP, EPA, NIOSH, and 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 that an indirect mechanism, such as inflammation or other epigenetic changes, may be responsible for most tumorigenic activity of beryllium in animals and humans (IARC, 2012, Document ID 0650). 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 immunological response, beryllium has been demonstrated to produce an inflammatory response in animal models similar to the response produced by other particles (Reeves et al., 1967, Document ID 1309; Swafford et al., 1997 (1392); Wagner et al., 1969 (1481)), possibly contributing to its carcinogenic potential. Studies conducted in rats have demonstrated that chronic inhalation of materials similar in solubility to beryllium results in increased pulmonary inflammation, Start Printed Page 2524fibrosis, epithelial hyperplasia, and, in some cases, pulmonary adenomas and carcinomas (Heinrich et al., 1995, Document ID 1513; NTP, 1993 (1333); Lee et al., 1985 (1466); Warheit et al., 1996 (1377)). This response is generally referred to as an “overload” response and is specific to particles of low solubility with a low order of toxicity, which are non-mutagenic and non-genotoxic (i.e., poorly soluble particles like titanium dioxide and non-asbestiform talc); this response is observed only in rats (Carter et al., 2006, Document ID 1556). “Overload” is described in ECETOC (2013) as inhalation of high concentrations of low solubility particles resulting in lung burdens that impair particle clearance mechanisms (ECETOC, 2013 as cited in Document ID 1807, Attachment 10, p. 3 (pdf p. 87)). Substantial data indicate that tumor formation in rats after exposure to some poorly 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. Because these specific particles (i.e., titanium dioxide and non-asbestiform talc) exhibit no cytotoxicity or genotoxicity, they are considered to be biologically inert (ECETOC, 2013; see Document ID 1807, Attachment 10, p. 3 (pdf p. 87)). Animal studies, as summarized above, have demonstrated a consistent scenario of beryllium exposure resulting in chronic pulmonary inflammation below an overload scenario. NIOSH submitted comments describing the findings from a low-dose study of beryllium metal among male and female F344 rats (Document ID 1960, p. 11). The study by Finch et al. (2000) indicated lung tumor rates of 4, 4, 12, 50, 61, and 91 percent in animals with beryllium metal lung burdens of 0, 0.3, 1, 3, 10, and 50 μg respectively (Finch et al., 2000 as cited in Document ID 1960, p. 11). NIOSH noted the lung burden levels were much lower than those from previous studies, such as a 1998 Finch et al. study with initial lung burdens of 15 and 60 μg (Document ID 1960, p. 11). Based on evidence from mammalian studies of the mutagenicity and genotoxicity of beryllium (as described in above in section V.E.1) and the evidence of tumorigenicity at lung burden levels well below overload, OSHA concludes that beryllium particles are not poorly soluble particles like titanium dioxide and non-asbestiform talc.
It has been hypothesized that the recruitment of neutrophils during the inflammatory response and subsequent release of oxidants from these cells play an important role in the pathogenesis of rat lung tumors (Borm et al., 2004, Document ID 1559; Carter and Driscoll, 2001 (1557); Carter et al., 2006 (1556); Johnston et al., 2000 (1504); Knaapen et al., 2004 (1499); Mossman, 2000 (1444)). This is one potential carcinogenic pathway for beryllium particles. Inflammatory mediators, acting at levels below overload doses 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 as well as mitogenic, inducing a proliferative response (Ferriola and Nettesheim, 1994, Document ID 0452; Coussens and Werb, 2002 (0496)). The resultant effect is an environment rich for neoplastic transformations and the progression of fibrosis and tumor formation. This is consistent with findings from the National Cancer Institute, which has estimated that one-third of all cancers may be due to chronic inflammation (NCI, 2010, Document ID 0532). However, an inflammation-driven contribution to the neoplastic transformation does not imply no risk at levels below inflammatory response; rather, the overall weight of evidence suggests 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. As summarized above, animal studies have consistently demonstrated beryllium exposure resulting in chronic pulmonary inflammation below overload conditions in multiple species (Groth et al., 1980, Document ID 1316; Finch et al., 1998 (1367); Nickel-Brady et al., 1994 (1312)). While OSHA recognizes chronic inflammation as one potential pathway to carcinogencity the Agency finds that other carcinogenic pathways such as genotoxicity and epigenetic changes may also contribute to beryllium-induced carcinogenesis.
During the public comment period OSHA received several comments on the carcinogenicity of beryllium. The NFFS agreed with OSHA that “the science is quite clear in linking these soluble Beryllium compounds” to lung cancer (Document ID 1678, p. 6). It also, however, contended that there is considerable scientific dispute regarding the carcinogenicity of beryllium metal (i.e., poorly soluble beryllium), citing findings by the EU's REACH Beryllium Commission (later clarified as the EU Beryllium Science and Technology Association) (Document ID 1785, p. 1; Document ID 1814) and a study by Strupp and Furnes (2010) (Document ID 1678, pp. 6-7, and Attachment 1). Materion, similarly, commented that “[a] report conclusion during the recent review of the European Cancer Directive for the European Commission stated regarding beryllium: `There was little evidence for any important health impact from current or recent past exposures in the EU' ” (Document ID 1958, p. 4).
The contentions of both Materion and NFFS regarding scientific findings from the EU is directly contradicted by the document submitted to the docket by the European Commission on Health, Safety and Hygiene at Work, discussed above. This document states that the European Chemicals Agency (ECHA) has determined that all forms of beryllium (soluble and poorly soluble) are carcinogenic (Category 1B) with the exception of aluminum beryllium silicates (which have not been allocated a classification) (Document ID 1692, pp. 2-3).
OSHA also disagrees with NFFS's other contention that there is a scientific dispute regarding the carcinogenicity of poorly soluble forms of beryllium. In coming to the conclusion that all forms of beryllium and beryllium compounds are carcinogenic, OSHA independently evaluated the scientific literature, including the findings of authoritative entities such as NIOSH, NTP, EPA, and IARC (see section V.E). The evidence from human, animal, and mechanistic studies together demonstrates that both soluble and poorly soluble beryllium compounds are carcinogenic (see sections V.E.2, V.E.3, V.E.4). The well-respected scientific bodies mentioned above came to the same conclusion: That both soluble and poorly soluble beryllium compounds are carcinogenic to humans.
As supporting documentation the NFFS submitted an “expert statement” by Strupp and Furnes (2010), which reviews the toxicological and epidemiological information regarding beryllium carcinogenicity. Based on select information in the scientific literature on lung cancer, the Strupp and Furnes (2010) study concluded that there was insufficient evidence in humans and animals to conclude that insoluble (poorly soluble) beryllium was carcinogenic (Document ID 1678, Attachment 1, pp. 21-23). Strupp and Furnes (2010) asserted that this was based on criteria established under Start Printed Page 2525Annex VI of Directive 67/548/EEC which establishes criteria for classification and labelling of hazardous substances under the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS). OSHA reviewed the Strupp and Furnes (2010) “expert statement” submitted by NFFS and found it to be unpersuasive. Its review of the epidemiological evidence mischaracterized the findings from the NIOSH cohort and the nested case-control studies (Ward et al., 1992; Sanderson et al., 2001; Schubauer-Berigan et al., 2008) and misunderstood the methods commonly used to analyze occupational cohort studies (Document ID 1725, pp. 27-28).
The Strupp and Furnes statement also did not include the more recent studies by Schubauer-Berigan et al. (2011, Document ID 1815, Attachment 105, 2011 (0626)), which demonstrated elevated rates for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28) in a study of 7 beryllium processing plants. In addition, Strupp and Furnes did not consider expert criticism from IARC on the studies by Levy et al. (2007) and Deubner et al., (2007), which formed the basis of their findings. NIOSH submitted comments that stated:
The Strupp (2011b) review of the epidemiological evidence for lung carcinogenicity of beryllium contained fundamental mischaracterizations of the findings of the NIOSH cohort and nested case-control studies (Ward et al. 1992; Sanderson et al. 2001; Schubauer-Berigan et al. 2008), as well as an apparent misunderstanding of the methods commonly used to analyze occupational cohort studies (Document ID 1960, Attachment 2, p. 10).
As further noted by NIOSH:
Strupp's epidemiology summary mentions two papers that were critical of the Sanderson et al. (2001) nested case-control study. The first of these, Levy et al. (2007a), was a re-analysis that incorporated a nonstandard method of selecting control subjects and the second, Deubner et al. (2007), was a simulation study designed to evaluate Sanderson's study design. Both of these papers have themselves been criticized for using faulty methods (Schubauer-Berigan et al. 2007; Kriebel, 2008; Langholz and Richardson, 2008); however, Strupp's coverage of this is incomplete. (Document ID 1960, Attachment 2, Appendix, p. 19).
NIOSH went on to state that while the Sanderson et al. (2001) used standard accepted methods for selecting the control group, the Deubner et al. (2007) study limited control group eligibility and failed to adequately match control and case groups (Document ID 1960, Attachment 2, Appendix, pp. 19-20). NIOSH noted that an independent analysis published by Langholz and Richardson (2009) and Hein et al., (2009) (as cited in Document ID 1960, Attachment 2, Appendix, p. 20) found that Levy et al.' s method of eliminating controls from the study had the effect of “always produc[ing] downwardly biased effect estimates and for many scenarios the bias was substantial.” (Document ID 1960, Attachment 2, Appendix, p. 20). NIOSH went on to cite numerous errors in the studies cited by Strupp (2011) (Document ID 1794, 1795).
OSHA finds NIOSH's criticisms of the Strupp (2011) studies as well as their criticism of studies by Levy et al., 2007 and Deubner et al., 2007 to be reliable and credible.
The Strupp and Furnes (2010) statement provided insufficient information on the extraction of beryllium metal for OSHA to fully evaluate the merit of the studies regarding potential genotoxicity of poorly soluble beryllium (Document ID 1678, Attachment 1, pp. 18-20). In addition, Strupp and Furnes did not consider the peer-reviewed published studies evaluating the genotoxicity of beryllium metal (see section V.E.1 and V.E.2).
In coming to the conclusion that the evidence is insufficient for classification under GHS, Strupp and Furnes failed to consider the full weight of evidence in their evaluation using the criteria set forth under Annex VI of Directive 67/548/EEC which establishes criteria for classification and labelling of hazardous substances under the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) (Document ID 1678, attachment 1, pp. 21-23). Thus, the Agency concludes that the Strupp and Furnes statement does not constitute the best available scientific evidence for the evaluation of whether poorly soluble forms of beryllium cause cancer.
Materion also submitted comments indicating there is an ongoing scientific debate regarding the relevance of the rat lung tumor response to humans with respect to poorly soluble beryllium compounds (Document ID 1807, Attachment 10, pp. 1-3 (pdf pp. 85-87)), Materion contended that the increased lung cancer risk in beryllium-exposed animals is due to a particle overload phenomenon, in which lung clearance of beryllium particles initiates a non-specific neutrophilic response that results in intrapulmonary lung tumors. The materials cited by Materion as supportive of its argument—Obedorster (1995), a 2009 working paper to the UN Subcommittee on the Globally Harmonized System of Classification and Labelling of Chemicals (citing ILSI (2000) as supporting evidence for poorly soluble particles), Snipes (1996), the Health Risk Assessment Guidance for Metals, ICMM (2007), and ECETOC (2013)—discuss the inhalation of high exposure levels of poorly soluble particles in rats and the relevance of these studies to the human carcinogenic response (Document ID 1807, Attachment 10, pp. 1-3 (pdf pp. 85-87)). Using particles such as titanium dioxide, carbon black, non-asbestiform talc, coal dust, and diesel soot as models, ILSI (2000) and ECETOC (2013) describe studies that have demonstrated that chronic inhalation of poorly soluble particles can result in pulmonary inflammation, fibrosis, epithelial cell hyperplasia, and adenomas and carcinomas in rats at exposure levels that exceed lung clearance mechanisms (the “overload” phenomenon) (ILSI (2000) 
, p. 2, as cited in Document ID 1807, Attachment 10, pp. 1-3 (pdf pp. 85-87)).
However, these expert reports indicate that the “overload” phenomenon caused by biologically inert particles (poorly soluble particles of low cytotoxicity for which there is no evidence of genotoxicity) is relevant only to the rat species. (Document ID 1807, Attachment 10, pp. 1-3 (pdf pp. 85-87)). OSHA finds that this model is not in keeping with the data presented for beryllium for several reasons. First, beryllium has been shown to be a “biologically active” particle due to its ability to induce an immune response in multiple species including humans, has been shown to be genotoxic in certain mammalian test systems, and induces epigenetic changes (e.g. DNA methylation) (as described in detail in sections V. D. 6, V.E.1, V.E.3 and V.E.4). Second, beryllium has been shown to produce lung tumors after inhalation or instillation in several animal species, including rats, mice, and monkeys (Finch et al., 1998, Document ID 1367; Schepers et al., 1957 (0458) and 1962 (1414); Wagner et al., 1969 (1481); Belinsky et al., 2002 (1300); Groth et al.,
Start Printed Page 25261980 (1316); Vorwald and Reeves, 1957 (1482); Nickell-Brady et al., 1994 (1312); Swafford et al., 1997 (1392); IARC, 2012 (1355)). In addition, poorly soluble beryllium has been demonstrated to produce chronic inflammation at levels below overload (Groth et al., 1980, Document ID 1316; Nickell-Brady et al., 1994 (1312); Finch et al., 1998 (1367); Finch et al., 2000 (as cited in Document ID 1960, p. 11)).
In addition, IARC and NAS performed an extensive review of the available animal studies and their findings were supportive of the OSHA findings of carcinogenicity (IARC, 2012, Document ID 0650; NAS, 2008 (1355)). OSHA performed an independent evaluation as outlined in section V.E.3 and found sufficient evidence of tumor formation in multiple species (rats, mice, and monkeys) after inhalation at levels below overload conditions. The Agency has found evidence supporting the hypothesis that multiple mechanisms may be at work in the development of cancer in experimental animals and humans and cannot dismiss the roles of inflammation (neutrophilic and T-cell mediated), genotoxicity, and epigenetic factors (see section V.E.1, V.E. 3, V.E.4). After evaluating the best scientific evidence available from epidemiological and animal studies (see section V.E) OSHA concludes the weight of evidence supports a mechanistic finding that both soluble and poorly soluble forms of beryllium and beryllium-containing compounds are carcinogenic.
F. Other Health Effects
Past studies on other health effects have been thoroughly reviewed by several scientific organizations (NTP, 1999, Document ID 1341; EPA, 1998 (0661); ATSDR, 2002 (1371); WHO, 2001 (1282); HSDB, 2010 (0533)). 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 on humans mostly occurred prior to the introduction of occupational and environmental standards set in 1970-1972 OSHA, 1971, see 39 FR 23513; EPA, 1973 (38 FR 8820)). (OSHA, 1971, see 39 FR 23513; ACGIH, 1971 (0543); ANSI, 1970 (1303)) and EPA, 1973 (38 FR 8820) 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. During the public comment period OSHA received comments suggesting that OSHA add dermal effects to this section. Therefore, dermal effects have been added, below, and are also discussed in the section on kinetics and metabolism (section V.B.2).
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, in one study, beryllium phosphate accumulated almost exclusively within sinusoidal (Kupffer) cells of the liver, while beryllium sulfate was found mainly in parenchymal cells. Conversely, beryllium sulphosalicylic acid complexes were rapidly excreted (Skilleter and Paine, 1979, Document ID 1410).
According to a few autopsies, beryllium-laden livers had central necrosis, mild focal necrosis and inflammation, as well as, occasionally, beryllium granuloma (Sprince et al., 1975, Document ID 1405).
2. Cardiovascular Effects
Severe cases of CBD 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, Document ID 1516). 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, Document ID 1378). Additionally, a study by Schubauer-Berigan et al. (2011) found an increase in mortality due to cor pulmonale in a follow-up study of workers at seven beryllium processing plants who were exposed to beryllium levels near the preceding OSHA PEL of 2.0 μg/m3 (Schubauer-Berigan et al., 2011, Document ID 1266).
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, 1957, Document ID 0458). Decreased arterial oxygen tension was observed in dogs exposed to 30 mg beryllium/m3 as beryllium oxide for 15 days (HSDB, 2010, Document ID 0533), 3.6 mg beryllium/m3 as beryllium oxide for 40 days (Hall et al., 1950, Document ID 1494), and 0.04 mg beryllium/m3 as beryllium sulfate for 100 days (Stokinger et al., 1950, Document ID 1484). These are thought 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 or kidney stones have been found in severe cases of CBD 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, Document ID 0453). The ATSDR reported that 10 percent of the CBD cases found in the BCR reported kidney stones. In addition, an excess of calcium in the blood and urine was frequently found in patients with CBD (ATSDR, 2002, Document ID 1371).
4. Ocular and Mucosal Effects
Soluble and poorly soluble beryllium compounds have been shown to cause ocular irritation in humans (VanOrdstrand et al., 1945, Document ID 1383; De Nardi et al., 1953 (1545); Nishimura, 1966 (1435); Epstein, 1991 (0526); NIOSH, 1994 (1261). In addition, soluble and poorly soluble beryllium has been shown to induce acute conjunctivitis with corneal maculae and diffuse erythema (HSDB, 2010, Document ID 0533).
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 shown to be directly irritating to mucous membranes (HSDB, 2010, Document ID 0533).
5. Dermal Effects
Several commenters suggested OSHA add dermal effects to this Health Effects section. National Jewish Health noted that rash and granulomatous reactions of the skin still occur in occupational settings (Document ID 1664, p. 5). The National Supplemental Screening Program also recommended including skin conditions such as dermatitis and nodules (Document ID 1677, p. 3). The American Thoracic Society also recommended including “beryllium sensitization, CBD, and skin disease as the major adverse health effects Start Printed Page 2527associated with exposure to beryllium at or below 0.1 μg/m3 and acute beryllium disease at higher exposures based on the currently available epidemiologic and experimental studies” (Document ID 1688, p. 2). OSHA agrees and has included dermal effects in this section of the final preamble.
As summarized in Epstein (1991), skin exposure to soluble beryllium compounds (mainly beryllium fluoride but also beryllium metal which may contain beryllium fluoride) resulted in irritant dermatitis with inflammation, and local edema. Beryllium oxide, beryllium alloys and nearly pure beryllium metal did not produce such responses in the skin of workers (Epstein, 1991, Document ID 0526). Skin lacerations or abrasions contaminated with soluble beryllium can lead to skin ulcerations (Epstein, 1991, Document ID 0526). Soluble and poorly soluble beryllium-compounds that penetrate the skin as a result of abrasions or cuts have been shown to result in chronic ulcerations and skin granulomas (VanOrdstrand et al., 1945, Document ID 1383; Lederer and Savage, 1954 (1467)). However, ulcerating granulomatous formation of the skin is generally associated with poorly soluble forms of beryllium (Epstein, 1991, Document ID 0526). Beryllium, beryllium oxide and other soluble and poorly soluble forms of beryllium have been classified as a skin irritant (category 2) in accordance with the EU Classification, Labelling and Packaging Regulation (Document ID 1669, p. 2). Contact dermatitis (skin hypersensitivity) was observed in some individuals exposed via skin to soluble forms of beryllium, especially individuals with a dermal irritant response (Epstein, 1991, Document ID 0526). Contact allergy has been observed in workers exposed to beryllium chloride (Document ID 0522).
G. Summary of Conclusions Regarding Health Effects
Through careful analysis of the best available scientific information outlined in this section, OSHA has determined that beryllium and beryllium-containing compounds can cause sensitization, CBD, and lung cancer. The Agency has determined through its review and evaluation of 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's review and evaluation of the studies outlined in section V.E. of this health effects section led to a finding that inhalation exposure to beryllium and beryllium-containing materials can cause lung cancer.
1. OSHA's Evaluation of the Evidence Finds That Beryllium Causes Sensitization Below the Preceding 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 has concluded that the scientific evidence supports the following mechanisms for the development of sensitization and CBD.
- Inhaled beryllium and beryllium-containing materials able to be retained and solubilized in the lungs have the ability to initiate sensitization and facilitate CBD development (section V.B.5). Genetic susceptibility may play a role in the development of sensitization and progression to CBD in certain individuals.
- 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 the capacity to dissolve beryllium compounds in the lung (section V.A.2a).
- Sensitization occurs through a T-cell mediated process with both soluble and poorly soluble beryllium and beryllium-containing compounds through direct antigen presentation or through further antigen processing 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 (section V.D.1).
- 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).
- Particle characteristics such as size, solubility, surface area, and other properties may play a role in the rate of development of beryllium sensitization and CBD. However, there is currently not sufficient information to delineate the biological role these characteristics may play.
- Animal studies have provided supporting evidence for T-cell proliferation in the development of granulomatous lung lesions after beryllium exposure (sections 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 (section V.D.1). While no clinical symptoms are associated with sensitization, a sensitized worker is at risk of developing CBD when inhalation exposure to beryllium has occurred. Epidemiological evidence that covers a wide variety of beryllium compounds and industrial processes demonstrates that sensitization and CBD are continuing to occur at present-day exposures below OSHA's preceding PEL (sections V.D.4; V.D.5 and section VI of this preamble).
- 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 appear to 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. OSHA's Evaluation of the Evidence Has Determined Beryllium To Be a Human Carcinogen
OSHA conducted an evaluation of the available scientific information regarding the carcinogenic potential of beryllium and beryllium-containing compounds (section V.E). Based on the 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 determined that beryllium and beryllium-containing materials are properly regarded as human carcinogens. This information is in accordance with findings from IARC, NTP, EPA, NIOSH, and ACGIH (section V.E). Key points from this analysis are summarized briefly here.
- 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 in multiple species of laboratory animals resulted in an increased Start Printed Page 2528incidence 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 (section V.E).
While OSHA has determined there is sufficient evidence of beryllium carcinogenicity, the Agency acknowledges that the exact tumorigenic mechanism for beryllium has yet to be determined. A number of mechanisms are likely 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 animals after inhalation exposure to poorly soluble particles at doses causing marked, chronic inflammation is due to a secondary mechanism unrelated to the genotoxicity of the particles (section V.E.5).
- A review conducted by the NAS (2008) (Document ID 1355) 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 are discussed 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 1970-1973 (ACGIH, 1971, Document ID 0543; ANSI, 1970 (1303); OSHA, 1971, see 39 FR 23513; EPA, 1973 (38 FR 8820)) and therefore are less relevant.
VI. Risk Assessment
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.” Section 6(b)(5) of the OSH Act, 29 U.S.C. 655(b). 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. Section II, Pertinent Legal Authority, of this preamble addresses the statutory bases for these requirements and how they have been construed by the Supreme Court and federal courts of appeals.
It is OSHA's practice to evaluate risk to workers and determine the significance of that risk based on the best available evidence. Using that evidence, OSHA identifies material health impairments associated with potentially hazardous occupational exposures, assesses whether exposed workers' risks are significant, and determines whether a new or revised rule will substantially reduce these risks. As discussed in Section II, Pertinent Legal Authority, when determining whether a significant risk exists OSHA considers whether there is a risk of at least one-in-a-thousand of developing amaterial health impairment from a working lifetime of exposure at the prevailing OSHA standard (referred to as the “preceding standard” or “preceding TWA PEL” in this preamble). For this purpose, OSHA generally assumes that a term of 45 years constitutes a working life. The Supreme Court has found that OSHA is not required to support its finding of significant risk with scientific certainty, but may instead rely on a body of reputable scientific thought and may make conservative assumptions (i.e., err on the side of protecting the worker) in its interpretation of the evidence (see Section II, Pertinent Legal Authority).
For single-substance standards governed by section 6(b)(5) of the OSH Act, 29 U.S.C. 655(b)(5), OSHA sets a permissible exposure limit (PEL) based on its risk assessment as well as feasibility considerations. These health and risk determinations are made in the context of a rulemaking record in which the body of evidence used to establish material impairment, assess risks, and identify affected worker population, as well as the Agency's preliminary risk assessment, are placed in a public rulemaking record and subject to public comment. Final determinations regarding the standard, including final determinations of material impairment and risk, are thus based on consideration of the entire rulemaking record.
OSHA's approach for the risk assessment for beryllium incorporates both: (1) A review of the literature on populations of workers exposed to beryllium at and below the preceding time-weighted average permissible exposure limit (TWA PEL) of 2 μg/m3; and (2) OSHA's own analysis of a data set of beryllium-exposed machinists. The Preliminary Risk Assessment included in the NPRM evaluated risk at several alternate TWA PELs that the Agency was considering (1 μg/m3, 0.5 μg/m3, 0.2 μg/m3, and 0.1 μg/m3), as well as OSHA's preceding TWA PEL of 2 μg/m3. OSHA's risk assessment relied on available epidemiological studies to evaluate the risk of sensitization and CBD for workers exposed to beryllium at and below the preceding TWA 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 preceding PEL and alternate PELs the Agency was considering. For this analysis, OSHA used data provided by National Jewish Health (NJH), a leading medical center specializing in the research and treatment of CBD, 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 both show significant risk of sensitization and CBD among workers exposed at and below the preceding TWA PEL of 2 μg/m3. They also show substantial reduction in risk where employers implemented a combination of controls, including stringent control of airborne beryllium levels and additional measures, such as respirators and dermal personal protective equipment (PPE) to further protect workers against dermal contact and airborne beryllium exposure.
To evaluate lung cancer risk, OSHA relied on a quantitative risk assessment published in 2011 by Schubauer-Berigan et al. (Document ID 1265). Schubauer-Berigan et al. found that lung cancer risk was strongly and significantly related to mean, cumulative, and maximum measures of workers' exposure; the authors predicted significant risk of lung cancer at the preceding TWA PEL, and substantial reductions in risk at the alternate PELs OSHA considered in the proposed rule, including the final TWA PEL of 0.2 μg/m3 (Schubauer-Berigan et al., 2011).
OSHA requested input on the preliminary risk assessment presented in the NPRM, and received comments from a variety of public health experts and organizations, unions, industrial organizations, individual employers, and private citizens. While many comments supported OSHA's general approach to the risk assessment and the conclusions of the risk assessment, some commenters raised specific concerns with OSHA's analytical methods or recommended additional studies for OSHA's consideration. Comments about the risk assessment as a whole are reviewed here, while comments on specific aspects of the risk assessment are addressed in the relevant sections throughout the remainder of Start Printed Page 2529this chapter and in the background document, Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama—CBD and Sensitization (OSHA, 2016), which can be found in the rulemaking docket (docket number OSHA-H005C-2006-0870) at www.regulations.gov. Following OSHA's review of all the comments submitted on the preliminary risk assessment, and its incorporation of suggested changes to the risk assessment, where appropriate, the Agency reaffirms its conclusion that workers' risk of material impairment of health from beryllium exposure at the preceding PEL of 2 μg/m3 is significant, and is substantially reduced but still significant at the new PEL of 0.2 μg/m3 (see this preamble at Section VII, Significance of Risk).
The comments OSHA received on its preliminary risk analysis generally supported OSHA's overall approach and conclusions. NIOSH indicated that OSHA relied on the best available evidence in its risk assessment and concurred with “OSHA's careful review of the available literature on [beryllium sensitization] and CBD, OSHA's recognition of dermal exposure as a potential pathway for sensitization, and OSHA's careful approach to assessing risk for [beryllium sensitization] and CBD” (Document ID 1725, p. 3). NIOSH agreed with OSHA's approach to the preliminary lung cancer risk assessment (Document ID 1725, p. 7) and the selection of a 2011 analysis (Schubauer-Berigan et al., 2011, Document ID 1265) as the basis of that risk assessment (Document ID 1725, p. 7). NIOSH further supported OSHA's preliminary conclusions regarding the significance of risk of material health impairment at the preceding TWA PEL of 2 μg/m3, and the substantial reduction of such risk at the new TWA PEL of 0.2 μg/m3 (Document ID 1725, p. 3). Finally, NIOSH agreed with OSHA's preliminary conclusion that compliance with the new PEL would lessen but not eliminate risk to exposed workers, noting that OSHA likely underestimated the risks of beryllium sensitization and CBD (Document ID 1725, pp. 3-4).
Other commenters also agreed with the general approach and conclusions of OSHA's preliminary risk assessment. NJH, for example, determined that “OSHA performed a thorough assessment of risk for [beryllium sensitization], CBD and lung cancer using all available studies and literature” (Document ID 1664, p. 5). Dr. Kenny Crump and Ms. Deborah Proctor commented, on behalf of beryllium producer Materion, that they “agree with OSHA's conclusion that there is a significant risk (>1/1000 risk of CBD) at the [then] current PEL, and that risk is reduced at the proposed PEL (0.2 μg/m3) in combination with stringent measures (ancillary provisions) to reduce worker's exposures” (Document ID 1660, p. 2). They further stated that OSHA's “finding is evident based on the available literature . . . and the prevalence data [OSHA] presented for the Cullman facility” (Document ID 1660, p. 2).
OSHA also received comments objecting to OSHA's conclusions regarding risk of lung cancer from beryllium exposure and suggesting additional published analyses for OSHA's consideration (e.g., Document ID 1659; 1661, pp. 1-3). One comment critiqued the statistical exposure-response model OSHA presented as one part of its preliminary risk analysis for sensitization and CBD (Document ID 1660). These comments are discussed and addressed in the remainder of this chapter.
A. Review of Epidemiological Literature on Sensitization and Chronic Beryllium Disease
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 preceding PEL of 2 μg/m3 (e.g., Kreiss et al., 1993, Document ID 1478; Henneberger et al., 2001 (1313); Schuler et al., 2005 (0919); Schuler et al., 2012 (0473)). In the mid-1990s, some facilities using beryllium began to aggressively monitor and reduce workplace exposures. In the NPRM, OSHA reviewed studies of workers at four plants where several rounds of BeLPT screening were conducted before and after implementation of new exposure control methods. These studies provide the best 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 ceramics facility in Tucson, AZ, a beryllium processing facility in Elmore, OH, and a machining facility in Cullman, AL—show that comprehensive exposure control programs that used engineering controls to reduce airborne exposure to beryllium, required the use of 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. In contrast, efforts to prevent sensitization and CBD by using engineering controls to reduce workers' beryllium exposures to median levels around 0.2 μg/m3, with no corresponding emphasis on PPE, were less effective than comprehensive exposure control programs implemented more recently. OSHA also reviewed additional, but more limited, information on the occurrence of sensitization and CBD among workers with low-level beryllium exposures at nuclear facilities and aluminum smelting plants. A summary discussion of the experiences at all of these facilities is provided in this section. Additional discussion of studies on these facilities and several other studies of sensitization and CBD among beryllium-exposed workers is provided in Section V, Health Effects.
The Health Effects section also discusses OSHA's findings and the supporting evidence concerning the role of particle characteristics and beryllium compound solubility in the development of sensitization and CBD among beryllium-exposed workers. First, it finds that 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. Second, it finds that both soluble and poorly soluble forms of beryllium are able to induce sensitization and CBD. Poorly soluble 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 particle size and solubility may influence the toxicity of beryllium, the available data are too limited to reliably account for these factors in the Agency's estimates of risk.
1. Reading, PA, Plant
Schuler et al. (2005, Document ID 0919) and Thomas et al. (2009, Document ID 0590) conducted studies of workers at a copper-beryllium processing facility in Reading, PA. Exposures at this plant were believed to be low throughout its history due to both 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/m , 97% < 0.5 μg/m ) (Schuler et al., 2005). Ninety-nine percent of personal lapel sample measurements were below the preceding OSHA TWA PEL of 2 μg/m ; 93 percent were below the new TWA Start Printed Page 2530PEL of 0.2 μg/m (Schuler et al., 2005). Schuler et al. (2005) screened 152 workers at the facility with the BeLPT in 2000. 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 both the preceding and final TWA PELs.
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 (Schuler et al., 2005).
After the initial BeLPT screening was conducted in 2000, the company began implementing new measures to further reduce workers' exposure to beryllium (Thomas et al. 2009, Document ID 0590). Requirements designed to minimize dermal contact with beryllium, including long-sleeve facility uniforms and polymer gloves, were instituted in production areas in 2000-2002. In 2001, the company installed local exhaust ventilation (LEV) in die grinding and polishing operations (Thomas et al., 2009, Figure 1). Personal lapel samples collected between June 2000 and December 2001, showed reduced exposures plant-wide (98 percent were below 0.2 μg/m3). Median, arithmetic mean, and geometric mean values less than or equal to 0.03 μg/m3 were reported in this period for all processes except one, a 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) (Thomas et al., 2009, Table 3). In January 2002, the company enclosed the wire annealing and pickling process in a restricted access zone (RAZ). Beginning in 2002, the company required use of powered air-purifying respirators (PAPRs) in the RAZ, and implemented stringent measures to minimize the potential for skin contact and beryllium transfer out of the zone, such as requiring RAZ workers to shower before leaving the zone (Thomas et al., 2009, Figure 1). While exposure samples collected by the facility were sparse following the enclosure, they suggest exposure levels comparable to the 2000-2001 samples in areas other than the RAZ (Thomas et al., 2009, Table 3). The authors 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 (Thomas et al., 2009, Document ID 0590). 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, which had been releasing beryllium into the surrounding area, 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 built was confirmed as sensitized. From these early results comparing the screening conducted on workers hired before 2000 and those hired in 2000 and later, especially following the enclosure of the RAZ, it appears that the greatest reduction in sensitization risk (to one sensitized worker, or 2.2 percent) was achieved after workers' exposures were reduced to below 0.1 μg/m3 and PPE to prevent dermal contact was instituted (Thomas et al., 2009).
2. Tucson, AZ, Plant
Kreiss et al. (1996, Document ID 1477), Cummings et al. (2007, Document ID 1369), and Henneberger et al. (2001, Document ID 1313) conducted studies of workers at a beryllia ceramics plant in Tucson, Arizona. Kreiss et al. (1996) screened 136 workers at this plant with the BeLPT in 1992. Full-shift area samples collected between 1983 and 1992 showed primarily low airborne beryllium levels at this facility (76 percent of area samples were at or below 0.1 μg/m3 and less than 1 percent exceeded 2 μg/m3). 4,133 short-term breathing zone measurements collected between 1981 and 1992 had a median of 0.3 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).
Kreiss et al. reported that eight (5.9 percent) of the 136 workers tested in 1992 were sensitized, six (4.4 percent) of whom were diagnosed with CBD. 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. Personal lapel samples taken on administrative workers during the 1990s were below the detection limit at the time, 0.2 μg/m3 (Cummings et al., 2007, Document ID 1369).
Following the 1992 screening, the facility reduced exposures in machining areas (for example, by enclosing additional machines and installing additional exhaust ventilation), resulting in median exposures of 0.2 μg/m3 in production jobs and 0.1 μg/m3 in production support jobs (Cummings et al., 2007). In 1998, a second screening found that 7 out of 74 tested workers hired after the 1992 screening (9.5 percent) were sensitized, one of whom was diagnosed with CBD. All seven of these sensitized workers had been employed at the plant for less than two years (Henneberger et al., 2001, Document ID 1313, Table 3). Of 77 Tucson workers hired prior to 1992 who were tested in 1998, 8 (10.4 percent) were sensitized and 7 of these (9.7 percent) were diagnosed with CBD (Henneberger et al., 2001).
Following the 1998 screening, the company continued efforts to reduce exposures, along with risk of sensitization and CBD, by implementing additional engineering and administrative controls and a comprehensive PPE program which included the use of respiratory protection (1999) and latex gloves (2000) (Cummings et al., 2007, Document ID 1369). Enclosures were installed for various beryllium-releasing processes by 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. 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 97 workers hired between 2000 and 2004, one case of sensitization was identified (1 percent) (Cummings et al., 2007).
3. Elmore, OH, Plant
Kreiss et al. (1997, Document ID 1360), Bailey et al. (2010, Document ID 0676), and Schuler et al. (2012, Document ID 0473) conducted studies of workers at a beryllium metal, alloy, and oxide production plant in Elmore, Ohio. Workers participated in several plant-wide BeLPT surveys beginning in 1993-1994 (Kreiss et al., 1997; Schuler et al., 2012) and in a series of screenings Start Printed Page 2531for workers hired in 2000 and later, conducted beginning in 2000 (Bailey et al., 2010).
Exposure levels at the plant between 1984 and 1993 were characterized using a mixture of general area, short-term breathing zone, and personal lapel samples (Kreiss et al., 1997, Document ID 1360). 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. 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. Kreiss et al. reported median sample values from the personal lapel samples 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. The authors reported that 43 (6.9 percent) of 627 workers tested in 1993-1994 were sensitized. 29 workers (including 5 previously identified) were diagnosed with CBD (29/632, or 4.6 percent) (Kreiss et al., 1997).
In 1996-1999, the company took further steps to reduce workers' beryllium exposures, including enclosure of some beryllium-releasing processes, establishment of restricted-access zones, and installation or updating of certain engineering controls (Bailey et al., 2010, Document ID 0676, Tables 1-2). Beginning in 1999, all new employees were required to wear loose-fitting PAPRs in manufacturing buildings. 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. By 2001, either half-mask respirators or PAPRs were required throughout 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).
Beginning in 2000, newly hired workers were offered periodic BeLPT testing to evaluate the effectiveness of the new exposure control program implemented by the company (Bailey et al., 2010). Bailey et al. compared the occurrence 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”) with that of 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. This four-fold reduction in sensitization suggests that beryllium-exposed workers' risk of sensitization (and therefore of CBD, which develops only following sensitization) can be much reduced by the combination of process controls, respiratory protection requirements, and PPE requirements applied in this facility. Because most of the workers in the study had been employed at the facility for less than two years, and CBD typically develops over a longer period of time (see section V, Health Effects), Bailey et al. did not report the incidence of CBD among the sensitized workers (Bailey et al., 2010). Schuler et al. (2012, Document ID 0473) 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, Document ID 0466). The study population included 264 workers employed in 1999 with up to 6 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. A set of 1999 exposure surveys and employee work histories was used to estimate employees' long-term lifetime weighted (LTW) average, cumulative, and highest-job-worked exposures for total, respirable, and submicron beryllium mass concentrations (Schuler et al., 2012; Virji et al., 2012).
As reported by Schuler et al. (2012), 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. Although follow-up time was too short (at most 6 years) to fully evaluate CBD in this group, 6 of those sensitized were diagnosed with CBD (2.3 percent, 6/264). Schuler et al. (2012) found 17 cases of sensitization (8.6%) within the first 3 quartiles of LTW average exposure (198 workers with LTW average total mass exposures lower than 1.1 µg/m ) and 4 cases of CBD (2.2%) within those first 3 quartiles (183 workers with LTW average total mass exposures lower than 1.07 µg/m )
The authors found 3 cases (4.6%) of sensitization among 66 workers with total mass LTW average exposures below 0.1 µg/m3, and no cases of sensitization among workers with total mass LTW average exposures below 0.09 µg/m3, suggesting that beryllium-exposed workers' risk can be much reduced or eliminated by reducing airborne exposures to average levels below 0.1 µg/m3.
Schuler et al. (2012, Document ID 0473) then used logistic regression to explore the relationship between estimated beryllium exposure and sensitization and CBD. For beryllium sensitization, the logistic models by Schuler et al. showed elevated odds ratios (OR) for LTW 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 LTW average (OR 1.37) and highest job (OR 1.32) exposures. 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. Average and highest job exposures were predictive of risk for sensitization, while cumulative exposure was predictive of risk for CBD (Schuler et al., 2012).
Materion submitted comments supporting OSHA's use of the Schuler et al. (2012) study as a basis for the final TWA PEL of 0.2 µg/m . Materion stated that “the best available evidence to establish a risk-based OEL [occupational exposure limit] is the study conducted by NIOSH and presented in Schuler 2012. The exposure assessment in Start Printed Page 2532Schuler et al. was based on a highly robust workplace monitoring dataset and the study provides improved data for determining OELs” (Document ID 1661, pp. 9-10). Materion also submitted an unpublished manuscript documenting an analysis it commissioned, entitled “Derived No-Effect Levels for Occupational Beryllium Exposure Using Cluster Analysis and Benchmark Dose Modeling” (Proctor et al., Document ID 1661, Attachment 5). In this document, Proctor et al. used data from Schuler et al. 2012 to develop a Derived No-Effect Level (DNEL) for beryllium measured as respirable beryllium, total mass of beryllium, and inhalable beryllium.
OSHA's beryllium standard measures beryllium as total mass; thus, the results for total mass are most relevant to OSHA's risk analysis for the beryllium standard. The assessment reported a DNEL of 0.14 µg/m3 for total mass beryllium (Document ID 1661, Attachment 5, p. 16). Materion commented that this finding “add[s] to the body of evidence that supports the fact that OSHA is justified in lowering the existing PEL to 0.2 µg/m3” (Document ID 1661, p. 11).
Proctor et al. characterized the DNEL of 0.14 µg/m3 as “inherently conservative because average exposure metrics were used to determine DNELs, which are limits not [to] be exceeded on a daily basis” (Document ID 1661, Attachment 5, p. 22). Materion referred to the DNELs derived by Proctor et al. as providing an “additional margin of safety” for similar reasons (Document ID 1661, p. 11).
Consistent with NIOSH comments discussed in the next paragraph, OSHA disagrees with this characterization of the DNEL as representing a “no effect level” for CBD or as providing a margin of safety for several reasons. The DNEL from Proctor et al. is based on CBD findings among a short-term worker population and thus cannot represent the risk presented to workers who are exposed over a working lifetime. Proctor et al. noted that it is “important to consider that these data are from relatively short-term exposures [median tenure 20.9 months] and are being used to support DNELs for lifetime occupational exposures,” but considered the duration of exposure to be sufficient because “CBD can develop with latency as short as 3 months of exposure, and . . . the risk of CBD declines over time” (Document ID 1661, Attachment 5, p. 19). In stating this, Procter et al. cite studies by Newman et al. (2001, Document ID 1354) and Harber et al. (2009, as cited in Document ID 1661). Newman et al. (2001) studied a group of workers in a machining plant with job tenures averaging 11.7 years, considerably longer than the worker cohort from the study used by Procter et al., and identified new cases of CBD from health screenings conducted up to 4 years after an initial screening. Harber et al., (2009) developed an analytic model of disease progression from beryllium exposure and found that, although the rate at which new cases of CBD declined over time, the overall proportion of individuals with CBD increased over time from initial exposure (see Figure 2 of Haber et al., 2009). Furthermore, the study used by Proctor et al. to derive the DNEL, Schuler et al. (2012), did report finding that the risk of CBD increased with cumulative exposure to beryllium, as summarized above. Therefore, OSHA is not convinced that a “no effect level” for beryllium that is based on the health experience of workers with a median job tenure of 20.9 months can represent a “no-effect level” for workers exposed to beryllium for as long as 45 years.
NIOSH commented on the results of Proctor et al.' s analysis and the underlying data set, noting several features of the dataset that are common to the beryllium literature, such as uncertain date of sensitization or onset of CBD and no “background” rate of beryllium sensitization or CBD, that make statistical analyses of the data difficult and add uncertainty to the derivation of a DNEL (Document ID 1725, p. 5). NIOSH also noted that risk of CBD may be underestimated in the underlying data set if workers with CBD were leaving employment due, in part, to adverse health effects (“unmeasured survivor bias”) and estimated that as much as 30 percent of the cohort could have been lost over the 6-year testing period (Document ID 1725, p. 5). NIOSH concluded that Proctor et al.' s analysis “does not contribute to the risk assessment for beryllium workers” (Document ID 1725, p. 5). OSHA agrees with NIOSH that the DNEL identified by Proctor et al. cannot be considered a reliable estimate of a no-effect level for beryllium.
4. Cullman, AL, Plant
Newman et al. (2001, Document ID 1354), Kelleher et al. (2001, Document ID 1363), and Madl et al. (2007, Document ID 1056) studied beryllium workers at a precision machining facility in Cullman, Alabama. After a case of CBD was diagnosed at the plant in 1995, the company began BeLPT screenings to identify workers at risk of CBD and implemented engineering and administrative controls designed to reduce workers' beryllium exposures in machining operations. Newman et al. (2001) conducted a series of BeLPT screenings of workers at the facility between 1995 and 1999. The authors reported 22 (9.4 percent) sensitized workers among 235 tested, 13 of whom were diagnosed with CBD within the study period. Personal lapel samples collected between 1980 and 1999 indicate that median exposures were generally well below the preceding PEL (≤0.35 µg/m3 in all job titles except maintenance (median 3.1 µg/m3 during 1980-1995) and gas bearings (1.05 µg/m3 during 1980-1995)).
Between 1995 and 1999, the company built enclosures around several beryllium-releasing operations; installed or updated LEV for several machining departments; replaced pressurized air hoses and dry sweeping with wet methods and vacuum systems for cleaning; changed the layout of the plant to keep beryllium-releasing processes close together; limited access to the production area of the plant; and required the use of company uniforms. Madl et al. (2007, Document ID 1056) reported that engineering and work process controls, rather than personal protective equipment, were used to limit workers' exposure to beryllium. 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 and non-machining jobs had medians of 0.16 µg/m3 and 0.08 µg/m3, respectively (Madl et al., 2007, Table IV). 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 and had therefore benefitted to some extent from the controls described above. 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, Document ID 1354). The later study by Madl. et al. reported seven sensitized workers who had been hired between 1995 and 1999, of whom four had developed CBD as of 2005 (2007, Table II) (total number of workers hired between 1995 and 1999 not reported).
Beginning in 2000 (after the implementation of controls between 1997 and 1999), exposures in all jobs at the machining facility were reduced to Start Printed Page 2533extremely low levels (Madl et al., 2007, Document ID 1056). Personal lapel samples collected between 2000 and 2005 had a median of 0.12 µg/m3 or less in all machining and non-machining processes (Madl. et al., 2007, Table IV). Only one worker hired after 1999 became sensitized (Madl et al. 2007, Table II). The worker had been employed for 2.7 years in chemical finishing, which had the highest median exposure of 0.12 µg/m3 (medians for other processes ranged from 0.02 to 0.11 µg/m3); Madl et al. 2007, Table II). This result from Madl et al. (2007) suggests that beryllium-exposed workers' risk of sensitization can be much reduced by steps taken to reduce workers' airborne exposures in this facility, including enclosure of beryllium-releasing processes, LEV, wet methods and vacuum systems for cleaning, and limiting worker access to production areas.
The Cullman, AL facility was also the subject of a case-control study published by Kelleher et al. in 2001 (Document ID 1363). After the diagnosis of a case of CBD at the plant in 1995, NJH researchers, including Kelleher, worked with the plant to conduct the medical surveillance program mentioned above, using the BeLPT to screen workers biennially for beryllium sensitization and offering sensitized workers further evaluation for CBD (Kelleher 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, Document ID 1358). Kelleher et al. used the dataset of 100 personal lapel samples collected by Martyny et al. and other NJH researchers to characterize exposures for each job in the plant. 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 average exposure estimates based on the total mass of beryllium reported in their exposure samples, Kelleher et al. calculated cumulative and LTW average 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 results, however, were inconclusive, probably due to the relatively small size of the dataset (Kelleher et al., 2001).
5. Aluminum Smelting Plants
Taiwo et al. (2008, Document ID 0621; 2010 (0583) and Nilsen et al. (2010, Document ID 0460) studied the relationship between beryllium exposure and adverse health effects among workers at aluminum smelting plants. Taiwo et al. (2008) studied a population of 734 employees at 4 aluminum smelters located in Canada (2), Italy (1), and the United States (1). In 2000, a company-wide beryllium exposure limit of 0.2 μg/m3 and an action level of 0.1 μg/m3, expressed as 8-hour TWAs, 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 four 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
|Smelter||Number samples||Median (μg/m3)||Arithmetic mean
(μg/m3)||Geometric mean (μg/m3)|
|Canadian smelter 1||246||0.03||0.09||0.03|
|Canadian smelter 2||329||0.11||0.29||0.08|
|Adapted from Taiwo et al., 2008, Document ID 0621, 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). 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
|Smelter||Employees tested||Normal||Abnormal BeLPT
|Canadian smelter 1||109||107||1||1|
|Canadian smelter 2||291||290||1||0|
|Adapted from Taiwo et al., 2008, Document ID 0621, 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 pulmonary function tests, respiratory symptoms, and radiographic evidence in the other.
In 2010, Taiwo et al. (Document ID 0583) published a study of beryllium-exposed workers from four companies, with a total of nine smelting operations. These workers included some of the workers from the 2008 study. 3,185 workers were determined to be “significantly exposed” to beryllium and invited to participate in BeLPT screening. Each company used different Start Printed Page 2534criteria to determine “significant” exposure, and the criteria appeared to vary considerably (Taiwo et al., 2010); thus, it is difficult to compare rates of sensitization across companies in this study. 1932 workers, about 60 percent of invited workers, participated in the program between 2000 and 2006, of whom 9 were determined to be sensitized (.4 percent). The authors stated that all nine workers were referred to a respiratory physician for further evaluation for CBD. Two were diagnosed with CBD (.1 percent), as described above (see Taiwo et al., 2008).
In general, there appeared to be a low level of sensitization and CBD among employees at the aluminum smelters studied by Taiwo et al. (2008; 2010). 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 noted that respiratory and dermal protection had been used at these plants to protect workers from other hazards (Taiwo et al., 2008).
A study by Nilsen et al. (2010, Document ID 0460) of aluminum workers in Norway also found a low rate of sensitization. In the study, 362 workers and 31 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 exposure measurements 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 was the case in the smelters studied by Taiwo et al. (2008; 2010).
6. Nuclear Weapons Facilities
Viet et al. (2000, Document ID 1344) and Arjomandi et al. (2010, Document ID 1275) evaluated beryllium-exposed nuclear weapons workers. 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. The program, which the authors reported had tested over 5,000 current and former Rocky Flats employees for sensitization, had identified a total of 127 sensitized individuals as of 1994 when Viet et al. initiated their study; 51 of these sensitized individuals had been diagnosed with CBD.
Using subjects from the BHSP, Viet et al. (2000) matched a total of 50 CBD cases to 50 controls who tested negative for beryllium sensitization 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 matched to 74 control individuals from the BHSP database who tested negative for beryllium sensitization.
Viet et al. (2000) developed exposure estimates for the cases and controls based on daily fixed airhead (FAH) beryllium air samples collected in one of 36 buildings at Rocky Flats where beryllium was used, the Building 444 Beryllium Machine Shop. Annual mean FAH samples in Building 444 collected between 1960 and 1988 ranged from a low of 0.096 μg/m3 (1988) to a high of 0.622 μg/m3 (1964) (Viet et al., 2000, Table II). Because exposures in this shop were better characterized than in other buildings, the authors developed estimates of exposures for all workers based on samples from Building 444. The authors' statistical analysis of the resulting data set included conditional logistic regression analysis, modeling the relationship between risk of each health outcome and individuals' log-transformed cumulative exposure estimate (CEE) and mean exposure estimate (MEE). These coefficients corresponded 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). Viet et al. 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.
Arjomandi et al. (2010) published a study of 50 sensitized workers from a nuclear weapons research and development facility who were evaluated for CBD. Quantitative exposure estimates for the workers were not presented; however, the authors characterized their likely exposures as low (possibly below 0.1 μg/m3 for most jobs). 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).
Five of the 50 evaluated 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. OSHA notes that this prevalence of CBD among sensitized workers is lower than the prevalence of CBD that has been observed in some other worker groups known to have exposures exceeding the action level of 0.1 μg/m3. For example, as discussed above, Newman et al. (2001, Document ID 1354) reported 22 sensitized workers, 13 of whom (59 percent) were diagnosed with CBD within the study period. Comparison of these results suggests that controlling respiratory exposure to beryllium may reduce risk of CBD among already-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 then develop CBD.
The published literature on beryllium sensitization and CBD discussed above shows that risk of both health effects can be significant in workplaces in compliance with OSHA's preceding PEL (e.g., Kreiss et al., 1996, Document ID 1477; Henneberger et al., 2001 (1313); Newman et al., 2001 (1354); Schuler et al., 2005 (0919), 2012 (0473); Madl et al., 2007 (1056)). For example, in the Tucson beryllia ceramics plant discussed above, Kreiss et al. (1996) reported that 8 (5.9 percent) of the 136 workers tested in 1992 were sensitized, 6 (4.4 percent) of whom were diagnosed with CBD. In addition, of 77 Tucson workers hired prior to 1992 who were tested in 1998, 8 (10.4 percent) were sensitized and 7 of these (9.7 percent) were diagnosed with CBD (Henneberger et al., 2001, Document ID 1313). Full-shift area samples showed airborne beryllium levels below the preceding PEL (76 percent of area samples collected between 1983 and 1992 were at or below 0.1 μg/m3 and less than 1 percent exceeded 2 μg/m3; short-term breathing zone measurements collected between 1981 and 1992 had a median of 0.3 μg/m3; personal lapel samples collected at the plant beginning in 1991 had a median of 0.2 μg/m3) (Kreiss et al., 1996).
Results from the Elmore, OH beryllium metal, alloy, and oxide production plant and Cullman, AL machining facility also showed significant risk of sensitization and CBD Start Printed Page 2535among workers with exposures below the preceding TWA PEL. Schuler et al. (2012, Document ID 0473) found 17 cases of sensitization (8.6%) among Elmore, OH workers within the first three quartiles of LTW average exposure (198 workers with LTW average total mass exposures lower than 1.1 μg/m3) and 4 cases of CBD (2.2%) within the first three quartiles of LTW average exposure (183 workers with LTW average total mass exposures lower than 1.07 μg/m3; note that follow-up time of up to 6 years for all study participants was very short for development of CBD). At the Cullman, AL machining facility, Newman et al. (2001, Document ID 1354) reported 22 (9.4 percent) sensitized workers among 235 tested in 1995-1999, 13 of whom were diagnosed with CBD. Personal lapel samples collected between 1980 and 1999 indicate that median exposures were generally well below the preceding PEL (≤0.35 μg/m3 in all job titles except maintenance (median 3.1 μg/m3 during 1980-1995) and gas bearings (1.05 μg/m3 during 1980-1995)).
There is evidence in the literature that although risk will be reduced by compliance with the new TWA PEL, significant risk of sensitization and CBD will remain in workplaces in compliance with OSHA's new TWA PEL of 0.2 μg/m3 and could extend down to the new action level of 0.1 μg/m3, although there is less information and therefore greater uncertainty with respect to significant risk from airborne beryllium exposures at and below the action level. For example, Schuler et al. (2005, Document ID 0919) reported substantial prevalences of sensitization (6.5 percent) and CBD (3.9 percent) among 152 workers at the Reading, PA facility who had BeLPT screening in 2000. These results showed significant risk at this facility, even though airborne exposures were primarily below both the preceding and final TWA PELs due to the low percentage of beryllium in the metal alloys used (median general area samples ≤0.1 μg/m3, 97% ≤0.5 μg/m3); 93% of personal lapel samples were below the new TWA PEL of 0.2 μg/m3). The only group of workers with no cases of sensitization or CBD, a group of 26 office administration workers, was the group with exposures below the new action level of 0.1 μg/m3 (median personal sample 0.01 μg/m3, range <0.01-0.06 μg/m3 (Schuler et al., 2005). The Schuler et al. (2012, Document ID 0473) study of short-term workers in the Elmore, OH facility found 3 cases (4.6%) of sensitization among 66 workers with total mass LTW average exposures below 0.1 μg/m3; 3 of these workers had LTW average exposures of approximately 0.09 μg/m3.
Furthermore, cases of sensitization and CBD continued to arise in the Cullman, AL machining plant after control measures implemented beginning in 1995 brought median airborne exposures below 0.2 μg/m3 (personal lapel samples between 1996 and 1999 in machining jobs had a median of 0.16 μg/m3 and 0.08 μg/m3 in non-machining jobs) (Madl et al., 2007, Document ID 1056, Table IV). At the time that Newman et al. (2001, Document ID 1354) 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 and had therefore benefitted to some extent from the exposure reductions. Four (6.7 percent) of these workers were found to be sensitized, two of whom were diagnosed with CBD and one with probable CBD (Newman et al., 2001). A later study by Madl. et al. (2007, Document ID 1056) reported seven sensitized workers who had been hired between 1995 and 1999, of whom four had developed CBD as of 2005 (Table II; total number of workers hired between 1995 and 1999 not reported).
The experiences of several facilities in developing effective industrial hygiene programs have shown the importance of minimizing both airborne exposure and dermal contact to effectively reduce risk of sensitization and CBD. Exposure control programs that have used a combination of engineering controls and PPE to reduce workers' airborne exposure and dermal contact have substantially lowered risk of sensitization among newly hired workers.
Of 97 workers hired between 2000 and 2004 in the Tucson, AZ plant after the introduction of mandatory respirator use in production areas beginning in 1999 and mandatory use of latex gloves beginning in 2000, one case of sensitization was identified (1 percent) (Cummings et al., 2007, Document ID 1369). In Elmore, OH, 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 percent (Bailey et al., 2010, Document ID 0676). In the Reading, PA facility, only one (2.2 percent) of 45 workers hired after workers' exposures were reduced to below 0.1 μg/m3 and PPE to prevent dermal contact was instituted was sensitized (Thomas et al., 2009, Document ID 0590). And, in the aluminum smelters discussed by Taiwo et al. (2008, Document ID 0621), where available exposure samples from four plants 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).
OSHA recognizes that 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 adequately 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 studies examining the post-2000, very low-exposed worker cohorts in Tucson, Reading, and Elmore (Cummings et al. 2007, Document ID 1369; Thomas et al. 2009 (0590); Bailey et al. 2010 (0676)). 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) (Madl et al., 2007, Document ID 1056, Table III). 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, Document ID 1070), and workers employed only in administration at a beryllium ceramics facility (Kreiss et al., 1996, Document ID 1477). Therefore, there is some evidence that cases of CBD can occur in work environments where beryllium exposures are quite low.
8. Community-Acquired CBD
In the NPRM, OSHA discussed an additional source of information on low-level beryllium exposure and CBD: Studies of community-acquired chronic beryllium disease (CA-CBD) in residential areas surrounding beryllium Start Printed Page 2536production facilities. The literature on CA-CBD, including the Eisenbud (1949, Document ID 1284), Leiben and Metzner (1959, Document ID 1343), and Maier et al. (2008, Document ID 0598) studies, documents cases of CBD among individuals exposed to airborne beryllium at concentrations below the new PEL. OSHA included a review of these studies in the NPRM as a secondary source of information on risk of CBD from low-level beryllium exposure. However, the available studies of CA-CBD have important limitations. These case studies do not provide information on how frequently individuals exposed to very low airborne levels develop CBD. In addition, the reconstructed exposure estimates for CA-CBD cases are less reliable than the exposure estimates for working populations reviewed in the previous sections. The literature on CA-CBD therefore was not used by OSHA as a basis for its quantitative risk assessment for CBD, and the Agency did not receive any comments or testimony on this literature. Nevertheless, these case reports and the broader CA-CBD literature indicate that individuals exposed to airborne beryllium below the final TWA PEL can develop CBD (e.g., Leiben and Metzner, 1959; Maier et al., 2008).
B. OSHA's Prevalence Analysis for Sensitization and CBD
OSHA evaluated exposure and health outcome data on a population of workers employed at the Cullman machining facility as one part of the Agency's Preliminary Risk Analysis presented in the NPRM. A summary of OSHA's preliminary analyses of these data, a discussion of comments received on the analyses and OSHA's responses to these comments, as well as a summary OSHA's final quantitative analyses, are presented in the remainder of this section. A more detailed discussion of the data, background information on the facility, and OSHA's analyses appears in the background document OSHA has placed in the record (Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama—CBD and Sensitization, OSHA, 2016).
NJH researchers, with consent and information provided by the Cullman 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 about work operations and conditions at the plant, developed exposure estimates for individual workers in the dataset, and helped to conduct quantitative analyses of the data to inform OSHA's risk assessment (Document ID tbd).
1. Worker Exposure Reconstruction
The work history database contains job history records for 348 workers. ERG calculated cumulative and average exposure estimates for each worker in the database. Cumulative exposure was calculated as,
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. However, individuals' beryllium exposure levels and sensitization status are not continuously monitored, so 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 attempted to represent workers' highest exposures by constructing 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 presented below.
2. Prevalence of Sensitization and CBD
In the database provided to OSHA, 7 workers were reported as sensitized only (that is, sensitized with no known development of CBD). 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-3, VI-4, and VI-5 below present the prevalence of sensitization and CBD cases across several categories of LTW average, cumulative, and HEJ exposure. Exposure values were grouped by quartile. For this analysis, OSHA excluded 8 workers with no job title listed in the data set (because their exposures could not be estimated); 7 workers whose date of hire was before 1969 (because this indicates they worked in the company's previous plant, for which no exposure measurements were available); and 14 workers who had zero exposure time in the data set, perhaps indicating that they had been hired but had not come to work at Cullman. After these exclusions, a total of 319 workers remained. None of the excluded workers were identified as having beryllium sensitization or CBD.
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-3—Prevalence of Sensitization and CBD by LTW Average Exposure Quartile in NJH Data Set
|LTW average exposure (μg/m3)||Group size||Sensitized only||CBD||Total sensitized||Total (%)||CBD (%)|
|Start Printed Page 2537|
Table VI-4—Prevalence of Sensitization and CBD by Cumulative Exposure Quartile in NJH Data Set
(μg/m3-yrs)||Group size||Sensitized only||CBD||Total sensitized||Total (%)||CBD (%)|
Table VI-5—Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile in NJH Data Set
|HEJ exposure (μg/m3)||Group size||Sensitized only||CBD||Total sensitized||Total (%)||CBD (%)|
Table VI-3 shows increasing prevalence of total sensitization and CBD with increasing LTW average 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. Because 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. This worker 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 6 workers sensitized (8.2 percent), of whom 4 (5.5 percent) were diagnosed with CBD. Among 6 sensitized workers in the third quartile (0.19-0.51 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-4, 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. These exposure levels are in the range of those OSHA was interested in evaluating for purposes of this rulemaking.
A sharp increase in prevalence of sensitization and CBD 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 5 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. In Table VI-5, the lowest prevalence is observed in the first quartile (0.0-0.086 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 other highly-exposed workers from early periods may have developed CBD and left the plant before sensitization testing began in 1995 (i.e., the healthy worker survivor effect).
The results of this prevalence analysis support OSHA's conclusion that maintaining exposure levels below the new TWA PEL will help to reduce risk Start Printed Page 2538of beryllium sensitization and CBD, and that maintaining exposure levels below the action level can further reduce risk of beryllium sensitization and CBD. However, risk of both sensitization and CBD remains even among the workers with the lowest airborne exposures in this data set.
C. OSHA's Statistical Modeling for Sensitization and CBD
1. OSHA's Preliminary Analysis of the NJH Data Set
In the course of OSHA's development of the proposed rule, OSHA's contractor (ERG) also developed a statistical analysis using the NJH data set and a discrete time proportional hazards analysis (DTPHA). This preliminary analysis predicted significant risks of both sensitization (96-394 cases per 1,000, or 9.6-39.4 percent) and CBD (44-313 cases per 1,000, or 4.4-31.3 percent) at the preceding TWA PEL of 2 μg/m3 for an exposure duration of 45 years (90 μg/m3-yr). The predicted risks of 8.2-39.9 cases of sensitization per 1,000 (0.8-3.9 percent) and 3.6 to 30.0 cases of CBD per 1,000 (0.4-3 percent) were approximately 10-fold less, but still significant, for a 45-year exposure at the new TWA PEL of 0.2 μg/m3 (9 μg/m3-yr).
In interpreting the risk estimates, OSHA took into consideration limitations in the preliminary statistical analysis, primarily study size-related constraints. Consequently, as discussed in the NPRM, OSHA did not rely on the preliminary statistical analysis for its significance of risk determination or to develop its benefits analysis. The Agency relied primarily on the previously-presented analysis of the epidemiological literature and the prevalence analysis of the Cullman data for its preliminary significance of risk determination, and on the prevalence analysis for its preliminary estimate of benefits. Although OSHA did not rely on the results of the preliminary statistical analysis for its findings, the Agency presented the DTPHA in order to inform the public of its results, explain its limitations, and solicit public comment on the Agency's approach.
Dr. Kenny Crump and Ms. Deborah Proctor submitted comments on OSHA's preliminary risk assessment (Document ID 1660). Crump and Proctor agreed with OSHA's review of the epidemiological literature and the prevalence analysis presented previously in this section. They stated, “we agree with OSHA's conclusion that there is a significant risk (>1/1000 risk of CBD) at the [then] current PEL, and that risk is reduced at the [then] proposed PEL (0.2 μg/m3) in combination with stringent measures (ancillary provisions) to reduce worker's exposures. This finding is evident based on the available literature, as described by OSHA, and the prevalence data presented for the Cullman facility” (Document ID 1660, p. 2). They also presented a detailed evaluation of the statistical analysis of the Cullman data presented in the NPRM, including a critique of OSHA's modeling approach and interpretation and suggestions for alternate analyses. However, they emphasized that the new beryllium rule should not be altered or delayed due to their comments regarding the statistical model (Document ID 1660, p. 2).
After considering comments on this preliminary model, OSHA instructed its contractor to change the statistical analysis to address technical concerns and to incorporate suggestions from Crump and Proctor, as well as NIOSH (Document ID 1660; 1725). OSHA reviews and addresses these comments on the preliminary statistical analysis and provides a presentation of the final statistical analysis in the background document (Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama—CBD and Sensitization, OSHA, 2016). The results of the final statistical analysis are summarized here.
2. OSHA's Final Statistical Analysis of the NJH Data Set
As noted above, Dr. Roslyn Stone of University of Pittsburgh School of Public Health reanalyzed for OSHA the Cullman data set in order to address concerns raised by Crump and Proctor (Document ID 1660). The reanalysis uses a Cox proportional hazards model instead of the DTPHA. The Cox model, a regression method for survival data, provides an estimate of the hazard ratio (HR) and its confidence interval.
Like the DTPHA, the Cox model can accommodate time-dependent data; however, the Cox model has an advantage over the DTPHA for OSHA's purpose of estimating risk to beryllium-exposed workers in that it does not estimate different “baseline” rates of sensitization and CBD for different years. Time-specific risk sets were constructed to accommodate the time-dependent exposures. P-values were based on likelihood ratio tests (LRTs), with p-values <0.05 considered to be statistically significant.
As in the preliminary statistical analysis, Dr. Stone used fractional polynomials 
to check for possible nonlinearities in the exposure-response models, and checked the effects of age and smoking habits using data on birth year and smoking (current, former, never) provided in the Cullman data set. Data on workers' estimated exposures and health outcomes through 2005 were included in the reanalysis.
The 1995 risk set (e.g., analysis of cases of sensitization and CBD identified in 1995) was excluded from all models in the reanalysis so as not to analyze long-standing (prevalent) cases of sensitization and CBD together with newly arising (incident) cases of sensitization and CBD. Finally, Dr. Stone used the testing protocols provided in the literature on the Cullman study population to determine the years in which each employee was scheduled to be tested, and excluded employees from the analysis for years in which they were not scheduled to be tested (Newman et al., 2001, Document ID 1354).
In the reanalysis of the NJH data set, the HR for sensitization increased significantly with increasing LTW average exposure (HR = 2.92, 95% CI = 1.51-5.66, p = 0.001; note that HRs are rounded to the second decimal place). Cumulative exposure was also a statistically significant predictor for beryllium sensitization, although it was not as strongly related to sensitization as LTW average exposure (HR = 1.04, 95% CI 1.00-1.07, p = 0.03). The HR for CBD increased significantly with increasing cumulative exposure (HR = 1.04, 95% CI = 1.01-1.08, p = 0.02). The HR for CBD increased somewhat with increasing LTW average exposure, but this increase was not significant at the 0.05 level (HR = 2.25, 95% CI = 0.94-5.35, p = 0.07).
None of the analyses Dr. Stone performed to check for nonlinearities in exposure-response or the effects of smoking or age substantially impacted the results of the analyses for beryllium sensitization or CBD. The sensitivity analysis recommended by Crump and Proctor, excluding workers hired prior to 1980 (see Document ID 1660, p. 11), did not substantially impact the results Start Printed Page 2539of the analyses for beryllium sensitization, but did affect the results for CBD. The HR for CBD using cumulative exposure dropped to slightly below 1 and was not statistically significant following exclusion of workers hired before 1980 (HR 0.96, 95% CI 0.81-1.13, p = 0.6). OSHA discusses this result further in the background document, concluding that the reduced follow-up time for CBD in the subcohort hired in 1980 or later, in combination with genetic risk factors that may attenuate both exposure-response and disease latency in some people, may explain the lack of significant exposure-response observed in this sensitivity analysis.
Because LTW average exposure was most strongly associated with beryllium sensitization, OSHA used the final model for LTW average exposure to estimate risk of sensitization at the preceding TWA PEL, the final TWA PEL, and several alternate TWA PELs it considered. Similarly, because cumulative exposure was most strongly associated with CBD, OSHA used the final model for cumulative exposure to estimate risk of CBD at the preceding, final, and alternate TWA PELs. In calculating these risks, OSHA used a small, fixed estimate of “baseline” risk (i.e., risk of sensitization or CBD among persons with no known exposure to beryllium), as suggested by Crump and Proctor (Document ID 1660) and NIOSH (Document ID 1725). Table VI-6 presents the risk estimates for sensitization and the corresponding 95 percent confidence intervals using two different fixed “background” rates of sensitization, 1 percent and 0.5 percent. Table VI-7 presents the risk estimates for sensitization and the corresponding 95 percent confidence intervals using a fixed “background” rate of CBD of 0.5 percent. 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). Since the Cox proportional hazards model does not estimate a baseline risk, this 95 percent interval fully represents statistical uncertainty in the risk estimates.
Table VI-6—Predicted Cases of Sensitization per 1,000 Workers Exposed at the Preceding and Alternate PELs Based on Cox Proportional Hazards Model, LTW Average Exposure Metric, With Corresponding Interval Based on the Uncertainty in the Exposure Coefficient.
[1 Percent and 0.5 percent baselines]
|Exposure level (μg/m3)||Estimated cases/1000,
.5% baseline||95% CI||Estimated cases/1000,
1% baseline||95% CI|
Table VI-7—Predicted Cases of CBD per 1,000 Workers Exposed at the Preceding and Alternative PELs Based on Cox Proportional Hazards Model, Cumulative Exposure Metric, with Corresponding Interval Based on the Uncertainty in the Exposure Coefficient
[0.5 percent baseline]
|Exposure level (μg/m3)||Exposure Duration|
|5 years||10 years||20 years||45 years|
|Cumulative (μg/m3-yrs)||Estimated cases/1000 95% CI||μg/m3-yrs||Estimated cases/1000 95% CI||μg/m3-yrs||Estimated cases/1000 95% CI||μg/m3-yrs||Estimated cases/1000 95% CI|
|2.0||10.0||7.55 5.34-10.67||20.0||11.39 5.70-22.78||40.0||25.97 6.5-103.76||90.0||203.60 9.02-4595.67|
|1.0||5.0||6.14 5.17-7.30||10.0||7.55 5.34-10.67||20.0||11.39 5.70-22.78||45.0||31.91 6.72-151.59|
|0.5||2.5||5.54 5.08-6.04||5.0||6.14 5.17-7.30||10.0||7.55 5.34-10.67||22.5||12.63 5.79-27.53|
|0.2||1.0||5.21 5.03-5.39||2.0||5.43 5.07-5.82||4.0||5.9 5.13-6.77||9.0||7.24 5.30-9.89|
|0.1||0.5||5.1 5.02-5.19||1.0||5.21 5.03-5.39||2.0||5.43 5.07-5.82||4.5||6.02 5.15-7.03|
The Cox proportional hazards model, used with the fixed “baseline” rates of 0.5 percent and 1 percent, predicted risks of sensitization totaling 43 and 86 cases per 1,000 workers, respectively, or 4.3 and 8.6 percent, at the preceding PEL of 2 μg/m . The predicted risk of CBD is 203 cases per 1,000 workers, or 20.3 percent, at the preceding PEL of 2 μg/m , assuming 45 years of exposure (cumulative exposure of 90 μg/m -yr).
The predicted risks of sensitization at the new PEL of 0.2 μg/m3 are substantially lower, at 6 and 12 cases per 1,000 for the baselines of 0.5% and 1.0%, respectively. The predicted risk of CBD is also much lower at the new TWA PEL of 0.2 μg/m3 (9 μg/m3-year), at 7 cases per 1,000 assuming 45 years of exposure.
Due to limitations in the Cox analysis, including the small 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, limited follow-Start Printed Page 2540up time on many workers, and sensitivity of the results to the “baseline” values assumed for sensitization and CBD, OSHA must interpret the model-based risk estimates presented in Tables VI-6 and VI-7 with caution. Uncertainties in these risk estimates are discussed in the background document (Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama—CBD and Sensitization, OSHA, 2016). However, these uncertainties do not alter OSHA's conclusions with regard to the significance of risk at the preceding PEL and alternate PELs that OSHA considered, which are based primarily on the Agency's review of the literature and the prevalence analysis presented earlier in this section (also see Section VII, Significance of Risk).
D. Lung Cancer
As discussed more fully in the Health Effects section of the preamble, OSHA has determined beryllium to be a carcinogen based on an extensive review of the scientific literature regarding beryllium and cancer (see Section V.E). This review included an evaluation of the human epidemiological, animal cancer, and mechanistic studies described in the Health Effects section of this preamble. OSHA's conclusion is supported by the findings of public health organizations such as the International Agency for Research on Cancer (IARC), which has determined beryllium and its compounds to be carcinogenic to humans (Group 1 category) (IARC 2012, Document ID 0650); the National Toxicology Program (NTP), which classifies beryllium and its compounds as known carcinogens (NTP 2014, Document ID 0389); and the Environmental Protection Agency (EPA), which considers beryllium to be a probable human carcinogen (EPA 1998, Document ID 0661).
The Sanderson et al. study previously discussed in Health Effects evaluated the association between beryllium exposure and lung cancer mortality based on data from a beryllium processing plant in Reading, PA (Sanderson et al., 2001, Document ID 1419). Specifically, this case-control study evaluated lung cancer mortality in a cohort of 3,569 male 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 identified lung cancer cases and 710 controls.
A conditional logistic regression analysis showed an increased risk of death from lung cancer in workers with higher exposures when dose estimates were lagged by 10 and 20 years (Sanderson et al., 2001, Document ID 1419). This lag was incorporated in order to account for exposures that did not contribute to lung cancer because they occurred after the induction of cancer. The authors noted that there was considerable uncertainty in the estimation of exposure levels for the 1940s and 1950s and in the shape of the dose-response curve for lung cancer. In a 2008 study, Schubauer-Berigan et al. reanalyzed the data, adjusting for potential confounders of hire age and birth year (Schubauer-Berigan et al., 2008, Document ID 1350). The study reported a significant increasing trend (p < 0.05) in lung cancer mortality when average (log transformed) exposure was lagged by 10 years. However, it did not find a significant trend when cumulative (log transformed) exposure was lagged by 0, 10, or 20 years (Schubauer-Berigan et al., 2008, Table 3).
In formulating the final rule, OSHA was particularly 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. (2001, Document ID 1419) case-control analysis were first hired during the 1940s and 50s when exposures were extremely high (estimated daily weighted averages (DWAs) >20 μg/m3 for most jobs) in comparison to the exposure range of interest to OSHA (Sanderson et al. 2001, Document ID 1419, Table II). 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 have needed to extrapolate from very high to 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 high exposures would have created substantial uncertainty in a risk assessment based on this particular study population.
In addition, the relatively high exposures of the least-exposed workers in the study population might have created 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 this study population, workers in the lowest quartile were exposed well above the preceding OSHA TWA PEL (average exposure <11.2 μg/m3) and may have had a significant lung cancer risk. This issue would have introduced further uncertainty into the lung cancer risks.
In 2011, Schubauer-Berigan et al. published a quantitative risk assessment that addressed several of OSHA's concerns regarding the Sanderson et al. analysis. This new 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, Document ID 1265). This study population was exposed, on average, to lower levels of beryllium and had fewer short-term workers than the previous cohort analyzed by Sanderson et al. (2001, Document ID 1250) and Schubauer-Berigan et al. (2008, Document ID 1350). Schubauer-Berigan et al. (2011) followed the study population through 2005 where possible, increasing the length of follow-up time overall by an additional 17 years of observation compared to the previous analyses. For these reasons, OSHA considered the Schubauer-Berigan (2011) analysis more appropriate than Sanderson et al. (2001) and Schubauer-Berigan (2008) for its risk assessment. OSHA therefore based its preliminary QRA for lung cancer on the results from Schubauer-Berigan et al. (2011).
OSHA received several comments about its choice of Schubauer-Berigan et al. (2011) as the basis for its preliminary QRA for lung cancer. NIOSH commented that OSHA's choice of Schubauer-Berigan et al. for its preliminary analysis was appropriate because “[n]o other study is available that presents quantitative dose-response information for lung cancer, across a range of beryllium processing facilities” (Document ID 1725, p. 7). In supporting OSHA's use of this study, NIOSH emphasized in particular the study's inclusion of relatively low-exposed workers from two facilities that began operations in the 1950s (after employer awareness of acute beryllium disease (ABD) and CBD led to efforts to minimize worker exposures to beryllium), as well as the presence of both soluble and poorly soluble forms of beryllium in the facilities studied (Document ID 1725, p. 7).
According to Dr. Paolo Boffetta, who submitted comments on this study, Start Printed Page 2541Schubauer-Berigan et al. (2011) is not the most relevant study available to OSHA for its lung cancer risk analysis. Dr. Boffetta argued that the most informative study of lung cancer risk in the beryllium industry after 1965 is one that he developed in 2015 (Boffetta et al., 2015), which he described as a pooled analysis of 11 plants and 4 distribution centers (Document ID 1659, p. 1). However, Dr. Boffetta did not provide OSHA with the manuscript of his study, which he stated was under review for publication. Instead, he reported some results of the study and directed OSHA to an abstract of the study in the 2015 Annual Conference of the Society for Epidemiologic Research (Document ID 1659; Document ID 1661, Attachment 1).
Because only an abstract of Boffetta et al.' s 2015 study was available to OSHA (see Document ID 1661, Attachment 1), OSHA could not properly evaluate it or use it as the basis of a quantitative risk assessment for lung cancer. Nevertheless, OSHA has addressed comments Dr. Boffetta submitted based on his analyses in the relevant sections of the final QRA for lung cancer below. Because it was not possible to use this study for its lung cancer QRA and OSHA is not aware of other studies appropriate for use in its lung cancer QRA (nor did commenters besides Dr. Boffetta suggest that OSHA use any additional studies for this purpose), OSHA finds that the body of available evidence has not changed since the Agency conducted its preliminary QRA based on Schubauer-Berigan et al. (2011, Document ID 1265). Therefore, OSHA concludes that Schubauer-Berigan et al. (2011) is the most appropriate study for its final lung cancer QRA, presented below.
1. QRA for Lung Cancer Based on Schubauer-Berigan et al. (2011)
The cohort studied by Schubauer-Berigan et al. (2011, Document ID 1265) included 5,436 male workers who had worked for at least 2 days at the Reading facility or at the beryllium processing plants in 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 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. (2001, Document ID 1250), Chen et al. (2001, Document ID 1593), and Couch et al. (2010, Document ID 0880).
Workers' cumulative exposures (μg/m3-days) were estimated by summing daily average exposures (assuming five workdays per week) (Schubauer-Berigan et al., 2011). To estimate mean exposure (μg/m3), cumulative exposure was divided by exposure time (in days), accounting where appropriate for lag time. Maximum exposure (μg/m3) was calculated as the highest annual DWA on record for a worker from the first exposure until the study cutoff date of December 31, 2005, again 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-8 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 (Schubauer-Berigan et al., 2011). Whereas the median worker from Hazleton had a mean exposure across his tenure of less than 1.5 μg/m3 and the median worker from Elmore had a mean exposure of less than 1 μg/m3, the median worker from Reading had a mean exposure of 25 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-8—Cohort Description and Distribution of Cases by Exposure Level
| || ||All plants||Reading plant||Hazleton plant||Elmore plant|
|Number of cases||293||218||30||45|
|Number of non-cases||5143||3337||583||1223|
|Median value for mean exposure||No lag||15.42||25||1.443||0.885|
|(μg/m3) among cases||10-year lag||15.15||25||1.443||0.972|
|Median value for cumulative exposure||No lag||2843||2895||3968||1654|
|(μg/m3-days) among cases||10-year lag||2583||2832||3648||1449|
|Median value for maximum exposure||No lag||25||25.1||3.15||2.17|
|(μg/m3) among cases||10-year lag||25||25||3.15||2.17|
|Number of cases with potential asbestos exposure||100 (34%)||68 (31%)||16 (53%)||16 (36%)|
|Number of cases who were professional workers||26 (9%)||21 (10%)||3 (10%)||2 (4%)|
| Table adapted from Schubauer-Berigan et al., 2011, Document ID 1265, Table 1.|
Schubauer-Berigan et al. analyzed the data set using a variety of exposure-response modeling approaches, including categorical analyses, continuous-variable piecewise log-linear models, and power models (2011, Document ID 1265). All models adjusted for birth cohort and plant. Because 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 curves 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 (those employed in 1968), smoking could not be controlled for directly in the models. Schubauer-Berigan et al. reported that within the subset with smoking information, there was little difference in smoking by cumulative or maximum exposure category, 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 (ten percent of cases) and workers believed to have asbestos exposure (one-third of cases). These models were Start Printed Page 2542intended to mitigate the potential impact of smoking and asbestos as confounders.
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, Document ID 1265). They selected the best-fitting categorical, power, and monotonic piecewise log-linear (PWL) models with a 10-year lag to generate HRs for male workers with a mean exposure of 0.5 μg/m (the current NIOSH Recommended Exposure Limit for beryllium).
In addition, they estimated the daily weighted average exposure that would be associated with an excess lung cancer mortality risk of one in one thousand (.005 μg/m3 to .07 μg/m3 depending on model choice). To estimate excess risk of cancer, they multiplied these hazard ratios by the 2004 to 2006 background lifetime lung cancer rate among U.S. males who had survived, cancer-free, to age 30. At OSHA's request, Dr. Schubauer-Berigan also estimated excess lung cancer risks for workers with mean exposures at the preceding PEL of 2 μg/m3 and at each of the other alternate PELs that were under consideration: 1 μg/m3, 0.2 μg/m3, and 0.1 μg/m3 (Document ID 0521). The resulting risk estimates are presented in Table VI-9 below.
Table VI-9—Excess Lung Cancer Risk per 1,000 [95% Confidence Interval] For Male Workers at Alternate PELs
[Based on Schubauer-Berigan et al., 2011]
|Exposure-response model||Mean exposure|
|0.1 μg/m3||0.2 μg/m3||0.5 μg/m3||1 μg/m3||2 μg/m3|
|Best monotonic PWL—all workers||7.3 [2.0-13]||15 [3.3-29]||45 [9-98]||120 [20-340]||140 [29-370]|
|Best monotonic PWL—excluding professional and asbestos workers||3.1 [<0-11]||6.4 [<0-23]||17 [<0-74]||39 [39-230]||61 [<0-280]|
|Best categorical—all workers||4.4 [1.3-8]||9 [2.7-17]||25 [6-48]||59 [13-130]||170 [29-530]|
|Best categorical—excluding professional and asbestos workers||1.4 [<0-6.0]||2.7 [<0-12]||7.1 [<0-35]||15 [<0-87]||33 [<0-290]|
|Power model—all workers||12 [6-19]||19 [9.3-29]||30 [15-48]||40 [19-66]||52 [23-88]|
|Power model—excluding professional and asbestos workers||19 [8.6-31]||30 [13-50]||49 [21-87]||68 [27-130]||90 [34-180]|
|Source: Schubauer-Berigan, Document ID 0521, pp. 6-10.|
Schubauer-Berigan et al. (2011, Document ID 1265) discuss several strengths, weaknesses, and uncertainties of their analysis. Strengths include a long (>30 years) follow-up time and the extensive exposure and work history data available for the development of exposure estimates for workers in the cohort. Weaknesses and uncertainties of the study include the limited information available on workers' smoking habits: As mentioned above, smoking information was available only for workers employed in 1968, about 25 percent of the cohort. Another potential weakness was that 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. This could cause the relationship between exposure level and lung cancer risk to appear weaker than it would in the absence of this source of error in the estimation of workers' beryllium exposures.
Schubauer-Berigan et al. (2011) did not discuss the reasons for basing risk estimates on mean exposure rather than cumulative exposure, which is more commonly used for lung cancer risk analysis. OSHA believes the decision may involve the non-monotonic relationship the authors 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 have been at high risk of lung cancer due to the tendency of beryllium to persist in the lung for long periods. This could lead to the appearance of a non-monotonic 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 authors' use of the mean exposure metric to be appropriate and scientifically defensible for this particular dataset.
Dr. Boffetta's comment, mentioned above, addressed the relevance of the Schubauer-Berigan et al. (2011) cohort to determining whether workers currently employed in the beryllium industry experience an increased lung cancer hazard (Document ID 1659, pp. 1-2). His comment also analyzed the methods and findings in Schubauer-Berigan et al. (2011) (Document ID 1659, pp. 2-3). Notably, he stated that his own study, Boffetta et al. (2015) provides better information for risk assessment than does Schubauer-Berigan et al. (2011) (Document ID 1659, pp. 1-2). As discussed above, OSHA cannot rely on a study for its QRA (Boffetta et al., 2015) that has not been submitted to the record and is not otherwise available to OSHA. However, in the discussion below, OSHA addresses Dr. Boffetta's study to the extent it can given the Start Printed Page 2543limited information available to the Agency. OSHA also responds to Dr. Boffetta's comments on Schubauer-Berigan et al. (2011, Document ID 1265) and Boffetta et al. (2014, Document ID 0403), which Dr. Boffetta asserts provides evidence that poorly soluble beryllium compounds are not associated with lung cancer (Document ID 1659, p. 1).
Boffetta argued that the most informative study in the modern (post-1965) beryllium industry is Boffetta et al. (2015, Document ID 1661, Attachment 1). According to Boffetta's comment, the study found an SMR of 1.02 (95% CI 0.94-1.10, based on 672 deaths) for the overall cohort and an SMR for lung cancer among workers exposed only to insoluble beryllium of 0.93 (95% CI 0.79-1.08, based on 157 deaths). Boffetta noted that his study was based on 23 percent more overall deaths than the Schubauer-Berigan et al. cohort (Document ID 1659, pp. 1-2). As stated earlier, this study is unpublished and was not provided to OSHA. The abstract provided by Materion (Document ID 1661, Attachment 1) included very little information beyond the SMRs reported; for example, it provided no information about the manufacturing plants and distribution centers included, workers' beryllium exposure levels, how the cohorts were defined, or how the authors determined the solubility of the beryllium to which workers were exposed. OSHA is therefore unable to evaluate the quality or conclusions of this study.
Dr. Boffetta also commented that there is a lack of evidence of increased lung cancer risk among workers exposed only to poorly soluble beryllium compounds (Document ID 1659, p. 1). To support this statement, he cited a study he published in 2014 of workers at four “insoluble facilities” (Boffetta et al., 2014) and Schubauer-Berigan et al.' s 2011 study, arguing that increased cancer risk in beryllium-exposed workers in those two studies was only observed in workers employed in Reading and Lorain prior to 1955. Workers employed at the other plants and workers who were first employed in Reading and Lorain after 1955, according to Dr. Boffetta, were exposed primarily to poorly soluble forms of beryllium and did not experience an increased risk of lung cancer. Dr. Boffetta further stated that his unpublished paper (Boffetta et al., 2015) shows a similar result (Document ID 1659, p. 1).
OSHA carefully considered Dr. Boffetta's argument regarding the status of poorly soluble beryllium compounds, and did not find persuasive evidence showing that the solubility of the beryllium to which the workers in the studies he cited were exposed accounts for the lack of statistically significantly elevated risk in the Boffetta et al. (2014) cohort or the Schubauer-Berigan et al. (2011) subcohort. While it is true that the SMR for lung cancer was not statistically significantly elevated in the Schubauer-Berigan et al. (2011) study when workers hired before 1955 in the Reading and Lorain plants were excluded from the study population, or in the study of four facilities published by Boffetta et al. in 2014, there are various possible reasons for these results that Dr. Boffetta did not consider in his comment. As discussed below, OSHA finds that the type of beryllium compounds to which these workers were exposed is not likely to explain Dr. Boffetta's observations.
As discussed in Section V, Health Effects and in comments submitted by NIOSH, animal toxicology evidence shows that poorly soluble beryllium compounds can cause cancer. IARC determined that poorly soluble forms of beryllium are carcinogenic to humans in its 2012 review of Group I carcinogens (see section V.E.5 of this preamble; Document ID 1725, p. 9; IARC, 2012, Document ID 0650). NIOSH noted that poorly soluble forms of beryllium remain in the lung for longer time periods than soluble forms, and can therefore create prolonged exposure of lung tissue to beryllium (Document ID 1725, p. 9). This prolonged exposure may lead to the sustained tissue inflammation that causes many forms of cancer and is believed to be one pathway for carcinogenesis due to beryllium exposure (see Section V, Health Effects).
The comments from NIOSH also demonstrate that the available information cannot distinguish between the effects of soluble and poorly soluble beryllium. NIOSH submitted information on the solubility of beryllium in the Schubauer-Berigan et al. (2011) cohort, stating that operations typically involving both soluble and poorly soluble beryllium were performed at all three of the beryllium plants included in the study (Document ID 1725, p. 9; Ward et al., 1992, Document ID 1378). Based on evaluations of the JEMs and work histories of employees in the cohort (which were not published in the 2011 Schubauer-Berigan et al. paper), NIOSH stated that “the vast majority of beryllium work-time at all three of these facilities was due to either insoluble or mixed chemical forms. In fact, insoluble beryllium was the largest single contributor to work-time (for beryllium exposure of known solubility class) at the three facilities across most time periods” (Document ID 1725, p. 9). NIOSH also provided figures showing the contribution of insoluble beryllium to exposure over time in the Schubauer-Berigan et al. (2011) study, as well as the relatively small proportion of work years during which workers in the study were exposed exclusively to either soluble or poorly soluble forms (Document ID 1725, pp. 10-11).
Boffetta et al. (2014, Document ID 0403) examined a population of workers allegedly exposed exclusively to poorly soluble beryllium compounds, in which overall SMR for lung cancer was not statistically significantly elevated (SMR 96.0, 95% CI 80.0-114.3). Boffetta et al. concluded, “[a]lthough a small risk for lung cancer is compatible with our results, we can confidently exclude an excess greater than 20%” in the study population (Boffetta et al., 2014, p. 592). Limitations of the study include a lack of information on many workers' job titles, a lack of any beryllium exposure measurements, and the very short-term employment of most cohort members at the study facilities (less than 5 years for 72 percent of the workers) (Boffetta et al., 2014).
OSHA reviewed this study, and finds that it does not contradict the findings of the Schubauer-Berigan et al. (2011) lung cancer risk analysis for several reasons. First, as shown in Table VI-9 above, none of the predictions of excess risk in the risk analysis exceed 20 percent (200 per 1,000 workers); most are well below this level, and thus are well within the range that Boffetta et al. (2014) state they cannot confidently exclude. Thus, the statement by Boffetta et al. that the risk of excess lung cancer is no higher than 20 percent is actually consistent with the risk findings from Schubauer-Berigan et al. (2011) presented above. Second, the fact that most workers in the cohort were employed for less than five years suggests that most workers' cumulative exposures to beryllium were likely to be quite low, which would explain the non-elevated SMR for lung cancer in the study population regardless of the type of beryllium to which workers were exposed. The SMR for workers employed in the study facilities for at least 20 years was elevated (112.7, CI 66.8-178.1) (Boffetta et al., 2014, Document ID 0403, Table 3),
supporting OSHA's observation that the lack of elevated SMR in the cohort overall may be due to short-term Start Printed Page 2544employment and low cumulative exposures.
Finally, the approach of Boffetta et al. (2014), which relies on SMR analyses, does not account for the healthy worker effect. SMRs are calculated by comparing disease levels in the study population to disease levels in the general population, using regional or national reported disease rates. However, because working populations tend to have lower disease rates than the overall population, SMRs can underestimate excess risk of disease in those populations. The SMR in Boffetta et al. (2014) for overall mortality in the study population was statistically significantly reduced (94.7, 95 percent CI 89.9-99.7), suggesting a possible healthy worker effect. The SMR for overall mortality was even further reduced in the category of workers with at least 20 years of employment (87.7, 95 percent CI 74.3-102.7), in which an elevated SMR for lung cancer was observed. NIOSH commented that “[i]n a modern industrial population, the expected SMR for lung cancer would be approximately 0.93 [Park et al. (1991)]” (Document ID 1725, p. 8). This is lower than the SMR for lung cancer (96) observed in Boffetta et al. (2014) and much lower than the SMR for lung cancer in the category of workers employed for at least 20 years (112.7), which is the group most likely to have had sufficient exposure and latency to show excess lung cancer (Boffetta et al., 2014, Document ID 0403, Tables 2 and 3). Thus, it appears that the healthy worker effect is another factor (in addition to low cumulative exposures) that may account for the findings of Boffetta et al.' s 2014 study.
Taken together, OSHA finds that the animal toxicology evidence on the carcinogenicity of poorly soluble beryllium forms, the long residence of poorly soluble beryllium in the lung, the likelihood that most workers in Schubauer-Berigan et al. (2011) were exposed to a mixture of soluble and poorly soluble beryllium forms, and the points raised above regarding Boffetta et al. (2014) rebut Boffetta's claim that low solubility of beryllium compounds is the most likely explanation for the lack of statistically significantly elevated SMR results.
Dr. Boffetta's comment also raised technical questions regarding the Schubauer-Berigan et al. (2011, Document ID 1265) risk analysis. He noted that risk estimates at low exposures are dependent on choice of model in their analysis; the authors' choice of a single “best” model was based on purely statistical criteria, and the results of the statistics used (AIC) were similar between the models” (Document ID 1659, p. 2). Therefore, according to Dr. Boffetta, “there is ample uncertainty about the shape of the dose-response function in the low-dose range” (Document ID 1659, p. 3).
OSHA agrees that it is difficult to distinguish a single “best” model from the set of models presented by Schubauer-Berigan et al. (2011), and that risk estimates at low exposure levels vary depending on choice of model. That is one reason OSHA presented results from all of the models (see Table VI-9). OSHA further agrees that there is uncertainty in the lung cancer risk estimates, the estimation of which (unlike for CBD) required extrapolation below beryllium exposure levels experienced by workers in the Schubauer-Berigan et al. (2011) study. However, the Schubauer-Berigan risk assessment's six best-fitting models all support OSHA's significant risk determination, as they all predict a significant risk of lung cancer at the preceding TWA PEL of 2 μg/m3 (estimates ranging from 33 to 170 excess lung cancers per 1,000 workers) and a substantially reduced, though still significant, risk of lung cancer at the new TWA PEL of 0.2 μg/m3 (estimates ranging from 3 to 30 excess lung cancers per 1,000 workers) (see Table VI-9).
Dr. Boffetta also noted that the risk estimates provided by Schubauer-Berigan et al. (2011, Document ID 1265) for OSHA's lung cancer risk assessment depend on the background lung cancer rate used in excess risk calculations, and that industrial workers may have a different background lung cancer risk than the U.S. population as a whole (Document ID 1659, p. 2). OSHA agrees that choice of background risk could influence the number of excess lung cancers predicted by the models the Agency relied on for its lung cancer risk estimates. However, choice of background risk did not influence OSHA's finding that excess lung cancer risks would be substantially reduced by a decrease in exposure from the preceding TWA PEL to the final TWA PEL, because the same background risk was factored into estimates of risk at both levels. Furthermore, the Schubauer-Berigan et al. (2011) estimates of excess lung cancer from exposure at the preceding PEL of 2 μg/m3 (ranging from 33 to 170 excess lung cancers per 1,000 workers, depending on the model) are much higher than the level of 1 per 1,000 that OSHA finds to be clearly significant. Even at the final TWA PEL of 0.2 μg/m3, the models demonstrate a range of risks of excess lung cancers of 3 to 30 per 1,000 workers, estimates well above the threshold for significant risk (see Section II, Pertinent Legal Authority). Small variations in background risk across different populations are highly unlikely to influence excess lung cancer risk estimates sufficiently to influence OSHA's finding of significant risk at the preceding TWA PEL, which is the finding OSHA relies on to support the need for a new standard.
Finally, Dr. Boffetta noted that the models that exclude professional and asbestos workers (the groups that Schubauer-Berigan et al. believed could be affected by confounding from tobacco and asbestos exposure) showed non-significant increases in lung cancer with increasing beryllium exposure. According to Dr. Boffetta, this suggests that confounding may contribute to the results of the models based on the full population. He speculates that if more precise information on confounding exposures were available, excess risk estimates might be further reduced (Document ID 1659, p. 2).
OSHA agrees with Dr. Boffetta that there is uncertainty in the Schubauer-Berigan et al. (2011) lung cancer risk estimates, including uncertainty due to limited information on possible confounding from associations between beryllium exposure level and workers' smoking habits or occupational co-exposures. However, in the absence of detailed smoking and co-exposure information, the models excluding professional and asbestos workers are a reasonable approach to addressing the possible effects of unmeasured confounding. OSHA's decision to include these models in its preliminary and final QRAs therefore represents the Agency's best available means of dealing with this uncertainty.
E. Risk Assessment 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 data set provided by NJH. OSHA has a high level of confidence in its finding that the risks of sensitization and CBD are above the benchmark of 1 in 1,000 at the preceding PEL, and the Agency believes that a comprehensive 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 and tightly controlled both respiratory exposure and dermal contact have substantially reduced risk of sensitization within the first years of exposure. These conclusions are supported by the results of several studies conducted in facilities dealing Start Printed Page 2545with a variety of production activities and physical forms of beryllium that have reduced workers' exposures substantially by implementing stringent exposure controls and PPE requirements since approximately 2000. In addition, these conclusions are supported by OSHA's analyses of the NJH data set, which contains highly-detailed exposure and work history information on several hundred beryllium workers.
Furthermore, OSHA believes that more stringent control of airborne beryllium exposures will reduce beryllium-exposed workers' significant risk of lung cancer. The risk estimates from the lung cancer study by Schubauer-Berigan et al. (2011, Document ID 1265; 0521), described above, range from 33 to 170 excess lung cancers per 1,000 workers exposed at the preceding PEL of 2 μg/m3, based on the study's six best-fitting models. These models each predict substantial reductions in risk with reduced exposure, ranging from 3 to 30 excess lung cancers per 1,000 workers exposed at the final PEL of 0.2 μg/m3. The evidence of lung cancer risk from the Schubauer-Berigan et al. (2011) risk assessment provides additional support for OSHA's conclusions regarding the significance of risk of adverse health effects for workers exposed to beryllium levels at and below the preceding PEL. However, the lung cancer risks required a sizable low dose extrapolation below beryllium exposure levels experienced by workers in the Schubauer-Berigan et al. (2011) study. As a result, there is greater uncertainty regarding the lung cancer risk estimates than there is for the risk estimates for beryllium sensitization and CBD. The conclusions with regard to significance of risk are presented and further discussed in section VII of the preamble.
VII. Significance of Risk
In this section, OSHA discusses its findings that workers exposed to beryllium at and below the preceding TWA PEL face a significant risk of material impairment of health or functional capacity within the meaning of the OSH Act, and that the new standards will substantially reduce this risk. To make the significance of risk determination for a new final 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 assuming exposure over a working lifetime. As discussed in section II, Pertinent Legal Authority, courts have stated that OSHA should consider all forms and degrees of material impairment—not just death or serious physical harm. To evaluate the significance of the health risks that result from exposure to hazardous chemical agents, OSHA relies on 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 (generally 45 years) at levels of exposure reflecting compliance with the preceding standard and compliance with the new standards (see Section II, Pertinent Legal Authority). When determining whether a significant risk exists OSHA considers whether there is a risk of at least one-in-a-thousand of developing a material health impairment from a working lifetime of exposure. The Supreme Court has found that OSHA is not required to support its finding of significant risk with scientific certainty, but may instead rely on a body of reputable scientific thought and may make conservative assumptions (i.e., err on the side of protecting the worker) in its interpretation of the evidence (Section II, Pertinent Legal Authority).
OSHA's findings in this section follow in part from the conclusions of the preceding sections V, Health Effects, and VI, Risk Assessment. In this preamble at section V, Health Effects, OSHA reviewed the scientific evidence linking occupational beryllium exposure to a variety of adverse health effects and determined that beryllium exposure causes sensitization, CBD, and lung cancer, and is associated with various other adverse health effects (see section V.D, V.E, and V.F). In this preamble at section VI, Risk Assessment, OSHA found that the available epidemiological data are sufficient to evaluate risk for beryllium sensitization, CBD, and lung cancer among beryllium-exposed workers. OSHA evaluated the risk of sensitization, CBD, and lung cancer from levels of airborne beryllium exposure that were allowed under the previous standard, as well as the expected impact of the new standards on risk of these conditions. In this section of the preamble, OSHA explains its determination that the risk of material impairments of health, particularly CBD and lung cancer, from occupational exposures allowable under the preceding TWA PEL of 2 μg/m3 is significant, and is substantially reduced but still significant at the new TWA PEL of 0.2 μg/m3. Furthermore, evidence reviewed in section VI, Risk Assessment, shows that significant risk of CBD and lung cancer could remain in workplaces with exposures as low as the new action level of 0.1 μg/m3. OSHA also explains here that the new standards will reduce the occurrence of sensitization.
In the NPRM, OSHA preliminarily determined that both CBD and lung cancer are material impairments of health. OSHA also preliminarily determined that a working lifetime (45 years) of exposure to airborne beryllium at the preceding time-weighted average permissible exposure limit (TWA PEL) of 2 μg/m3 would pose a significant risk of both CBD and lung cancer, and that this risk is substantially reduced but still significant at the new TWA PEL of 0.2 μg/m3. OSHA did not make a preliminary determination as to whether beryllium sensitization is a material impairment of health because, as the Agency explained in the NPRM, it was not necessary to make such a determination. The Agency's preliminary findings on CBD and lung cancer were sufficient to support the promulgation of new beryllium standards.
Upon consideration of the entire rulemaking record, including the comments and information submitted to the record in response to the preliminary Health Effects, Risk Assessment, and Significance of Risk analyses (NPRM Sections V, VI, and VIII), OSHA reaffirms its preliminary findings that long-term exposure at the preceding TWA PEL of 2 μg/m3 poses a significant risk of material impairment of workers' health, and that adoption of the new TWA PEL of 0.2 μg/m3 and other provisions of the final standards will substantially reduce this risk.
Material Impairment of Health
As discussed in Section V, Health Effects, CBD is a respiratory disease caused by exposure to beryllium. CBD develops when 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 (Document ID 1319); ACCP, 1965 (1286); Kriebel et al., 1988a (1292) and b (1473)).
In early, asymptomatic stages of CBD, small granulomatous lesions and mild inflammation occur in the lungs. Over time, the granulomas can spread and lead to lung fibrosis (scarring) and Start Printed Page 2546moderate to severe loss of pulmonary function, with symptoms including a persistent dry cough and shortness of breath (Saber and Dweik, 2000, Document ID 1421). 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 (Conradi et al., 1971, Document ID 1319; ACCP, 1965 (1286); Kriebel et al., 1988 (1292); Kriebel et al., 1988 (1473)).
Dr. Lee Newman, speaking at the public hearing on behalf of the American College of Occupational and Environmental Medicine (ACOEM), testified on his experiences treating patients with CBD: “as a physician who has spent most of my [practicing] career seeing patients with exposure to beryllium, with beryllium sensitization, and with chronic beryllium disease including those who have gone on to require treatment and to die prematurely of this disease . . . [I've seen] hundreds and hundreds, probably over a thousand individuals during my career who have suffered from this condition” (Document ID 1756, Tr. 79). Dr. Newman further testified about his 30 years of experience treating CBD in patients at various stages of the disease:
. . . some of them will go from being sensitized to developing subclinical disease, meaning that they have no symptoms. As I mentioned earlier, most of those will, if we actually do the tests of their lung function and their oxygen levels in their blood, those people are already demonstrating physiologic abnormality. They already have disease affecting their health. They go on to develop symptomatic disease and progress to the point where they require treatment. And sometimes to the extent of even requiring a [lung] transplant (Document ID 1756, Tr. 131).
Dr. Newman described one example of a patient who developed CBD from his occupational beryllium exposure and “who went on to die prematurely with a great deal of suffering along the way due to the condition chronic beryllium disease” (Document ID 1756, Tr. 80).
During her testimony at the public hearing, Dr. Lisa Maier of National Jewish Health (NJH) provided an example from her experience with treating CBD patients. “This gentleman started to have a cough, a dry cough in 2011 . . . His symptoms progressed and he developed shortness of breath, wheezing, chills, night sweats, and fatigue. These were so severe that he was eventually hospitalized” (Document ID 1756, Tr. 105). Dr. Maier noted that this patient had no beryllium exposure prior to 2006, and that his CBD had developed from beryllium exposure in his job melting an aluminum alloy in a foundry casting airplane parts (Document ID 1756, Tr. 105-106). She described how her patient could no longer work because of his condition. “He requires oxygen and systemic therapy . . . despite aggressive treatment [his] test findings continue to demonstrate worsening of his disease and increased needs for oxygen and medications as well as severe side effects from medications. This patient may well need a lung transplant if this disease continues to progress . . . ” (Document ID 1756, Tr. 106-107).
The likelihood, speed, and severity of individuals' transition from asymptomatic to symptomatic CBD is understood to vary widely, with some individuals responding differently to exposure cessation and treatment than others (Sood, 2009, Document ID 0456; Mroz et al., 2009 (1443)). In the public hearing, Dr. Newman testified that the great majority of individuals with very early stage CBD in a cross-sectional study he published (Pappas and Newman, 1993) had physiologic impairment. Thus, even before x-rays or CAT scans found evidence of CBD, the lung functions of those individuals were abnormal (Document ID 1756, Tr. 112). Materion commented that the best available evidence on the transition from asymptomatic to more severe CBD is a recent longitudinal study by Mroz et al. (2009, Document ID 1443), which found that 19.3 percent of individuals with CBD developed clinical abnormalities requiring oral immunosuppressive therapy (Document ID 1661, pp. 5-6). The authors' overall conclusions in that study include a finding that adverse physiological changes among initially asymptomatic CBD patients progress over time, requiring many individuals to be treated with corticosteroids, and that the patients' levels of beryllium exposure may affect progression (Mroz et al., 2009). Dr. Maier, a co-author of the study, testified that studies “indicate that higher levels of exposure not only are risk factors for [developing CBD in general] but also for more severe [CBD] (Document ID 1756, Tr. 111).
Treatment of CBD using inhaled and systemic steroid therapy has been shown to ease symptoms and slow or prevent some aspects of disease progression. As explained below, these treatments can be most effectively applied when CBD is diagnosed prior to development of symptoms. In addition, the forms of treatment that can be used to manage early-stage CBD have relatively minor side effects on patients, while systemic steroid treatments required to treat later-stage CBD often cause severe side effects.
In the public hearing, Dr. Newman and Dr. Maier testified about their experiences treating patients with CBD at various stages of the disease. Dr. Newman stated that patients' outcomes depend greatly on how early they are diagnosed. “So there are those people who are diagnosed very late in the course of disease where there's little that we can do to intervene and they are going to die prematurely. There are those people who may be detected with milder disease where there are opportunities to intervene” (Document ID 1756, Tr. 132). Both Dr. Maier and Dr. Newman emphasized the importance of early detection and diagnosis, stating that removing the patient from exposure and providing treatment early in the course of the disease can slow or even halt progression of the disease (Document ID 1756, Tr. 111, 132).
Dr. Maier testified that inhaled steroids can be used to treat relatively mild symptoms that may occur in early stages of the disease, such as a cough during exercise (Document ID 1756, Tr. 139). Inhaled steroids, she stated, are commonly used to treat other health conditions and have fewer and milder side effects than forms of steroid treatment that are used to treat more severe forms of CBD (Document ID 1756, Tr. 140). Early detection of CBD helps physicians to properly treat early-onset symptoms, since appropriate forms of treatment for early stage CBD can differ from treatments for conditions it is commonly mistaken for, such as chronic obstructive pulmonary disease Start Printed Page 2547(COPD) and asthma (Document ID 1756, Tr. 140-141).
CBD in later stages is often managed using systemic steroid treatments such as corticosteroids. In workers with CBD whose beryllium exposure has ceased, corticosteroid therapy 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, Document ID 0370). Thus, although there is no cure for CBD, properly-timed treatment can lead to CBD regression in some patients (Sood, 2004, Document ID 1331). Other patients have shown short-term improvements from corticosteroid treatment, but then developed serious fibrotic lesions (Marchand-Adam et al., 2008). Ms. Peggy Mroz, of NJH, discussed the results of the Marchand-Adam et al. study in the hearing, stating that treatment of CBD using steroids has been most successful when treatment begins prior to the development of lung fibrosis (Document ID 1756, Tr. 113). Once fibrosis has developed in the lungs, corticosteroid treatment cannot reverse the damage (Sood, 2009, Document ID 0456). Persons with late-stage CBD experience severe respiratory insufficiency and may require supplemental oxygen (Rossman, 1991, Document 1332). Historically, late-stage CBD often ended in death (NAS, 2008, Document ID 1355). While the use of steroid treatments can help to reduce the effects of CBD, OSHA is not aware of any studies showing the effect of these treatments on the frequency of premature death among patients with CBD.
Treatment with corticosteroids has severe side effects (Trikudanathan and McMahon, 2008, Document ID 0366; Lipworth, 1999 (0371); Gibson et al., 1996 (1521); Zaki et al., 1987 (1374)). Adverse effects associated with long-term corticosteroid use include, but are not limited to: increased risk of opportunistic infections (Lionakis and Kontoyiannis, 2003, Document ID 0372; Trikudanathan and McMahon, 2008 (0366)); accelerated bone loss or osteoporosis leading to increased risk of fractures or breaks (Hamida et al., 2011, Document ID 0374; Lehouck et al., 2011 (0355); Silva et al., 2011 (0388); Sweiss et al., 2011 (0367); Langhammer et al., 2009 (0373)); psychiatric effects including depression, sleep disturbances, and psychosis (Warrington and Bostwick, 2006, Document ID 0365; Brown, 2009 (0377)); adrenal suppression (Lipworth, 1999, Document ID 0371; Frauman, 1996 (0356)); ocular effects including cataracts, ocular hypertension, and glaucoma (Ballonzoli and Bourcier, 2010, Document ID 0391; Trikudanathan and McMahon, 2008 (0366); Lipworth, 1999 (0371)); an increase in glucose intolerance (Trikudanathan and McMahon, 2008, Document ID 0366); excessive weight gain (McDonough et al., 2008, Document ID 0369; Torres and Nowson, 2007 (0387); Dallman et al., 2007 (0357); Wolf, 2002 (0354); Cheskin et al., 1999 (0358)); increased risk of atherosclerosis and other cardiovascular syndromes (Franchimont et al., 2002, Document ID 0376); skin fragility (Lipworth, 1999, Document ID 0371); and poor wound healing (de Silva and Fellows, 2010, Document ID 0390).
Based on the above, 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 that can cause severe and lasting side effects, and may in some cases cause premature death.
Furthermore, OSHA has determined that early-stage CBD, an asymptomatic period during which small lesions and inflammation appear in the lungs, is also a material impairment of health. OSHA bases this conclusion on evidence and expert testimony that early-stage CBD is a measurable change in an individual's state of health that, with and sometimes without continued exposure, can progress to symptomatic disease (e.g., Mroz et al., 2009 (1443); 1756, Tr. 131). Thus, prevention of the earliest stages of CBD will prevent development of more serious disease. In OSHA's Lead standard, promulgated in 1978, the Agency stated its 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 the beginnings of illness the standard must be selected to prevent an earlier point of 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 (43 FR 52952, 52954).
Since the Lead rulemaking, OSHA has also found other non-symptomatic (or sub-clinical) health conditions to be material impairments of health. In the Bloodborne Pathogens 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). OSHA stated: “Becoming a carrier [of HBV] 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 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 and Bloodborne Pathogens standards. Early stage CBD involves lung tissue inflammation without symptoms 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 determined 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 finds all stages of CBD to be material impairments of health within the meaning of section 6(b)(5) of the OSH Act (29 U.S.C. 655(b)(5)).
In reviewing OSHA's Lead standard in United Steelworkers of America, AFL-CIO v. Marshall, 647 F.2d 1189, 1252 (D.C. Cir. 1980) (Lead I), the D.C. Circuit affirmed that the OSH Act “empowers OSHA to set a PEL that prevents the subclinical effects of lead that lie on a continuum shared with overt lead disease.” See also AFL-CIO v. Marshall, 617 F.2d 636, 654 n.83 (D.C. Cir. 1979) (upholding OSHA's authority to prevent early symptoms of a disease, even if the effects of the disease are, at that point, reversible). According to the Court, OSHA only had to demonstrate, Start Printed Page 2548on the basis of substantial evidence, that preventing the subclinical effects would help prevent the clinical phase of disease (United Steelworkers of America, AFL-CIO, 647 F.2d at 1252). Thus, OSHA has the authority to regulate to prevent asymptomatic CBD whether or not it is properly labeled as a material impairment of health.
OSHA has also determined that exposure to beryllium can cause beryllium sensitization. Sensitization is a precursor to development of CBD and an essential step for development of the disease. As discussed in Section V, Health Effects, only sensitized individuals can develop CBD (NAS, 2008, Document ID 1355).
As explained above, OSHA has the authority to promulgate regulations designed to prevent precursors to material impairments of health. Therefore, OSHA's new beryllium standards aim to prevent sensitization as well as the development of CBD and lung cancer. OSHA's risk assessment for sensitization, presented in section VI, informs the Agency's understanding of what exposure control measures have been successful in preventing sensitization, which in turn prevents development of CBD. Therefore, OSHA addresses sensitization in this section on significance of risk.
As discussed in Section VI, Risk Assessment, the risk assessment for beryllium sensitization and CBD relied on two approaches: (1) OSHA's review of epidemiological studies of sensitization and CBD that contain information on exposures in the range of interest to OSHA (2 μg/m3 and below), and (2) OSHA's analysis of a NJH data set on sensitization and CBD in a group of beryllium-exposed machinists in Cullman, AL.
OSHA's review of the literature includes studies of beryllium-exposed workers at a Tucson, AZ ceramics plant (Kreiss et al., 1996, Document ID 1477; Henneberger et al., 2001 (1313); Cummings et al., 2007 (1369)); a Reading, PA copper-beryllium processing plant (Schuler et al., 2005, Document ID 0919; Thomas et al., 2009 (0590)); a Cullman, AL beryllium machining plant (Newman et al., 2001, Document ID 1354; Kelleher et al., 2001 (1363); Madl et al., 2007 (1056)); an Elmore, OH metal, alloy, and oxide production plant (Kreiss et al., 1993 Document ID 1478; Bailey et al., 2010 (0676); Schuler et al., 2012 (0473)); aluminum smelting facilities (Taiwo et al. 2008, Document ID 0621; 2010 (0583); Nilsen et al., 2010 (0460)); and nuclear facilities (Viet et al., 2000, Document ID 1344; Arjomandi et al., 2010 (1275)).
The published literature on beryllium sensitization and CBD discussed in section VI shows that the risk of both can be significant in workplaces where exposures are at or below OSHA's preceding PEL of 2 μg/m (e.g., Kreiss et al., 1996, Document ID 1477; Henneberger et al., 2001 (1313); Newman et al., 2001 (1354); Schuler et al., 2005 (0919), 2012 (0473); Madl et al., 2007 (1056)). For example, in the Tucson ceramics plant mentioned above, Kreiss et al. (1996) reported that eight (5.9 percent) 
of the 136 workers tested in 1992 were sensitized, six (4.4 percent) of whom were diagnosed with CBD. In addition, of 77 Tucson workers hired prior to 1992 who were tested in 1998, eight (10.4 percent) were sensitized and seven of these (9.7 percent) were diagnosed with CBD (Henneberger et al., 2001, Document ID 1313). Full-shift area samples showed most airborne beryllium levels below the preceding PEL: 76 percent of area samples collected between 1983 and 1992 were at or below 0.1 μg/m3 and less than 1 percent exceeded 2 μg/m3; short-term breathing zone measurements collected between 1981 and 1992 had a median of 0.3 μg/m3; and personal lapel samples collected at the plant beginning in 1991 had a median of 0.2 μg/m3 (Kreiss et al., 1996).
Results from the Elmore, OH beryllium metal, alloy, and oxide production plant and the Cullman, AL machining facility also showed significant risk of sensitization and CBD among workers with exposures below the preceding TWA PEL. Schuler et al. (2012, Document ID 0473) found 17 cases of sensitization (8.6 percent) among Elmore, OH workers within the first three quartiles of LTW average exposure (198 workers with LTW average total mass exposures lower than 1.1 μg/m3) and 4 cases of CBD (2.2 percent) within those quartiles of LTW average exposure (183 workers with LTW average total mass exposures lower than 1.07 μg/m3; note that follow-up time of up to 6 years for all study participants was very short for development of CBD). At the Cullman, AL machining facility, Newman et al. (2001, Document ID 1354) reported 22 (9.4 percent) sensitized workers among 235 tested in 1995-1999, 13 of whom were diagnosed with CBD within the study period. Personal lapel samples collected between 1980 and 1999 indicate that median exposures were generally well below the preceding PEL (≤0.35 μg/m3 in all job titles except maintenance (median 3.1 μg/m3 during 1980-1995) and gas bearings (1.05 μg/m3 during 1980-1995)).
Although risk will be reduced by compliance with the new TWA PEL, evidence in the epidemiological studies reviewed in section VI, Risk Assessment, shows that significant risk of sensitization and CBD could remain in workplaces with exposures as low as the new action level of 0.1 μg/m3. For example, Schuler et al. (2005, Document ID 0919) reported substantial prevalences of sensitization (6.5 percent) and CBD (3.9 percent) among 152 workers at the Reading, PA facility screened with the BeLPT in 2000. These results showed significant risk at this facility, even though airborne exposures were primarily below both the preceding and final TWA PELs due to the low percentage of beryllium in the metal alloys used (median general area samples ≤0.1 μg/m3, 97% < 0.5 μg/m3; 93% of personal lapel samples below the new TWA PEL of 0.2 μg/m3). The only group of workers with no cases of sensitization or CBD, a group of 26 office administration workers, was the group with exposures below the new action level of 0.1 μg/m3 (median personal sample 0.01 μg/m3, range <0.01-0.06 μg/m3) (Schuler et al., 2005). The Schuler et al. (2012, Document ID 0473) study of short-term workers in the Elmore, OH facility found three cases (4.6%) of sensitization among 66 workers with total mass LTW average exposures below 0.1 μg/m3. All three of these sensitized workers had LTW average exposures of approximately 0.09 μg/m3.
Furthermore, cases of sensitization and CBD continued to arise in the Cullman, AL machining plant after control measures implemented beginning in 1995 brought median airborne exposures below 0.2 μg/m3 (personal lapel samples between 1996 and 1999 in machining jobs had a median of 0.16 μg/m3 and the median was 0.08 μg/m3 in non-machining jobs) Start Printed Page 2549(Madl et al., 2007, Document ID 1056, Table IV). At the time that Newman et al. (2001, Document ID 1354) 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 and had therefore benefitted to some extent from the exposure reductions. 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). A later study by Madl. et al. (2007, Document ID 1056) reported seven sensitized workers who had been hired between 1995 and 1999, of whom four had developed CBD as of 2005 (Table II; total number of workers hired between 1995 and 1999 not reported).
The enhanced industrial hygiene programs that have proven effective in several facilities demonstrate the importance of minimizing both airborne exposure and dermal contact to effectively reduce risk of sensitization and CBD. Exposure control programs that have used a combination of engineering controls, PPE, and stringent housekeeping measures to reduce workers' airborne exposure and dermal contact have substantially lowered risk of sensitization among newly-hired workers.
Of 97 workers hired between 2000 and 2004 in the Tucson, AZ plant after the introduction of a comprehensive program which included the use of respiratory protection (1999) and latex gloves (2000), one case of sensitization was identified (1 percent) (Cummings et al., 2007, Document ID 1369). In Elmore, OH, 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 percent (Bailey et al., 2010, Document ID 0676). In the Reading, PA facility, after workers' exposures were reduced to below 0.1 μg/m3 and PPE to prevent dermal contact was instituted, only one (2.2 percent) of 45 workers hired was sensitized (Thomas et al. 2009, Document ID 0590). And, in the aluminum smelters discussed by Taiwo et al. (2008, Document ID 0621), where available exposure samples from four plants 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).
OSHA notes that 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 adequately 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 studies examining the post-2000 worker cohorts with very low exposures in Tucson, Reading, and Elmore (Cummings et al. 2007, Document ID 1369; Thomas et al. 2009, (0590); Bailey et al. 2010, (0676)). 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) (Madl et al., 2007, Document ID 1056, Table III). 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, Document ID 1070), and workers employed only in administration at a beryllium ceramics facility (Kreiss et al., 1996, Document ID 1477). Therefore, there is some evidence that cases of CBD can occur in work environments where beryllium exposures are quite low.
In summary, the epidemiological literature on beryllium sensitization and CBD that OSHA's risk assessment relied on show sufficient occurrence of sensitization and CBD to be considered significant within the meaning of the OSH Act. These demonstrated risks are far in excess of 1 in 1,000 among workers who had full-shift exposures well below the preceding TWA PEL of 2 μg/m and workers who had median full-shift exposures down to the new action level of 0.1 μg/m . These health effects occurred among populations of workers whose follow-up time was much less than 45 years. As stated 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 of occupational exposure to airborne beryllium is likely to be higher than the prevalence of CBD observed among these workers.
In either case, based on these studies, the risks to workers from long-term exposure at the preceding TWA PEL and below are clearly significant. OSHA's review of epidemiological studies further showed that worker protection programs that effectively reduced the risk of beryllium sensitization and CBD incorporated engineering controls, work practice controls, and personal protective equipment (PPE) that reduce workers' airborne beryllium exposure and dermal contact with beryllium. OSHA has therefore determined that an effective worker protection program should incorporate both airborne exposure reduction and dermal protection provisions.
OSHA's conclusions on significance of risk at the final PEL and action level are further supported by its analysis of the data set provided to OSHA by NJH from which OSHA derived additional information on sensitization and CBD at exposure levels of interest. 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 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 (0.9 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 new TWA PEL of 0.2 μg/m3, and extensive exposure data collected in workers' breathing zones, as is preferred by OSHA. Unlike the Tucson, Reading, and Elmore facilities after 2000, 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 estimating exposure accounting for respirators. Also unlike the Tucson, Elmore, and Reading facilities, glove use was not reported to be mandatory in the Cullman facility. Therefore, 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 used at other facilities.
OSHA analyzed the prevalence of beryllium sensitization and CBD among Start Printed Page 2550workers at the Cullman facility who were exposed to airborne beryllium levels at and below the preceding TWA PEL of 2 μg/m3. In addition, a statistical modeling analysis of the NJH 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 section VI, Risk Assessment and in the background document (Risk Analysis of the NJH Data Set from the Beryllium Machining Facility in Cullman, Alabama—CBD and Sensitization, OSHA, 2016).
Tables VII-1 and VII-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 data set, including workers with and without a diagnosis of CBD.
Table VII-1—Prevalence of Sensitization and CBD by LTW Average Exposure Quartile in NJH Data Set
|LTW average exposure (μg/m3)||Group size||Sensitized only||CBD||Total||Total (%)||CBD (%)|
|Source: Section VI, Risk Assessment.|
Table VII-2—Prevalence of Sensitization and CBD by Highest-Exposed Job Exposure Quartile in NJH Data Set
|HEJ exposure (μg/m3)||Group size||Sensitized only||CBD||Total||Total (%)||CBD (%)|
|Source: Section VI, Risk Assessment.|
The preceding PEL of 2 μg/m is close to the upper bound of the highest quartile of LTW average (0.51-2.15 μg/m ) and HEJ (0.954-2.213 μg/m ) exposure levels. In the highest quartile of LTW average exposure, there were 12 cases of sensitization (15.4 percent), including eight (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 ).
The new TWA 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 six (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 8-9 percent. OSHA considers these rates to be evidence that the risks of developing sensitization and CBD are significant among workers exposed at and below the preceding TWA PEL, and even below the new TWA PEL. These risks are much higher than the benchmark for significant risk of 1 in 1,000. Much lower prevalences of sensitization and CBD were found among workers with exposure levels less than or equal to about 0.08 μg/m3, although these risks are still significant. Two sensitized workers (2.2 percent), including one case of CBD (1.0 percent), were found among workers with LTW average exposure levels less than or equal to 0.08 μg/m3. One case of sensitization (1.2 percent) and no cases of CBD were found among workers with HEJ exposures of at most 0.086 μg/m3. Strict control of airborne exposure to levels below 0.1 μg/m3 using engineering and work practice controls can, therefore, substantially 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 VIII, Summary of the Economic Analysis and Regulatory Flexibility Analysis), the Agency finds that workers in facilities that meet the action level of 0.1 μg/m3 will face lower risks of sensitization and CBD than workers in facilities that cannot meet the action level.
Table VII-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 or her employment.Start Printed Page 2551
Table VII-3—Prevalence of Sensitization and CBD by Cumulative Exposure Quartile in NJH Data Set
|Cumulative exposure (μg/m3-yrs)||Group size||Sensitized only||CBD||Total||Total %||CBD %|
|Source: Section VI, Risk Assessment.|
A 45-year working lifetime of occupational exposure at the preceding PEL would result in 90 μg/m3-years of exposure, 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 previous PEL. Workers with 45 years of exposure to the new TWA PEL of 0.2 μg/m3 would have a cumulative exposure (9 μg/m3-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 the higher exposure levels (<1.467 μg/m3-years). The third cumulative quartile, at which a sharp increase in sensitization and CBD appears, is bounded by 1.468 and 7.008 μg/m3-years. This is equivalent to 0.73-3.50 years of exposure at the preceding PEL of 2 μg/m3, or 7.34-35.04 years of exposure at the new TWA PEL of 0.2 μg/m3. Prevalence of both sensitization and CBD is substantially lower in the second cumulative quartile (0.148-1.467 μg/m3-years). This is equivalent to approximately 0.7 to 7 years at the new TWA PEL of 0.2 μg/m3, or 1.5 to 15 years at the action level of 0.1 μg/m3. Risks at all levels of cumulative exposure presented in Table 3 are significant. These findings support OSHA's determination that maintaining exposure levels below the new TWA PEL will help to protect workers against risk of beryllium sensitization and CBD. Moreover, while OSHA finds that significant risk remains at the PEL, OSHA's analysis shows that further reductions of risk will ensue if employers are able to reduce exposure to the action level or even below.
Lung cancer, a frequently fatal disease, is a well-recognized material impairment of health. OSHA has determined that beryllium causes lung cancer based on an extensive review of the scientific literature regarding beryllium and cancer. This review included an evaluation of the human epidemiological, animal cancer, and mechanistic studies described in section V, Health Effects. OSHA's conclusion that beryllium is carcinogenic is supported by the findings of expert public health and governmental organizations such as the International Agency for Research on Cancer (IARC), which has determined beryllium and its compounds to be carcinogenic to humans (Group 1 category) (IARC, 2012, Document ID 0650); the National Toxicology Program (NTP), which classifies beryllium and its compounds as known carcinogens (NTP, 2014, Document ID 0389); and the Environmental Protection Agency (EPA), which considers beryllium to be a probable human carcinogen (EPA, 1998, Document ID 0661).
OSHA's review of epidemiological studies of lung cancer mortality among beryllium workers found that most of them did not characterize exposure levels sufficiently to evaluate the risk of lung cancer at the preceding and new TWA PELs. However, as discussed in this preamble at section V, Health Effects and section VI, Risk Assessment, Schubauer-Berigan et al. published a quantitative risk assessment based on beryllium exposure and lung cancer mortality among 5,436 male workers first employed at beryllium processing plants in Reading, PA, Elmore, OH, and Hazleton, PA, prior to 1970 (Schubauer-Berigan et al., 2011, Document ID 1265). This 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 LTW average exposure of less than 1.5 μg/m3, while the median worker from Elmore had a LTW average 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 the preliminary risk assessment for lung cancer on the Schubauer-Berigan risk analysis.
Schubauer-Berigan et al. (2011, Document ID 1265) analyzed the data set using a variety of exposure-response modeling approaches, described in this preamble at section VI, Risk Assessment. The authors found that lung cancer mortality risk was strongly and significantly correlated with mean, cumulative, and maximum measures of workers' exposure to beryllium (all of the models reported in the study). They selected the best-fitting models to generate risk estimates for male workers with a mean exposure of 0.5 μg/m (the current NIOSH Recommended Exposure Limit for beryllium). In addition, they estimated the daily weighted average exposure that would be associated with an excess lung cancer mortality risk of one in one thousand (.005 μg/m to .07 μg/m depending on model choice). At OSHA's request, the authors also estimated excess lifetime risks for workers with mean exposures at the preceding TWA PEL of 2 μg/m as well as at each of the alternate TWA PELs that were under consideration: 1 μg/m , 0.2 μg/m , and 0.1 μg/m . Table VII-4 presents the estimated excess risk of lung cancer mortality associated with various levels of beryllium exposure, based on the final models presented in Schubauer-Berigan et al' s risk assessment.
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Table VII-4—Excess Risk of Lung Cancer Mortality per 1,000 Male Workers at Alternate PELs (based on Schubauer-Berigan et al., 2011)
|Exposure-response model||Mean exposure|
|0.1 μg/m3||0.2 μg/m3||0.5 μg/m3||1 μg/m3||2 μg/m3|
|Best monotonic PWL-all workers||7.3||15||45||120||140|
|Best monotonic PWL—excluding professional and asbestos workers||3.1||6.4||17||39||61|
|Best categorical—all workers||4.4||9||25||59||170|
|Best categorical—excluding professional and asbestos workers||1.4||2.7||7.1||15||33|
|Power model—all workers||12||19||30||40||52|
|Power model—excluding professional and asbestos workers||19||30||49||68||90|
|Source: Schubauer-Berigan, Document ID 0521, pp. 6-10.|
The lowest estimate of excess lung cancer deaths from the six final models presented by Schubauer-Berigan et al. is 33 per 1,000 workers exposed at a mean level of 2 μg/m3, the preceding TWA PEL. Risk estimates as high as 170 lung cancer deaths per 1,000 result from the other five models presented. Regardless of the model chosen, the excess risk of about 33 to 170 per 1,000 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 new PEL of 0.2 μg/m3 is expected to reduce these risks significantly, to somewhere between 2.7 and 30 excess lung cancer deaths per 1,000 workers. At the new action level of 0.1 μg/m3, risk falls within the range of 1.4 to 19 excess lung cancer deaths. These risk estimates still fall above the threshold of 1 in 1,000 that OSHA considers clearly significant. However, the Agency believes the lung cancer risks should be regarded as less certain than the risk estimates for CBD and sensitization discussed previously. While the risk estimates for CBD and sensitization at the preceding and new TWA PELs were determined from exposure levels observed in occupational studies, the lung cancer risks were extrapolated from much higher exposure levels.
As discussed throughout this section, OSHA used the best available scientific evidence to identify adverse health effects of occupational 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, CBD, and beryllium sensitization, and has evaluated the risk of these effects from exposures allowed under the preceding and new TWA PELs. The Agency has, additionally, reviewed the medical literature, as well as previous policy determinations and case law regarding material impairment of health, and has determined that CBD, at all stages, and lung cancer constitute material health impairments.
OSHA has determined that long-term exposure to beryllium at the preceding TWA PEL would pose a risk of CBD and lung cancer greater than the risk of 1 per 1,000 exposed workers the Agency considers clearly significant, and that adoption of the new TWA PEL, action level, and dermal protection requirements of the final standards will substantially reduce this risk. OSHA believes substantial evidence supports its determinations, including its choices of the best available published studies on which to base its risk assessment, its examination of the prevalence of sensitization and CBD among workers with exposure levels comparable to the preceding TWA PEL and new TWA PEL in the NJH data set, and its selection of the Schubauer-Berigan QRA to form the basis for its lung cancer risk estimates. The previously-described analyses demonstrate that workers with occupational exposure to airborne beryllium at the preceding PEL face risks of developing CBD and dying from lung cancer that far exceed the value of 1 in 1,000 used by OSHA as a benchmark of clearly significant risk. Furthermore, OSHA's risk assessment indicates that risk of CBD and lung cancer can be significantly reduced by reduction of airborne exposure levels, and that dermal protection measures will additionally help reduce risk of sensitization and, therefore, of CBD.
OSHA's risk assessment also indicates that, despite the reduction in risk expected with the new PEL, the risks of CBD and lung cancer to workers with average exposure levels of 0.2 μg/m3 are still significant and could extend down to 0.1 μg/m3, although there is greater uncertainty in this finding for 0.1 μg/m3 since there is less information available on populations exposed at and below this level. Although significant risk remains at the new TWA PEL, OSHA is also required to consider the technological and economic feasibility of the standard in determining exposure limits. As explained in Section VIII, Summary of the Final Economic Analysis and Final Regulatory Flexibility Analysis, OSHA determined that the new TWA PEL of 0.2 μg/m3 is both technologically and economically feasible in the general industry, construction, and shipyard sectors. OSHA was unable to demonstrate, however, that a lower TWA PEL of 0.1 μg/m3 would be technologically feasible. Therefore, OSHA concludes that, in setting a TWA PEL of 0.2 μg/m3, the Agency is reducing the risk to the extent feasible, as required by the OSH Act (see section II, Pertinent Legal Authority). In this context, the Agency finds that the action level of 0.1 μg/m3, dermal protection requirements, and other ancillary provisions of the final rule are critically important in reducing the risk of sensitization, CBD, and lung cancer among workers exposed to beryllium. Together, these provisions, along with the new TWA PEL of 0.2 μg/m3, will substantially reduce workers' risk of material impairment of health from occupational beryllium exposure.
VIII. Summary of the Final Economic Analysis and Final Regulatory Flexibility Analysis
OSHA's Final Economic Analysis and Final Regulatory Flexibility Analysis (FEA) addresses issues related to the costs, benefits, technological and economic feasibility, and the economic impacts (including impacts on small entities) of this final beryllium rule and evaluates regulatory alternatives to the final rule. Executive Orders 13563 and Start Printed Page 255312866 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). Executive Order 13563 emphasized the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules, and of promoting flexibility. The full FEA 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 FEA is to:
- Identify the establishments and industries potentially affected by the final rule;
- Estimate current exposures and the technologically feasible methods of controlling these exposures;
- Estimate the benefits resulting from employers coming into compliance with the final rule in terms of reductions in cases of lung cancer, chronic beryllium disease;
- Evaluate the costs and economic impacts that establishments in the regulated community will incur to achieve compliance with the final rule;
- Assess the economic feasibility of the final rule for affected industries; and
- Assess the impact of the final rule on small entities through a Final Regulatory Flexibility Analysis (FRFA), to include an evaluation of significant regulatory alternatives to the final rule that OSHA has considered.
Significant Changes to the FEA Between the Proposed Standards and the Final Standards
OSHA made changes to the Preliminary Economic Analysis (PEA) for several reasons:
- Changes to the rule, summarized in Section I of the preamble and discussed in detail in the Summary and Explanation;
- Comments on the PEA;
- Updates of economic data; and
- Recognition of errors in the PEA.
OSHA revised its technological and economic analysis in response to these changes and to comments received on the NPRM. The FEA contains some costs that were not included in the PEA and updates data to use more recent data sources and, in some cases, revised methodologies. Detailed discussions of these changes are included in the relevant sections throughout the FEA.
The Final Economic Analysis contains the following chapters:
Chapter I. Introduction
Chapter II. Market Failure and 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. Final Regulatory Flexibility Analysis
Table VIII-1 provides a summary of OSHA's best estimate of the costs and benefits of the final rule using a discount rate of 3 percent. As shown, the final rule is estimated to prevent 90 fatalities and 46 beryllium-related illnesses annually once it is fully effective, and the estimated cost of the rule is $74 million annually. Also as shown in Table VIII-1, the discounted monetized benefits of the final rule are estimated to be $561 million annually, and the final rule is estimated to generate net benefits of $487 million annually. Table VIII-1 also presents the estimated costs and benefits of the final rule using a discount rate of 7 percent.
Table VIII-1—Annualized Benefits, Costs and Net Benefits of OSHA's Final Beryllium Standard
[3 Percent Discount Rate, 2015 dollars]
|Beryllium Work Areas||129,648|
|Written Exposure Control Plan||2,339,058|
|Protective Work Clothing & Equipment||1,985,782|
|Hygiene Areas and Practices||2,420,584|
|Total Annualized Costs (Point Estimate)||73,868,230|
|Annual Benefits: Number of Cases Prevented:|
|Fatal Lung Cancers (Midpoint Estimate)||4|
|Fatal Chronic Beryllium Disease||86|
|Monetized Annual Benefits (Midpoint Estimate)||$560,873,424|
|Sources: US DOL, OSHA, Directorate of Standards and Guidance, Office of Regulatory Analysis|
The remainder of this section (Section VIII) of the preamble is organized as follows:
B. Market Failure and the Need for Regulation
C. Profile of Affected Industries
D. Technological Feasibility
E. Costs of Compliance
F. Economic Feasibility Analysis and Regulatory Flexibility Determination
G. Benefits and Net Benefits
H. Regulatory Alternatives
I. Final Regulatory Flexibility Analysis.
B. Market Failure and the Need for Regulation
Employees in work environments addressed by the final beryllium rule are exposed to a variety of significant hazards that can and do cause serious injury and death. As described in Chapter II of the FEA in support of the final rule, OSHA concludes there is a demonstrable failure of private markets to protect workers from exposure to unnecessarily high levels beryllium and that private markets, as well as information dissemination programs, workers' compensation systems, and tort liability options, each may fail to protect workers from beryllium exposure, resulting in the need for a more protective OSHA beryllium rule.
After carefully weighing the various potential advantages and disadvantages of using a regulatory approach to improve upon the current situation, OSHA concludes that, in the case of beryllium exposure, the final mandatory standards represent the best choice for reducing the risks to employees.
C. Profile of Affected Industries
Chapter III of the FEA presents profile data for industries potentially affected by the final beryllium rule. This Chapter provides the background data used throughout the remainder of the FEA including estimates of what industries are affected, and their economic and beryllium exposure characteristics. OSHA identified the following application groups as affected by the standard:
- Beryllium Production
- Beryllium Oxide Ceramics and Composites
- Nonferrous Foundries
- Secondary Smelting, Refining, and Alloying
- Precision Turned Products
- Copper Rolling, Drawing, and Extruding
- Fabrication of Beryllium Alloy Products
- Dental Laboratories
- Aluminum Production
- Coal-Fired Electric Power GenerationStart Printed Page 2554
- Abrasive Blasting
Table VIII-3 shows the affected industries by application group and selected economic characteristics of these affected industries. Table VIII-4 provides industry-by-industry estimates of current exposure.
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D. Technological Feasibility of the Final Standard on Occupational Exposure to Beryllium
The OSH Act requires OSHA to demonstrate that a proposed health standard is technologically feasible (29 U.S.C. 655(b)(5)). As described in the preamble to the final rule (see Section II, Pertinent Legal Authority), technological feasibility has been interpreted broadly to mean “capable of being done” (Am. Textile Mfrs. Inst. v. Donovan, 452 U.S. 490, 509-510 (1981) (“Cotton Dust”)). A standard is technologically feasible if the protective measures it requires already exist, can be brought into existence with available technology, or can be created with technology that can reasonably be expected to be developed, i.e., technology that “looms on today's horizon” (United Steelworkers of Am., AFL-CIO-CLC v. Marshall, 647 F.2d 1189, 1272 (D.C. Cir. 1980) (“Lead I”); Amer. Iron & Steel Inst. v. OSHA, 939 F.2d 975, 980 (D.C. Cir. 1991) (“Lead II”); AFL-CIO v. Brennan, 530 F.2 109, 121 (3rd Cir. 1975)). Courts have also interpreted technological feasibility to mean that, for health standards, a typical firm in each affected industry will reasonably be able to implement engineering and work practice controls that can reduce workers' exposures to meet the permissible exposure limit in most operations most of the time, without reliance on respiratory protection (see Lead I, 647 F.2d at 1272; Lead II, 939 F.2d at 990).
OSHA's technological feasibility analysis is presented in Chapter IV of the FEA. The technological feasibility analysis identifies the affected industries and application groups in which employees can reasonably be expected to be exposed to beryllium, summarizes the available air sampling data used to develop employee exposure profiles, and provides descriptions of engineering controls and other measures employers can take to reduce their employees' exposures to beryllium. For each affected industry sector or application group, OSHA provides an assessment of the technological feasibility of compliance with the final permissible exposure limit (PEL) of 0.2 μg/m3 as an 8-hour TWA and a 15-minute short-term exposure limit (STEL) of 2.0 μg/m3.
The technological feasibility analysis covers twelve application groups that correspond to specific industries or production processes that involve the potential for occupational exposures to materials containing beryllium and that OSHA has determined fall within the scope of this final beryllium standard. Within each of these application groups, exposure profiles have been developed to characterize the distribution of the available exposure measurements by job title or group of jobs. Each section includes descriptions of existing, or baseline, engineering controls for operations that generate beryllium exposure. For those job groups in which current exposures were found to exceed the final PEL, OSHA identifies and describes additional engineering and work practice controls that can be implemented to reduce exposure and achieve compliance with the final PEL. For each application group or industry, a final determination is made regarding the technological feasibility of achieving the proposed permissible exposure limits based on the use of engineering and work practice controls and without reliance on the use of respiratory protection. The determination is made based on the legal standard of whether the PEL can be achieved for most operations most of the time using such controls. In a separate chapter on short-term exposures, OSHA also analyzes the feasibility of achieving compliance with the Short-Term Exposure Limit (STEL).
The analysis is based on the best evidence currently available to OSHA, including a comprehensive review of the industrial hygiene literature, National Institute for Occupational Safety and Health (NIOSH) Health Hazard Evaluations and case studies of beryllium exposure, site visits conducted by an OSHA contractor (Eastern Research Group (ERG)), and inspection data from OSHA's Integrated Management Information System (IMIS) and OSHA's Information System (OIS). OSHA also obtained information on beryllium production processes, worker exposures, and the effectiveness of existing control measures from Materion Corporation, the primary beryllium producer in the United States, interviews with industry experts, and comments submitted to the rulemaking docket in response to the Notice of Proposed Rulemaking and informal public hearings. All of this evidence is in the rulemaking record.
The twelve application groups are:
- Primary Beryllium Production,
- Beryllium Oxide Ceramics and Composites,
- Nonferrous Foundries,
- Secondary Smelting, Refining, and Alloying, Including Handling of Scrap and Recycled Materials,
- Precision Turned Products,
- Copper Rolling, Drawing, and Extruding,
- Fabrication of Beryllium Alloy Products,
- Dental Laboratories,
- Abrasive Blasting,
- Coal-Fired Electric Power Generation,
- Aluminum Production
For discussion purposes, the twelve application groups are divided into four general categories based on the distribution of exposures in the exposure profiles: (1) Application groups in which baseline exposures for most jobs are already at or below the final PEL of 0.2 μg/m3; (2) application groups in which baseline exposures for one or more jobs exceed the final PEL of 0.2 μg/m3, but additional controls have been identified that could achieve exposures at or below the final PEL for most of the operations most of the time; (3) application groups in which exposures in one or more jobs routinely exceed the preceding PEL of 2.0 μg/m3, and therefore substantial reductions in exposure would be required to achieve the final PEL; and (4) application groups in which exposure to beryllium occurs due to trace levels of beryllium found in dust or fumes that nonetheless can result in exposures that exceed 0.1 μg/m3 as an 8-hour TWA under foreseeable conditions.
The application groups in category 1, where exposures for most jobs are already at or below the final PEL of 0.2 μg/m3, typically handle beryllium alloys containing a low percentage of beryllium (<2 percent) using processes that do not result in significant airborne exposures. These four application groups are (1) copper rolling, drawing, and extruding; (2) fabrication of beryllium alloy products; (3) welding; and (4) aluminum production. The handling of beryllium alloys in solid form is not expected to result in exposures of concern. For example, beryllium alloys used in copper rolling, drawing, and extruding typically contain 2 percent beryllium by weight or less (Document ID 0081, Attachment 1). One facility noted that the copper-beryllium alloys it used contained as little as 0.1 percent beryllium (Document ID 0081, Attachment 1). These processes, such as rolling operations that consist of passing beryllium alloys through a rolling press to conform to a desired thickness, tend to produce less particulate and fume than high energy processes. Exposures can be controlled using containment, exhaust ventilation, and work practices that include rigorous housekeeping. In addition, the heating of metal during welding operations results in the release of fume, but the beryllium in the welding fume accounts for a relatively small percentage of the beryllium exposure. Worker exposure to beryllium Start Printed Page 2583during welding activities is largely attributable to flaking oxide scale on the base metal, which can be reduced through chemically stripping or pickling the beryllium alloy piece prior to welding on it, and/or enhancing exhaust ventilation (Corbett, 2006; Kent, 2005; Materion Information Meeting, 2012).
For application groups in category 2, where baseline exposures for one or more jobs exceed the final PEL of 0.2 μg/m 3, but additional controls have been identified that could achieve exposures at or below the final PEL for most of the operations most of the time, workers may encounter higher content beryllium (20 percent or more by weight), or higher temperature processes (Document ID 1662, p. 4.) The application groups in the second category are: (1) Precision turned products and (2) secondary smelting, refining, and alloying. While the median exposures for most jobs in these groups are below the preceding PEL of 2.0 μg/m3, the median exposures for some jobs in these application groups exceed the final PEL of 0.2 μg/m3 when not adequately controlled. For these application groups, additional exposure controls and work practices will be required to reduce exposures to or below the final PEL for most operations most of the time. For example, personal samples collected at a precision turned products facility that machined pure beryllium metal and high beryllium content materials (40-60 percent) measured exposures on two machinists of 2.9 and 6.6 μg/m3 (ERG Beryllium Site 4, 2003). A second survey at this same facility conducted after an upgrade to the ventilation systems in the mill and lathe departments measured PBZ exposures for these machinists of 1.1 and 2.3 μg/m3 (ERG Beryllium Site 9, 2004), and it was noted that not all ventilation was optimally positioned, indicating that further reduction in exposure could be achieved. In 2007, the company reported that after the installation of enclosures on milling machines and additional exhaust, average exposures to mill and lathe operators were reduced to below 0.2 µg/m3 (ICBD, 2007). For secondary smelting operations, several surveys conducted at electronic recycling and precious metal recovery operations indicate that exposures for mechanical processing operators can be controlled to or below 0.2 µg/m3. However, for furnace operations in secondary smelting, the median value in the exposure profile exceeds the preceding PEL. Furnace operations involve high temperatures that produce significant amounts of fumes and particulate that can be difficult to contain. Therefore, the reduction of 8-hour average exposures to or below the final PEL may not be achievable for most furnace operations involved with secondary smelting of beryllium alloys. In these cases, the supplemental use of respiratory protection for specific job tasks will be needed to adequately protect furnace workers for operations where exposures are found to exceed 0.2 μg/m3 despite the implementation of all feasible engineering and work practice controls.
The application groups in category 3 include application groups for which the exposure profiles indicate that exposures in one or more jobs routinely exceed the preceding PEL of 2.0 μg/m3. The three application groups in this category are: (1) Beryllium production, (2) beryllium oxide ceramics production, and (3) nonferrous foundries. For the job groups in which exposures have been found to routinely exceed the preceding PEL, OSHA identifies additional exposure controls and work practices that the Agency has determined can reduce exposures to or below the final PEL, most of the time. For example, OSHA concluded that exposures to beryllium resulting from material transfer, loading, and spray drying of beryllium oxide powders can be reduced to or below 0.2 µg/m3 with process enclosures, ventilation hoods, and diligent housekeeping for material preparation operators working in beryllium oxide ceramics and composites facilities (FEA, Chapter IV-04). However, for furnace operations in primary beryllium production and nonferrous foundries, and shakeout operations at nonferrous foundries, OSHA recognizes that even after installation of feasible controls, supplemental use of respiratory protection may be needed to protect workers adequately (FEA, Chapter IV-03 and IV-05). The evidence in the rulemaking record is insufficient to conclude that these operations would be able to reduce the majority of the exposure to levels below 0.2 μg/m3 most of the time, and therefore some increased supplemental use of respiratory protection may be required for certain tasks in these jobs.
Category 4 includes application groups that encounter exposure to beryllium due to trace levels found in dust or fumes that nonetheless can exceed 0.1 μg/m3 as an 8-hour TWA under foreseeable conditions. The application groups in this category are (1) coal-fired power plants in which exposure to beryllium can occur due to trace levels of beryllium in the fly ash during very dusty maintenance operations, such as cleaning the air pollution control devices; (2) aluminum production in which exposure to beryllium can occur due to naturally occurring trace levels of beryllium found in bauxite ores used to make aluminum; and (3) abrasive blasting using coal and copper slag that can contain trace levels of beryllium. Workers who perform abrasive blasting using either coal or copper slag abrasives are potentially exposed to beryllium due to the high total exposure to the blasting media. Due to the very small amounts of beryllium in these materials, the final PEL for beryllium will be exceeded only during operations that generate excessive amount of visible airborne dust, for which engineering controls and respiratory protection are already required. However, the other workers in the general vicinity do not experience these high exposures if proper engineering controls and work practices, such as temporary enclosures and maintaining appropriate distance during the blasting or maintenance activities, are implemented.
During the rulemaking process, OSHA requested and received comments regarding the feasibility of the PEL of 0.2 μg/m3, as well as the proposed alternative PEL of 0.1 µg/m3 (80 FR 47565, 47780 (Aug. 7, 2015)). OSHA did this because it recognizes that significant risk of beryllium disease is not eliminated at an exposure level of 0.2 μg/m3. As discussed below, OSHA finds that the proposed PEL of 0.2 μg/m3 can be achieved through engineering and work practice controls in most operations most of the time in all the affected industry sectors and application groups, and therefore is feasible for these industries and application groups under the OSH Act. OSHA could not find, however, that the proposed alternative PEL of 0.1 μg/m3 is also feasible for all of the affected industry sectors and application groups.
The majority of commenters, including stakeholders in labor and industry, public health experts, and the general public, explicitly supported the proposed PEL of 0.2 µg/m3 (NIOSH, Document ID 1671, Attachment 1, p. 2; National Safety Council, 1612, p. 3; Beryllium Health and Safety Committee Task Group, 1655, p. 2; Newport News Shipbuilding, 1657, p. 1; National Jewish Health (NJH), 1664, p. 2; the Aluminum Association, 1666, p. 1; the Boeing Company, 1667, p. 1; American Industrial Hygiene Association, 1686, p. 2; United Steelworkers (USW), 1681, p. 7; Andrew Brown, 1636, p. 6; Department of Defense, 1684, p. 1). In addition, Materion Corporation, the sole Start Printed Page 2584primary beryllium production company in the U.S., and USW, jointly submitted a draft proposed rule that included an exposure limit of 0.2 μg/m3 (Document ID 0754, p. 4). In its written comments, Materion explained that it is feasible to control exposure to levels below 0.2 μg/m3 through the use of engineering controls and work practices in most, but not all, operations:
Based on many years' experience in controlling beryllium exposures, its vigorous product stewardship program in affected operations, and the judgment of its professional industrial hygiene staff, Materion Brush believes that the 0.2 μg/m3 PEL for beryllium, based on median exposures, can be achieved in most operations, most of the time. Materion Brush does recognize that it is not feasible to reduce exposures to below the PEL in some operations, and in particular, certain beryllium production operations, solely through the use of engineering and work practice controls (Document ID 1052).
On the other hand, the Nonferrous Founders' Society (NFFS) asserted that OSHA had not demonstrated that the final PEL of 0.2 µg/m3 was feasible for the nonferrous foundry industry (Document ID 1678, pp. 2-3). NFFS asserted that “OSHA has failed to meet its burden of proof that a ten-fold reduction to the current two micrograms per cubic meter limit is technologically or economically feasible in the non-ferrous foundry industry” (Document ID 1678, pp. 2-3; 1756, Tr. 18). In written testimony submitted as a hearing exhibit, NFFS claimed that OSHA's supporting documentation in the PEA had no “concrete assurance on technologic feasibility either by demonstration or technical documentation” (Document ID 1732, Appendix A, p. 4).
However, contrary to the NFFS comments, which are addressed at greater length in Section IV-5 of the FEA, OSHA's exposure profile is based on the best available evidence for nonferrous foundries; the exposure data are taken from NIOSH surveys, an ERG site visit, and the California Cast Metals Association (Document ID 1217; 1185; 0341, Attachment 6; 0899). Materion also submitted substantial amounts of monitoring data, process descriptions and information of engineering controls that have been implemented in its facilities to control beryllium exposure effectively, including operations that involve the production of beryllium alloys using the same types of furnace and casting operations as those conducted at nonferrous foundries producing beryllium alloys (Document ID 0719; 0720; 0723). Furthermore, Materion submitted the above-referenced letter to the docket stating that, based on its many years of experience controlling beryllium exposures, a PEL of 0.2 μg/m3 can be achieved in most operations, most of the time (Document ID 1052). Materion's letter is consistent with the monitoring data Materion submitted, and OSHA considers its statement regarding feasibility at the final PEL relevant to nonferrous foundries because Materion has similar operations in its facilities, such as beryllium alloy production. As stated in Section IV-5 of the FEA, the size and configuration of nonferrous foundries may vary, but they all use similar processes; they melt and pour molten metal into the prepared molds to produce a casting, and remove excess metal and blemishes from the castings (NIOSH 85-116, 1985). While the design may vary, the basic operations and worker job tasks are similar regardless of whether the casting metal contains beryllium.
In the NPRM, OSHA requested that affected industries submit to the record any available exposure monitoring data and comments regarding the effectiveness of currently implemented control measures to inform the Agency's final feasibility determinations. During the informal public hearings, OSHA asked the NFFS panel to provide information on current engineering controls or the personal protective equipment used in foundries claiming to have difficulty complying with the preceding PEL, but no additional information was provided (Document ID 1756; Tr. 24-25; 1785, p. 1). Thus, the NFFS did not provide any sampling data or other evidence regarding current exposure levels or existing control measures to support its assertion that a PEL of 0.2 μg/m3 is not feasible, and did not show that the data in the record are insufficient to demonstrate technological feasibility for nonferrous foundry industry.
In sum, while OSHA agrees that two of the operations in the nonferrous foundry industry, furnace and shakeout operations, employing a relatively small percentage of workers in the industry, may not be able to achieve the final PEL of 0.2 μg/m3 most of the time, evidence in the record indicates that the final PEL is achievable in the other six job categories in this industry. Therefore, in the FEA, OSHA finds the PEL of 0.2 μg/m3 is technologically feasible for the nonferrous foundry industry.
OSHA also recognizes that engineering and work practice controls may not be able to consistently reduce and maintain exposures to the final PEL of 0.2 μg/m3 in some job categories in other application groups, due to the processing of materials containing high concentrations of beryllium, which can result in the generation of substantial amounts of fumes and particulate. For example, the final PEL of 0.2 μg/m3 cannot be achieved most of the time for furnace operations in primary beryllium production and for some furnace operation activities in secondary smelting, refining, and alloying facilities engaged in beryllium recovery and alloying. Workers may need supplementary respiratory protection during these high exposure activities where exposures exceed the final PEL of 0.2 μg/m3 or STEL of 2.0 μg/m3 with engineering and work practice controls. In addition, OSHA has determined that workers who perform open-air abrasive blasting using mineral grit (i.e., coal slag) will routinely be exposed to levels above the final PEL (even after the installation of feasible engineering and work practice controls), and therefore, these workers will also be required to wear respiratory protection.
Overall, however, based on the information discussed above and the other evidence in the record and described in Chapter IV of the FEA, OSHA has determined that for the majority of the job groups evaluated exposures are either already at or below the final PEL, or can be adequately controlled to levels below the final PEL through the implementation of additional engineering and work practice controls for most operations most of the time. Therefore, OSHA concludes that the final PEL of 0.2 μg/m3 is technologically feasible.
In contrast, the record evidence does not show that it is feasible for most operations in all affected industries and application groups to achieve the alternative PEL of 0.1 μg/m3 most of the time. As discussed below, although a number of operations can achieve this level, they may be interspersed with operations that cannot, and OSHA sees value in having a uniform PEL that can be enforced consistently for all operations, rather than enforcing different PELs for the same contaminant in different operations.
Several commenters supported a PEL of 0.1 μg/m3. Specifically, Public Citizen; the American Federation of Labor and Congress of Industrial Organizations (AFL-CIO); the International Union, United Automobile, Aerospace, and Agriculture Implement Workers of America (UAW); North America's Building Trades Unions (NABTU); and the American College of Occupational and Environmental Medicine contended that OSHA should adopt this lower level because of the residual risk at 0.2 μg/m3
Start Printed Page 2585(Document ID 1689, p. 7; 1693, p. 3; 1670, p. 1; 1679, pp. 6-7; 1685, p. 1; 1756, Tr. 167). Two of these commenters, Public Citizen and the AFL-CIO, also contended that a TWA PEL of 0.1 μg/m3 is feasible (Document ID 1756, Tr. 168-169, 197-198). Neither of those commenters, however, submitted any additional evidence to the record that OSHA could rely on to conclude that a PEL of 0.1 μg/m3 is achievable.
On the other hand, the Beryllium Health and Safety Committee and NJH specifically rejected a PEL of 0.1 μg/m3 in their comments. They explained that they believed the proposed PEL of 0.2 μg/m3 and the ancillary provisions would reduce the prevalence of beryllium sensitization and chronic beryllium disease (CBD) and be the best overall combination for protecting workers when taking into consideration the analytical chemistry capabilities and economic considerations (Document ID 1655, p. 16; 1664, p. 2).
Based on the record evidence, OSHA cannot conclude that the alternative PEL of 0.1 μg/m3 is achievable most of the time for at least one job category in 8 of the 12 application groups or industries included in this analysis: Primary beryllium production; beryllium oxide ceramics and composites; nonferrous foundries; secondary smelting, refining, and alloying, including handling of scrap and recycled materials; precision turned products; dental laboratories; abrasive blasting; and coal-fired electric power generation. In general, OSHA's review of the available sampling data indicates that the alternative PEL of 0.1 μg/m3 cannot be consistently achieved with engineering and work practice controls in application groups that use materials containing high percentages of beryllium or that involve processes that result in the generation of substantial amounts of fumes and particulate. Variability in processes and materials for operations involving the heating or machining of beryllium alloys or beryllium oxide ceramics also makes it difficult to conclude that exposures can be routinely reduced to below 0.1 μg/m3. For example, in the precision turned products industry, OSHA has concluded that exposures for machinists machining pure beryllium or high beryllium alloys can be reduced to or below 0.2 μg/m3, but not 0.1 μg/m3. Additionally, OSHA has determined that job categories that involve high-energy operations will not be able to consistently achieve 0.1 μg/m3 (e.g., abrasive blasting with coal slag in open-air). These operations can cause workers to have elevated exposures even when available engineering and work practice controls are used.
In other cases, paucity of data or other data issues prevent OSHA from determining whether engineering and work practice controls can reduce exposures to or below 0.1 μg/m3 most of the time (see Chapter IV of the FEA). A large portion of the sample results obtained by OSHA for the dental laboratories industry and for two of the job categories in the coal-fired electric power generation industry (operations workers and routine maintenance workers) were below the reported limit of detection (LOD). Because the LODs for many of these samples were higher than 0.1 μg/m3, OSHA could not assess whether exposures were below 0.1 μg/m3. For example, studies of dental laboratories showed that use of well-controlled ventilation can consistently reduce exposures to below the LOD of 0.2 μg/m3. However, without additional information, OSHA cannot conclude that exposures can be reduced to or below 0.1 μg/m3 most of the time. Therefore, OSHA cannot determine if a PEL of 0.1 μg/m3 would be feasible for the dental laboratory industry.
The lack of available data has also prevented OSHA from determining whether exposures at or below of 0.1 μg/m3 can be consistently achieved for machining operators in the beryllium oxide ceramics and composites industry. As discussed in Section IV-4 of the FEA, the exposure profile for dry (green) machining and lapping and plate polishing (two tasks within the machining operator job category) is based on 240 full-shift PBZ samples obtained over a 10-year period (1994 to 2003). The median exposure levels in the exposure profile for green machining and lapping and polishing are 0.16 μg/m3 and 0.29 μg/m3, respectively. While the record indicates that improvements in exposure controls were implemented over time (Frigon, 2005, Document ID 0825; Frigon, 2004 (Document ID 0826)), data showing to what extent exposures have been reduced are not available. Nonetheless, because the median exposures for green machining are already below 0.2 μg/m3, and the median exposures for lapping and polishing are only slightly above the PEL of 0.2 μg/m3, OSHA concluded that the controls that have been implemented are sufficient to reduce exposures to at or below 0.2 μg/m3 most of the time. However, without additional information, OSHA cannot conclude that exposures could be reduced to or below 0.1 μg/m3 most of the time for these tasks.
Most importantly for this analysis, the available evidence demonstrates that the alternative PEL of 0.1 μg/m3 is not achievable in five out of the eight job categories in the nonferrous foundries industry: Furnace operator, shakeout operator, pouring operator, material handler, and molder. As noted above, the first two of these job categories, furnace operator and shakeout operator, which together employ only a small fraction of the workers in this industry, cannot achieve the final PEL of 0.2 μg/m3 either, but evidence in the record demonstrates that nonferrous foundries can reduce the exposures of most of the rest of the workers in the other six job categories to or below the final PEL of 0.2 μg/m3, most of the time. However, OSHA's feasibility determination for the pouring operator, material handler, and molder job categories, which together employ more than half the workers at these foundries, does not allow the Agency to conclude that exposures for those jobs can be consistently lowered to the alternative PEL of 0.1 μg/m3. See Section IV-5 of the FEA. Thus, OSHA cannot conclude that most operations in the nonferrous foundries industry can achieve a PEL of 0.1 μg/m3, most of the time. Accordingly, OSHA finds that the alternative PEL of 0.1 μg/m3 is not feasible for the nonferrous foundries industry.
OSHA has also determined either that information in the rulemaking record demonstrates that 0.1 μg/m3 is not consistently achievable in a number of operations in other affected industries or that the information is insufficient to establish that engineering and work practice controls can consistently reduce exposures to or below 0.1 μg/m3. Therefore, OSHA finds that the proposed alternative PEL of 0.1 μg/m3 is not appropriate, and the rule's final PEL of 0.2 μg/m3 is the lowest exposure limit that can be found to be technologically feasible through engineering and work practice controls in all of the affected industries and application groups included in this analysis.
Because of this inability to achieve 0.1 μg/m3 in many operations, if OSHA were to adopt a PEL of 0.1 μg/m3, a substantial number of employees would be required to wear respirators. As discussed in the Summary and Explanation for paragraph (f), Methods of Compliance, use of respirators in the workplace presents a number of independent safety and health concerns. Workers wearing respirators may experience diminished vision, and respirators can impair the ability of employees to communicate with one another. Respirators can impose physiological burdens on employees due to the weight of the respirator and increased breathing resistance Start Printed Page 2586experienced during operation. The level of physical work effort required, the use of protective clothing, and environmental factors such as temperature extremes and high humidity can interact with respirator use to increase the physiological strain on employees. Inability to cope with this strain as a result of medical conditions such as cardiovascular and respiratory diseases, reduced pulmonary function, neurological or musculoskeletal disorders, impaired sensory function, or psychological conditions can place employees at increased risk of illness, injury, and even death. The widespread, routine use of respirators for extended periods of time that may be required by a PEL of 0.1 μg/m3 creates more significant concerns than the less frequent respirator usage that is required by a PEL of 0.2 μg/m3.
Furthermore, OSHA concludes that it would complicate both compliance and enforcement of the rule if it were to set a PEL of 0.1 μg/m3 for some industries or operations and a PEL of 0.2 μg/m3 for the remaining industries and operations where technological feasibility at the lower PEL is either unattainable or unknown. OSHA may exercise discretion to issue a uniform PEL if it determines that the PEL is technologically feasible for all affected industries (if not for all affected operations) and that a uniform PEL would constitute better public policy. See Pertinent Legal Authority (discussing the Chromium decision). In declining to lower the PEL to 0.1 μg/m3 for any segment of the affected industries, OSHA has made that determination here. Therefore, OSHA has determined that the proposed alternative PEL of 0.1 μg/m3 is not appropriate.
OSHA also evaluated the technological feasibility of the final STEL of 2.0 μg/m3 and the alternative STEL of 1.0 μg/m3. An analysis of the available short-term exposure measurements presented in Chapter IV, Section 15 of the FEA indicates that elevated exposures can occur during short-term tasks such as those associated with the operation and maintenance of furnaces at primary beryllium production facilities, at nonferrous foundries, and at secondary smelting operations. Peak exposures can also occur during the transfer and handling of beryllium oxide powders. OSHA finds that in many cases, the control of peak short-term exposures associated with these intermittent tasks will be necessary to reduce workers' TWA exposures to or below the final PEL. The short-term exposure data presented in the FEA show that the majority (79%) of these exposures are already below 2.0 μg/m3.
A number of stakeholders submitted comments related to the proposed and alternative STELs. Some of these stakeholders supported a STEL of 2.0 μg/m3. Materion stated that a STEL of 2.0 μg/m3 for controlling the upper range of worker short term exposures is sufficient to prevent CBD (Document ID 1661, p. 3). Other commenters recommended a STEL of 1.0 μg/m3 (Document ID 1661, p. 19; 1681, p. 7). However, no additional engineering controls capable of reducing short term exposures to at or below 1.0 μg/m3 were identified by these commenters. OSHA provides a full discussion of the public comments in the Summary and Explanation section of this preamble. OSHA has determined that the implementation of engineering and work practice controls required to maintain full shift exposures at or below a PEL of 0.2 μg/m3 will reduce short term exposures to 2.0 μg/m3 or below, and that a STEL of 1.0 μg/m3 would require additional respirator use. Furthermore, OSHA notes that the combination of a PEL of 0.2 μg/m3 and a STEL of 2.0 μg/m3 would, in most cases, keep workers from being exposed to 15 minute intervals of 1.0 μg/m3. See Table IV.78 of Chapter IV of the FEA.
Therefore, OSHA concludes that the STEL of 2.0 μg/m3 can be achieved for most operations most of the time, given that most short-term exposures are already below 2.0 μg/m3. OSHA recognizes that for a small number of tasks, short-term exposures may exceed the final STEL, even after feasible control measures to reduce TWA exposure to or below the final PEL have been implemented, and therefore, some limited use of respiratory protection will continue to be required for short-term tasks in which peak exposures cannot be reduced to less than 2.0 μg/m3 through use of engineering controls.
After careful consideration of the record, including all available data and stakeholder comments in the record, OSHA has determined that a STEL of 2.0 μg/m3 is technologically feasible. Thus, as explained in the Summary and Explanation for paragraph (c), OSHA has retained the proposed value of 2.0 μg/m3 as the final STEL.
E. Costs of Compliance
In Chapter V, Costs of Compliance, OSHA assesses the costs to general industry, maritime, and construction establishments in all affected application groups of reducing worker exposures to beryllium to an eight-hour time-weighted average (TWA) permissible exposure limit (PEL) of 0.2 μg/m3 and to the final short-term exposure limit (STEL) of 2.0 μg/m3, as well as of complying with the final standard's ancillary provisions. These ancillary provisions encompass the following requirements: Exposure monitoring, regulated areas (and competent person in construction), a written exposure control plan, protective work clothing, hygiene areas and practices, housekeeping, medical surveillance, medical removal, familiarization, and worker training. This final cost assessment is based in part on OSHA's technological feasibility analysis presented in Chapter IV of the FEA; analyses of the costs of the final standard conducted by OSHA's contractor, Eastern Research Group (ERG); and the comments submitted to the docket in response to the request for information (RFI) as part of the Small Business Regulatory Enforcement Fairness Act (SBREFA) process, comments submitted to the docket in response to the PEA, comments during the hearings conducted in March 2016, and comments submitted to the docket after the hearings concluded.
Table VIII-4 presents summary of the annualized costs. All costs in this chapter are expressed in 2015 dollars and were annualized using a discount rate of 3 percent. (Costs at other discount rates are presented in the chapter itself). Annualization periods for expenditures on equipment are based on equipment life, and one-time costs are annualized over a 10-year period. Chapter V provides detailed explanation of the basis for these cost estimates.
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F. Economic Feasibility and Regulatory Flexibility Determination
In Chapter VI, OSHA investigates the economic impacts of its final beryllium rule on affected employers. This impact investigation has two overriding objectives: (1) To establish whether the final rule is economically feasible for all affected application groups/industries,
and (2) to determine if the Agency can certify that the final rule will not have a significant economic impact on a substantial number of small entities.
Table VIII-5 presents OSHA's screening analysis, which shows costs as percentage of revenues and as a percentage of profits. The chapter explains why these screening analysis Start Printed Page 2591results can reasonably be viewed as economically feasible. Section VIII.j shows similar results for small and very small entities.
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In Chapter VII, OSHA estimates the benefits and net benefits of the final beryllium rule. The methodology for these estimates largely remains the same as in the PEA. OSHA did not receive many comments challenging any aspect Start Printed Page 2597of the benefits analysis presented in the PEA. There are, however, a few significant alterations, such as: Using an empirical turnover rate as part of the estimation of exposure response functions, full analysis of the population model with varying turnover (a model only briefly presented in the PEA), and presentation of a statistical proportional hazard model in response to comment. The other large change to the benefits analysis is the result of the increase in the scope of the rule to protect workers in the construction and ship-building industries. In the proposed rule, coverage of these latter industries was only presented as an alternative and therefore were not included in the benefits in the PEA, but they are covered by the final rule.
This chapter proceeds in five steps. The first step estimates the numbers of diseases and deaths prevented by comparing the current (baseline) situation to a world in which the final PEL is adopted in a final standard, and in which employees are exposed throughout their working lives to either the baseline or the final PEL. The second step also assumes that the final PEL is adopted, but uses the results from the first step to estimate what would happen under a realistic scenario in which new employees will not be exposed above the final PEL, while employees already at work will experience a combination of exposures below the final PEL and baseline exposures that exceed the final PEL over their working lifetime. The comparison of these steps is given in Table VIII-6. OSHA also presents in Chapter VII similar kinds of results for a variety of other risk assessment and population models.
The third step covers the monetization of benefits. Table VIII-7 presents the monetization of benefits at various interest rates and monetization values.
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In the fourth step, OSHA estimates the net benefits of the final rule by comparing the monetized benefits to the costs presented in Chapter V of the FEA. These values are presented in Table VIII-8. The table shows that benefits exceed costs for all situations except for the low estimate of benefits using a 7 percent discount rate. The low estimate of benefits reflects the assumption that the ancillary provisions have no independent effect in reducing cases of CBD. OSHA considers this assumption to be very unlikely, based on the available evidence.
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In the fifth step, OSHA provides a sensitivity analysis to explore the robustness of the estimates of net benefits with respect to many of the assumptions made in developing and applying the underlying models. This is done because the models underlying each step inevitably need to make a variety of assumptions based on limited data. OSHA invited comments on each aspect of the data and methods used in this chapter, and received none specifically on the sensitivity analysis. Because dental laboratories constituted a significant source of both costs and benefits to the proposal, the PEA indicated that OSHA was particularly interested in comments regarding the appropriateness of the model, assumptions, and data for estimating the benefits to workers in that industry. Although the Agency did not receive any comments on this question directly, the American Dental Association's comments relevant to the underlying use of beryllium alloys in dental labs are addressed in Chapter III of the FEA. The Agency has not altered its main estimates of the exposure profile for dental laboratory workers, but provides sensitivity analyses in the FEA to examine the outcome if a lower percentage of dental laboratories were to substitute materials that do not contain beryllium for beryllium-containing materials. OSHA also estimates net benefits with a variety of scenarios in which dental laboratories are not included. All of these results are presented in Chapter VII of the FEA.
H. Regulatory Alternatives
Chapter VIII presents the costs, benefits and net benefits of a variety of regulatory alternatives.
I. Final Regulatory Flexibility Analysis
The Regulatory Flexibility Act, (RFA), Public Law 96-354, 94 Stat. 1164 (codified at 5 U.S.C. 601), requires Federal agencies to consider the economic impact that a final rulemaking will have on small entities. The RFA states that whenever an agency promulgates a final rule that is required to conform to the notice-and-comment rulemaking requirements of section 553 of the Administrative Procedure Act (APA), the agency shall prepare a final regulatory flexibility analysis (FRFA). 5 U.S.C. 604(a).
However, 5 U.S.C. 605(b) of the RFA states that Section 604 shall not apply to any final rule if the head of the agency certifies that the rule will not, if promulgated, have a significant economic impact on a substantial number of small entities. As discussed in Chapter VI of the FEA, OSHA was unable to so certify for the final beryllium rule.
For OSHA rulemakings, as required by 5 U.S.C. 604(a), the FRFA must contain:
1. A statement of the need for, and objectives of, the rule;
2. a statement of the significant issues raised by the public comments in response to the initial regulatory flexibility analysis, a statement of the assessment of the agency of such issues, and a statement of any changes made in the proposed rule as a result of such comments;
3. the response of the agency to any comments filed by the Chief Counsel for Advocacy of the Small Business Administration (SBA) in response to the proposed rule, and a detailed statement of any change made to the proposed rule in the final rule as a result of the comments;
4. a description of and an estimate of the number of small entities to which the rule will apply or an explanation of why no such estimate is available;
5. a description of the projected reporting, recordkeeping and other Start Printed Page 2600compliance requirements of the rule, including an estimate of the classes of small entities which will be subject to the requirement and the type of professional skills necessary for preparation of the report or record;
6. a description of the steps the agency has taken to minimize the significant economic impact on small entities consistent with the stated objectives of applicable statutes, including a statement of the factual, policy, and legal reasons for selecting the alternative adopted in the final rule and why each one of the other significant alternatives to the rule considered by the agency which affect the impact on small entities was rejected; and for a covered agency, as defined in section 609(d)(2), a description of the steps the agency has taken to minimize any additional cost of credit for small entities.
The Regulatory Flexibility Act further states that the required elements of the FRFA may be performed in conjunction with or as part of any other agenda or analysis required by any other law if such other analysis satisfies the provisions of the FRFA. 5 U.S.C. 605(a).
In addition to these elements, OSHA also includes in this section the recommendations from the Small Business Advocacy Review (SBAR) Panel and OSHA's responses to those recommendations.
While a full understanding of OSHA's analysis and conclusions with respect to costs and economic impacts on small entities requires a reading of the complete FEA and its supporting materials, this FRFA will summarize the key aspects of OSHA's analysis as they affect small entities.
• The Need for, and Objective of, the Rule
The objective of the final beryllium standard is to reduce the number of fatalities and illnesses occurring among employees exposed to beryllium. This objective will be achieved by requiring employers to install engineering controls where appropriate and to provide employees with the equipment, respirators, training, medical surveillance, and other protective measures necessary to perform their jobs safely. The legal basis for the rule is the responsibility given the U.S. Department of Labor through the Occupational Safety and Health Act of 1970 (OSH Act). The OSH Act provides that, in promulgating health standards dealing with toxic materials or harmful physical agents, the Secretary “shall set the standard which most adequately assures, to the extent feasible, on the basis of the best available evidence, that no employee will suffer material impairment of health or functional capacity even if such employee has regular exposure to the hazard dealt with by such standard for the period of his working life.” 29 U.S.C. 655(b)(5). See Section II of the preamble for a more detailed discussion.
Chronic beryllium disease (CBD) is a hypersensitivity, or allergic reaction, to beryllium that leads to a chronic inflammatory disease of the lungs. It takes months to years after final beryllium exposure before signs and symptoms of CBD occur. Removing an employee with CBD from the beryllium source does not always lead to recovery. In some cases CBD continues to progress following removal from beryllium exposure. CBD is not a chemical pneumonitis but an immune-mediated granulomatous lung disease. OSHA's final risk assessment, presented in Section VI of the preamble, indicates that there is significant risk of beryllium sensitization and chronic beryllium disease from a 45-year (working life) exposure to beryllium at the current TWA PEL of 2 μg/m3. The risk assessment further indicates that there is significant risk of lung cancer to workers exposed to beryllium at the current TWA PEL of 2 μg/m3. The final standard, with a lower PEL of 0.2 μg/m3, will help to address these health concerns. See the Health Effects and Risk Assessment sections of the preamble for further discussion.
• Summary of Significant Issues Raised by Comments on the Initial Regulatory Flexibility Analysis (IRFA) and OSHA's Assessment of, and Response to, Those Issues
This section of the FRFA focuses only on public comments concerning significant issues raised on the Initial Regulatory Flexibility Analysis (IRFA). OSHA received only one such comment.
The Non-Ferrous Founders' Society claimed that the costs of the rule will disproportionately affect small employers and result in job losses to foreign competition (Document ID 1678, p. 3). This comment is addressed in the FEA in the section on International Trade Effects in Chapter VI: Economic Feasibility Analysis and Regulatory Flexibility Determination. The summary of OSHA's response is that, in general, metalcasters in the U.S. have shortened lead times, improved productivity through computer design and logistics management, expanded design and development services to customers, and provided a higher quality product than foundries in China and other nations where labor costs are low (Document ID 1780, p. 3-12). All of these measures, particularly the higher quality of many U.S. metalcasting products and the ability of domestic foundries to fulfill orders quickly, are substantial advantages for U.S. metalcasters that may outweigh the very modest price increases that might occur due to the final rule. For a more detailed response please see the section on International Trade Effects in Chapter VI of the FEA.
Response to Comments by the Chief Counsel for Advocacy of the Small Business Administration and OSHA'S Response to Those Comments
The Chief Counsel for Advocacy of the Small Business Administration (“Advocacy”) did not provide OSHA with comments on this rule.
• A Description of, and an Estimate of, the Number of Small Entities To Which the Rule Will Apply
OSHA has analyzed the impacts associated with this final rule, including the type and number of small entities to which the standard will apply. In order to determine the number of small entities potentially affected by this rulemaking, OSHA used the definitions of small entities developed by the Small Business Administration (SBA) for each industry.
OSHA estimates that approximately 6.600 small business entities would be affected by the beryllium standard. Within these small entities, 33,800 workers are exposed to beryllium and would be protected by this final standard. A breakdown, by industry, of the number of affected small entities is provided in Table III-14 in Chapter III of the FEA.
OSHA estimates that approximately 5,280 very small entities—those with fewer than 20 employees—would be affected by the beryllium standard. Within these very small entities, 11,800 workers are exposed to beryllium and would be protected by the standard. A breakdown, by industry, of the number of affected very small entities is provided in Table III-15 in Chapter III of the FEA.
A Description of the Projected Reporting, Recordkeeping, and Other Compliance Requirements of the Rule
Tables VIII-9 and VIII-10 show the average costs of the beryllium standard and the costs of compliance as a percentage of profits and revenues by NAICS code for, respectively, small entities (classified as small by SBA) and very small entities (those with fewer than 20 employees). The full derivation of these costs is presented in Chapter V. The cost for SBA-defined small entities ranges from a low of $832 per entity for Start Printed Page 2601entities in NAICS 339116a: Dental Laboratories, to a high of about $599,836 for NAICS 331313: Alumina Refining and Primary Aluminum Production.
The annualized cost for very small entities ranges from a low of $542 for entities in NAICS 339116a: Dental Laboratories, to a high of about $34,222 for entities in NAICS 331529b: Other Nonferrous Metal Foundries (except Die-Casting).
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Description of the Steps OSHA Has Taken To Minimize the Significant Economic Impact on Small Entities Consistent With the Stated Objectives of Applicable Statutes and Statement of the Reasons For Selecting the Alternative Adopted in the Final Rule
OSHA has made a number of changes in the final beryllium rule that will serve to minimize significant impacts on small entities consistent with the objectives of the OSH Act. These changes are explained in more detail in Section XVI: Summary and Explanation in this preamble.
During the SBAR Panel, SERs requested a clearer definition of the triggers for medical surveillance. This concern was rooted in the cost of BeLPTs and the trigger of potential skin contact. For the final rule, the Agency has removed skin contact as a trigger for medical surveillance. OSHA has also reduced the frequency of medical surveillance from annually (in the proposed rule) to biennially in the final rule.
In the final rule, OSHA has added a performance option, as an alternative to scheduled monitoring, to allow employers to comply with exposure assessment requirements. This performance option should allow employers more flexibility, and often lower cost, in complying with the exposure assessment requirements.
Some SERs were already applying many of the protective controls and practices that would be required by the ancillary provisions of the standard. However, many SERs objected to the requirements regarding hygiene facilities. For this final rule, OSHA has concluded that all affected employers currently have hand washing facilities. OSHA has also concluded that no affected employers will be required to install showers. OSHA noted in the PEA that some facilities already have showers. There were no comments challenging the Agency's preliminary determinations regarding the existing availability of shower facilities or the means of preventing contamination, so the Agency concludes that all employers have showers where needed. Therefore, employers will not need to provide any new shower facilities to comply with the standard.
Similarly, in the PEA the Agency included no additional costs for readily accessible washing facilities, under the expectation that employers already have such facilities in place (PEA p. IX-19). Although the abrasive blasters exposed to beryllium in maritime and construction work may not have been expressly addressed in the PEA, OSHA notes that their employers are typically already required to provide readily accessible washing facilities to comply with other OSHA standards such as its sanitation standard at 29 CFR 1926.51(f)(1).
In the absence of additional comment, OSHA is not including any costs for washing facilities in the FEA.
OSHA's shipyard standard at 29 CFR 1915.58(e) requires handwashing facilities “at or adjacent to each toilet facility” and “equipped with . . . running water and soap, or with waterless skin-cleansing agents that are capable of . . . neutralizing the contaminants to which the employee may be exposed.” OSHA's construction standard at 29 CFR 1926.51(f)(1) requires “adequate washing facilities for employees engaged in . . . operations where contaminants may be harmful to the employees. Such facilities shall be in near proximity to the worksite and shall be so equipped as to enable employees to remove such substances.”Start Printed Page 2610
The Agency has determined that the long-term rental of modular units was representative of costs for a range of reasonable approaches to comply with the change room part of the provision. Alternatively, employers could renovate and rearrange their work areas in order to meet the requirements of this provision.
Finally, in the final rule, OSHA has extended the compliance deadlines for change rooms from one year to two years and for engineering controls from two years to three years.
• Regulatory Alternatives
For the convenience of those persons interested only in OSHA's regulatory flexibility analysis, this section repeats the discussion presented in Chapter VIII of the FEA, but only for the regulatory alternatives to the final OSHA beryllium standard that would have lowered costs.
Each regulatory alternative presented here is described and analyzed relative to the final rule. Where appropriate, the Agency notes whether the regulatory alternative, to have been a legitimate candidate for OSHA consideration, required evidence contrary to the Agency's final findings of significant risk and feasibility. For this chapter on the Final Regulatory Flexibility Analysis, the Agency is only presenting regulatory alternatives that would have reduced costs for small entities. (See Chapter VIII for the full list of all alternatives analyzed.) There are 14 alternatives that would have reduced costs for small entities (and for all businesses in total). Using the numbering scheme from Chapter VIII of the FEA, these are Regulatory Alternatives #1a, #2a, #2b, #5, #6, #7, #8, #9, #10, #11, #12, #13, #15, #16, #18, and #22. OSHA has organized these 16 cost-reducing alternatives (and a general discussion of considered phase-ins of the rule) into four categories: (1) Scope; (2) exposure limits; (3) methods of compliance; and (4) ancillary provisions.
(1) Scope Alternatives
The scope of the beryllium final rule applies to general industry work, construction and maritime activities. In addition, the final rule provides an exemption for those working with materials containing only trace amounts of beryllium (less than 0.1% by weight) when the employer has objective data that employee exposure to beryllium will remain below the action level as an 8-hour TWA under any foreseeable conditions.
The first set of regulatory alternatives would alter the scope of the final standard by differing in coverage of groups of employees and employers. Regulatory Alternatives #1a, #2a, and #2b would decrease the scope of the final standard.
Regulatory Alternative #1a would exclude all operations where beryllium exists only as a trace contaminant; that is, where the materials used contain less than 0.1% beryllium by weight, with no other conditions. OSHA has identified two industries with workers engaged in general industry work that would be excluded under Regulatory Alternative #1a: Primary aluminum production and coal-fired power generation.
Table VIII-11 presents, for informational purposes, the estimated costs, benefits, and net benefits of Regulatory Alternative #1a using alternative discount rates of 3 percent and 7 percent. In addition, this table presents the incremental costs, incremental benefits, and incremental net benefits of this alternative relative to the final rule. Table VIII-11 also breaks out costs by provision, and benefits by type of disease and by morbidity/mortality prevented. (Note: “morbidity” cases are cases where health effects are limited to non-fatal illness; in these cases there is no further disease progression to fatality).
As shown in Table VIII-11, Regulatory Alternative #1a would decrease the annualized cost of the rule from $73.9 million to $64.6 million using a 3 percent discount rate and from $76.6 million to $67.0 million using a 7 percent discount rate. Annualized benefits in monetized terms would decrease from $560.9 million to $515.7 million, using a 3 percent discount rate, and from $249.1 million to $229.0 million using a 7 percent discount rate. Net benefits would decrease from $487.0 million to $451.1 million using a 3 percent discount rate and from $172.4 million to $162.0 million using a 7 percent discount rate.
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Regulatory Alternative #2a would exclude construction and maritime work from the scope of the final standard. For example, this alternative would exclude abrasive blasters, pot tenders, and cleanup staff working in Start Printed Page 2612construction and shipyards who have the potential for airborne beryllium exposure during blasting operations and during cleanup of spent media.
Table VIII-12 presents the estimated costs, benefits, and net benefits of Regulatory Alternative #2a using alternative discount rates of 3 percent and 7 percent. In addition, this table presents the incremental costs, incremental benefits, and incremental net benefits of these alternatives relative to the final rule. Table VIII-12 also breaks out costs by provision and benefits by type of disease and by morbidity/mortality.
As shown in Table VIII-12, Regulatory Alternative #2a would decrease costs from $73.9 million to $62.0 million, using a 3 percent discount rate, and from $76.6 million to $64.4 million using a 7 percent discount rate. Annualized benefits would decrease from $560.9 million to $533.3 million, using a 3 percent discount rate, and from $249.1 million to $236.8 million using a 7 percent discount rate. Net benefits would change from $487.0 million to $471.3 million, using a 3 percent discount rate, and is essentially unchanged at a discount rate of 7 percent, with the final rule having net benefits of $172.4 million while the alternative has $172.5 million. Thus, at a 7 percent discount rate, the costs exceed the benefits for this alternative by $0.1 million per year. However, OSHA believes that for these industries, the cost estimate is severely overestimated because 45 percent of the costs are for exposure monitoring assuming that employers use the periodic monitoring option. Employers in this sector are far more likely to use the performance based monitoring options at considerably reduced costs. If this is the case, benefits would exceed costs even at a 7 percent discount rate.
Regulatory Alternative #2b would eliminate the ancillary provisions in the final rule for the shipyard and construction sectors and for any operations where beryllium exists only as a trace contaminant. Accordingly, only the final TWA PEL and STEL would apply to employers in these sectors and operations (through 29 CFR 1910.1000 Tables Z-1 and Z-2, 1915.1000 Table Z, and 1926.55 Appendix A). Operations in general industry where the ancillary provisions would be eliminated under Regulatory Alternative #2b include aluminum smelting and production and coal-powered utility facilities and any other operations where beryllium is present only as a trace contaminant (in addition to all operations in construction and shipyards).
As shown in Table VIII-13, Regulatory Alternative #2b would decrease the annualized cost of the rule from $73.9 million to $53.5 million using a 3 percent discount rate, and from $76.6 to $55.6 million using a 7 percent discount rate. Annualized benefits would decrease from $560.9 million to $493.3 million, using a 3 percent discount rate, and from $249.1 million to $219.1 million, using a 7 percent discount rate. Net benefits would decrease from $487.0 million to $439.8 million, using a 3 percent discount rate, and from $172.4 million to $163.5 million, using a 7 percent discount rate.
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