Occupational Exposure to Beryllium

DEPARTMENT OF LABOR

Occupational Safety and Health Administration

29 CFR Parts 1910, 1915, and 1926

[Docket No. OSHA-H005C-2006-0870]

RIN 1218-AB76

Occupational Exposure to Beryllium

AGENCY:

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

ACTION:

Final rule.

SUMMARY:

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/m

3

) as an 8-hour time-weighted average and 2.0 μg/m

3

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.

DATES:

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.

ADDRESSES:

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.

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

meilinger.francis2@dol.gov.

For technical inquiries, contact William Perry or Maureen Ruskin, Directorate of Standards and Guidance, Room N-3718, OSHA, U.S. Department of Labor, 200 Constitution Avenue NW., Washington, DC 20210; telephone (202) 693-1950.

SUPPLEMENTARY INFORMATION:

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

X. Federalism

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

Introduction

(a) Scope and Application

(b) Definitions

(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

(j) Housekeeping

(k) Medical Surveillance

(l) Medical Removal

(m) Communication of Hazards

(n) Recordkeeping

(o) Dates

(p) Appendix A (General Industry)

Authority and Signature

Amendments to Standards

Citation Method

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/m

3

) as an 8-hour time-weighted average (TWA) and 2.0 μg/m

3

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

industry, 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/m

3

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'

skin 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.

1

1

Note that the main analysis of costs and benefits presented in this FEA does not take into account the lag in effective dates but, instead, assumes that the rule takes effect in Year 1. To account for the lag in effective dates, OSHA has provided in the sensitivity analysis in Chapter VII of the FEA an estimate of its separate effects on costs and benefits relative to the main analysis. This analysis, which appears in Table VII-16 of the FEA, indicates that if employers delayed implementation of all provisions until legally required, and no benefits occurred until all provisions went into effect, this would decrease the estimated costs by 3.9 percent; the estimated benefits by 8.5 percent, and the estimated net benefits of the standard by 9.2 percent (to $442 million).

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]

Annualized Costs:

Control Costs

$12,269,190

Rule Familiarization

180,158

Exposure Assessment

13,748,676

Regulated Areas

884,106

Beryllium Work Areas

129,648

Medical Surveillance

7,390,958

Medical Removal

1,151,058

Written Exposure Control Plan

2,339,058

Protective Work Clothing & Equipment

1,985,782

Hygiene Areas and Practices

2,420,584

Housekeeping

22,763,595

Training

8,284,531

Respirators

320,885

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

Beryllium-Related Mortality

90

Beryllium Morbidity

46

Monetized Annual Benefits (Midpoint Estimate)

$560,873,424

Net Benefits:

Net Benefits

$487,005,194

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)).

Significant Risk

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

overprotection” (

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

at 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”).

Feasibility

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).

Technological Feasibility

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

OSHA'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)).

Economic Feasibility

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

a 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/m

3

as an 8-hour time-weighted average (TWA), and 25 µg/m

3

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/m

3

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/m

3

as an 8-hour TWA; 5 µg/m

3

as an acceptable ceiling concentration; and 25 µg/m

3

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/m

3

as an 8-hour TWA and 25 µg/m

3

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/m

3

to 1 µg/m

3

. 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/m

3

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/m

3

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/m

3

(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/m

3

, and adopted OSHA's PEL of 2 μg/m

3

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/m

3

could lead to CBD. The RFI also cited studies describing the relationship between beryllium sensitization and CBD (67 FR at 70708). In addition,

OSHA stated that beryllium had been identified as a carcinogen by organizations such as NIOSH, the International Agency for Research on Cancer (IARC), and the Environmental Protection Agency (EPA); and cancer had been evidenced in animal studies (67 FR at 70709).

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

et seq.

).

The Panel included representatives from OSHA, the Solicitor's Office of the Department of Labor, the Office of Advocacy within the Small Business Administration, and the Office of Information and Regulatory Affairs of the Office of Management and Budget. Small Entity Representatives (SERs) made oral and written comments on the 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/m

3

or higher, and that the greatest reduction in risk was achieved when exposures for all processes were lowered to 0.1 µg/m

3

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/m

3

(81 FR 36704-36759, June 7, 2016). The DOE action level triggers workplace precautions and control measures such as periodic monitoring, exposure

reduction or minimization, regulated areas, hygiene facilities and practices, respiratory protection, protective clothing and equipment, and warning signs (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/m

3

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.

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.

ATSDR, 2002.

The physical and chemical properties of beryllium were realized early in the 20th century, and it has since gained commercial importance in a wide range of industries. Beryllium is lightweight, hard, spark resistant, non-magnetic, and has a high melting point. It lends strength, electrical and thermal conductivity, and fatigue resistance to alloys (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).

Industrial Uses

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/m

3

(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/m

3

(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

pair 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.

2

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).

2

The five selected peer reviewers were John Balmes, MD, University of California-San Francisco; Patrick Breysse, Ph.D., Johns Hopkins University, Bloomberg School of Public Health; Terry Gordon, Ph.D., New York University School of Medicine; Milton Rossman, MD, University of Pennsylvania School of Medicine; Kyle Steenland, Ph.D., Emory University, Rollins School of Public Health.

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/m

3

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/m

3

and even below the action level of .1 µg/m

3

. 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

NPRM 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.

Introduction

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(CH

3

)

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.

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

Be

2

CO

3

(OH)/Be

2

CO

5

H

2

181.07

Not combustible or explosive

None.

Beryllium Sulfate

BeSO

4

105.1

Not combustible or explosive

Slightly soluble.

Beryllium Nitrate

BeN

2

O

6

/Be(NO

3

)

2

133.0

Enhances combustion of other substances

Very soluble (1.66 × 10

6

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

BeCl

2

79.9

Not combustible or explosive

Soluble.

Beryllium Fluoride

BeF

2

47.0

Not combustible or explosive

Very soluble.

Beryllium Phosphate

Be

3

(PO

4

)

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.

a. Solubility

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 (BeCl

2

), fluoride (BeF

2

), nitrate (Be(NO

3

)

2

), phosphate (Be

3

(PO

4

)

2

), and sulfate (tetrahydrate) (BeSO

4

· 4H

2

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(OH

2

)

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 (Be

2

CO

3

(OH)

2

), and sulfate (anhydrous) (BeSO

4

) 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

was greater than that of the single-constituent beryllium oxide powder. The authors speculated that copper in the particles rapidly dissolves, exposing the small inclusions of beryllium oxide, which have higher specific surface areas (SSA) 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

and biologically relevant toxicity endpoints of either sensitization or CBD.

Numerous studies have been conducted evaluating the particle size generated during basic industrial and machining operations. In a study by Cohen

et al.

(1983), a multi-cyclone sampler was utilized to measure the size mass distribution of the beryllium aerosol at a beryllium-copper alloy casting operation (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

area 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.

ER09JA17.000

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

lungs 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.

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/cm

2

, 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

preceding 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

poorly 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.

4. Metabolism

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/m

3

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/m

3

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/m

3

(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/m

3

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/m

3

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

exposure 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/m

3

and most were less than 10 μg/m

3

.' ” (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/m

3

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

time 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

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