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Introduction

Beryllium is a low-density metal that is used in a number of industries, including the automotive, aerospace, defense, medical, and electronics industries, for various applications because it is exceptionally strong, is light in weight compared with other metals, has high heat-absorbing capability, and has dimensional stability in a wide range of temperatures. The three forms of beryllium-containing materials used in manufacturing processes are beryllium alloys, metallic beryllium, and beryllium oxide. Beryllium alloys are made primarily with copper, nickel, or aluminum. The amount of beryllium in alloys depends on the desired strength and electric conductivity of the product. Beryllium-copper alloys are the most commonly used and are found in electric connectors and relays, bushings and bearings in aircraft and heavy machinery, submarine cable housing and pivots, switches in automobiles, telecommunication equipment, computers, home appliances, cellular phones, and connectors for fiber optics (Kolanz 2001; ATSDR 2002). The aeronautics and defense industries use alloys that have a high beryllium content (40-100%) to make electro-optical targeting and infrared countermeasure devices, missile systems, and radar systems (Kolanz 2001). Beryllium metal is used in aircraft disk brakes, fusion reactors, nuclear devices, satellite systems, missile-guidance systems, navigational systems, heat shields, high-speed computer and audio components, and x-ray machines for mammography. Applications of beryllium oxide include high-technology ceramics, electric insulators, gyroscopes, military-vehicle armor, rocket nozzles, crucibles, laser structural components, automotive ignition systems, and radar electronic countermeasure systems (Kolanz 2001; ATSDR 2002; Kreiss et al. 2007).

HISTORICAL REVIEW OF OCCUPATIONAL EXPOSURE LIMITS

It has long been recognized that exposure to beryllium in occupational settings poses health hazards, primarily in the forms of acute beryllium disease and chronic beryllium disease (CBD). In 1949, the U.S. Atomic Energy Commission (now the U.S. Department of Energy [DOE]) recommended the first occupational exposure limit (OEL) for beryllium of 2.0 μg/m3. That limit was adopted by the American Conference of Governmental Industrial Hygienists (ACGIH), the National Institute for Occupational Safety and Health (NIOSH), the Occupational Safety and Health Administration (OSHA), the American Industrial Hygiene Association, and the American National Standards Institute (see Table 1-1). The OEL of 2.0 μg/m3 still stands although it has been challenged on several occasions.

The basis of the original standard was an estimate of the toxicity of beryllium in relation to other metals. It was assumed that beryllium toxicity was comparable with that of heavy metals on an atom-for-



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Health Effects of Beryllium Exposure: A Literature Review 1 Introduction Beryllium is a low-density metal that is used in a number of industries, including the automotive, aerospace, defense, medical, and electronics industries, for various applications because it is exceptionally strong, is light in weight compared with other metals, has high heat-absorbing capability, and has dimensional stability in a wide range of temperatures. The three forms of beryllium-containing materials used in manufacturing processes are beryllium alloys, metallic beryllium, and beryllium oxide. Beryllium alloys are made primarily with copper, nickel, or aluminum. The amount of beryllium in alloys depends on the desired strength and electric conductivity of the product. Beryllium-copper alloys are the most commonly used and are found in electric connectors and relays, bushings and bearings in aircraft and heavy machinery, submarine cable housing and pivots, switches in automobiles, telecommunication equipment, computers, home appliances, cellular phones, and connectors for fiber optics (Kolanz 2001; ATSDR 2002). The aeronautics and defense industries use alloys that have a high beryllium content (40-100%) to make electro-optical targeting and infrared countermeasure devices, missile systems, and radar systems (Kolanz 2001). Beryllium metal is used in aircraft disk brakes, fusion reactors, nuclear devices, satellite systems, missile-guidance systems, navigational systems, heat shields, high-speed computer and audio components, and x-ray machines for mammography. Applications of beryllium oxide include high-technology ceramics, electric insulators, gyroscopes, military-vehicle armor, rocket nozzles, crucibles, laser structural components, automotive ignition systems, and radar electronic countermeasure systems (Kolanz 2001; ATSDR 2002; Kreiss et al. 2007). HISTORICAL REVIEW OF OCCUPATIONAL EXPOSURE LIMITS It has long been recognized that exposure to beryllium in occupational settings poses health hazards, primarily in the forms of acute beryllium disease and chronic beryllium disease (CBD). In 1949, the U.S. Atomic Energy Commission (now the U.S. Department of Energy [DOE]) recommended the first occupational exposure limit (OEL) for beryllium of 2.0 μg/m3. That limit was adopted by the American Conference of Governmental Industrial Hygienists (ACGIH), the National Institute for Occupational Safety and Health (NIOSH), the Occupational Safety and Health Administration (OSHA), the American Industrial Hygiene Association, and the American National Standards Institute (see Table 1-1). The OEL of 2.0 μg/m3 still stands although it has been challenged on several occasions. The basis of the original standard was an estimate of the toxicity of beryllium in relation to other metals. It was assumed that beryllium toxicity was comparable with that of heavy metals on an atom-for-

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Health Effects of Beryllium Exposure: A Literature Review TABLE 1-1 Selected Exposure Guidelines and Actions Taken on Beryllium Agency Year Guideline or Action Notes and References DOE 1949 2 µg/m3 OEL (DWA) DWA is averaged from samples over quarterly periods   1999 0.2 µg/m3 (8-h TWA action level) Action level triggers worker-protection measures; issued while waiting for OSHA to complete rule-making (64 Fed. Reg. 68854 [1999]).   2006 Worker safety and health program 71 Fed. Reg. 6858 (2006) ACGIH 1959 2 µg/m3 TLV (8-h TWA) ACGIH 2006   1975 A2 carcinogen (suspected human carcinogen) ACGIH 2006   1997 A1 carcinogen (confirmed human carcinogen) ACGIH 2006   1999 0.2 µg/m3 TLV (8-h TWA, inhalable particulate mass, sensitizer; notice to change) ACGIH 2006   2005 0.05 µg/m3 TLV (8-h TWA, inhalable particulate mass, sensitizer, skin exposure; notice of intended change) ACGIH 2006 NIOSH 1972 2 µg/m3 REL (8-h TWA) NIOSH 1972   1977 0.5 µg/m3 REL (10-h TWA) Potential occupational carcinogen; NIOSH recommended that OSHA reduce PEL (NIOSH 1977); not clear from documentation whether REL in 1977 was for 8 h or 10 h. NIOSH (2005) reports it as 10-h TWA OSHA 1971 2 µg/m3 PEL (8-h TWA) PEL was adopted from ANSI standard (OSHA 2002)   1975 1 µg/m3 PEL (8-h TWA; proposed value) Proposed value is based on presumption of carcinogenicity; never promulgated (40 Fed. Reg. 48814 [1975]; OSHA 2002)   1999, 2001 OSHA petitioned to issue an emergency temporary standard Petition denied by OSHA, but OSHA stated its intent to begin data-gathering (OSHA 2002)   2002 Request for information issued 67 Fed. Reg. 70700 (2002) AIHA 1964 2 µg/m3 hygienic standard (8-h TWA) AIHA 1964 ANSI 1970 2 µg/m3 OEL for particles ≤5 µm (8-h TWA) ANSI 1970 IARC 1993 Human carcinogen (Group 1) IARC 1993 EPA 1998 RfC = 0.02 µg/m3 Value based on sensitization and progression to CBD (EPA 1998a)     Air unit risk = 2.4 × 10−3 per µg/m3 Value based on lung cancer (EPA 1998a)     Community PEL (24-h ambient air limit) = 0.01 µg/m3 40 CFR § 61.32 ABBREVIATIONS: ACGIH, Agency for Toxic Substances and Disease Registry; AIHA, American Industrial Hygiene Association; ANSI, American National Standards Institute; CBD, chronic beryllium disease; DOE, U.S. Department of Energy; DWA, daily weighted average; EPA, U.S. Environmental Protection Agency; IARC, International Agency for Research on Cancer; NIOSH, National Institute for Occupational Safety and Health; OEL, occupational exposure limit; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; RfC, reference concentration (inhalation); RfD, reference dose (oral); TLV, Threshold Limit Value; TWA, time-weighted average.

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Health Effects of Beryllium Exposure: A Literature Review atom basis. Mercury and lead had occupational exposure limits of around 100 μg/m3, so that value was divided by 20 because the atomic weight of beryllium is about one-twentieth that of mercury and lead. The resulting value was divided by 2.5 to provide a margin of safety because understanding of CBD was lacking. The adequacy of the OEL of 2.0 μg/m3 was evaluated periodically in the 1960s; each time, it was deemed adequate because acute beryllium disease has become a rare occurrence and the incidence of CBD was considerably reduced, even though the standard was not routinely achieved at facilities (Kolanz 2001). Current scientific questions about exposure to beryllium in the workplace are related to CBD and cancer. Over the last 40 years, much has been learned about how beryllium causes CBD, and the diagnostic criteria for the disease have changed. Advances in medical and diagnostic technology allow physicians to identify beryllium exposed workers with evidence of sensitization or milder forms of CBD (see Chapter 3). Research into dose-response relationships indicates that particle size, chemical form, concentration, and genetic factors may all play a role in determining whether a person develops CBD. In addition, there has been debate over beryllium’s carcinogenic potential. In 1975, OSHA proposed to lower its permissible exposure limit to 1 μg/m3 on the presumption that beryllium was a carcinogen. However, that revision was never promulgated, because of a Supreme Court ruling that existing OSHA standards can be made more stringent only if there is documented evidence that there is significant risk in the workplace (Industrial Union Dept. AFL-CIO vs American Petroleum Institute, 448 US 607 [1980]). OSHA was petitioned in 1999 and 2001 to issue an emergency temporary standard. The petitions were denied, but the agency indicated that it would begin data-gathering to revisit the adequacy of the standard for protecting worker health. In 2002, the agency issued a formal request for information (67 Fed. Reg. 70700 [2002]), but it has not yet issued any updates. Other agencies have taken action in re-evaluating their occupational exposure guidelines for beryllium. In 1999, DOE established an action level of 0.2 μg/m3 intended to trigger workplace precautions and control measures to protect workers at DOE facilities (64 Fed. Reg. 68854 [1999]). That action level is applicable only to DOE and DOE-contractor facilities and was established because DOE considered the OEL of 2 μg/m3 to be inadequate to protect worker health. In 2005, ACGIH proposed to lower its Threshold Limit Value (TLV) for beryllium to 0.05 μg/m3 (ACGIH 2006). That lower value is intended to prevent sensitization and CBD. OTHER EXPOSURE GUIDELINES Exposure guidelines for beryllium designed for the general public have been established by the U.S. Environmental Protection Agency (EPA 1998a). For inhalation exposures, EPA has the reference concentration (RfC), which is defined as an estimate (with uncertainty spanning perhaps an order of magnitude or greater) of a continuous inhalation exposure of the human population (including susceptible subpopulations) that is likely to be without an appreciable risk of deleterious health effects during a lifetime. For beryllium, the principal health end point selected to derive the RfC was beryllium sensitization and progression to CBD. Observations from an occupational-exposure study (Kreiss et al. 1996) and a community-exposure study (Eisenbud et al. 1949) supported a lowest observed-adverse-effect level (LOAEL) of 0.20 μg/m3. That value was adjusted by applying two uncertainty factors of 3 to account for the poor quality of the exposure assessments in those and other supporting epidemiologic studies and to account for use of an LOAEL instead of a no-observed-adverse-effect level. The adjustment resulted in an RfC of 0.02 μg/m3. EPA also classifies beryllium as a likely human carcinogen on the basis of epidemiologic studies that found increases in lung cancer and supporting evidence from animal studies that beryllium induces lung cancer in rats and monkeys. For carcinogens, EPA calculates an inhalation unit risk, which is the upper-bound excess lifetime cancer risk estimated to result from continuous exposure to an agent at a concentration of 1 μg/m3. For beryllium, the unit risk is estimated to be 2.4 × 10−3 per μg/m3. The cancer dose-response assessment for that estimate was originally performed in 1987 and based on an

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Health Effects of Beryllium Exposure: A Literature Review occupational-exposure study (Wagoner et al. 1980). Dose-response assessments from animal studies yielded similar estimates of risk, but EPA considered epidemiologic data to be a better basis for quantifying cancer risks. In 1998, EPA noted that new epidemiologic studies had been published but found that they shared the same limitations as the Wagoner et al. (1980) study in lacking individual exposure monitoring or job-history data to support a better quantitative dose-response assessment. However, EPA also noted that a NIOSH study that was in the process of being published appeared to have exposure data that might be suitable for performing quantitative cancer estimates. Until those data were published, EPA recommended that its original unit risk of 2.4 × 10−3 per μg/m3 be retained. On the basis of that value, it was estimated that air concentrations of 0.04, 0.004, and 0.0004 μg/m3 would result in cancer risks of 1 × 10−4, 1 × 10−5, and 1 × 10−6, respectively. The NIOSH study was published in 2001 (Sanderson et al. 2001a), but EPA has issued no new reassessment of beryllium cancer risks. COMMITTEE’S TASK An ad hoc committee under the oversight of the standing Committee on Toxicology (COT) of the National Research Council was tasked with writing two reports in support of the development of chronic inhalation exposure levels for beryllium used in military aerospace applications. For this, its first report, the committee was asked to provide an independent review of the toxicologic, epidemiologic, and other relevant data on beryllium. It was asked to review both carcinogenic and noncarcinogenic effects. In its second report, which is in development, the committee will estimate chronic inhalation exposure levels for military personnel and civilian contractor workers that are unlikely to produce adverse health effects. The committee will provide carcinogenic risk estimates for various inhalation exposure levels. It will consider genetic susceptibility among worker subpopulations. If sufficient data are available, the committee will evaluate whether beryllium-alloy exposure levels should be different from those of other forms of beryllium because of differences in particle size. The committee will identify specific tests for worker surveillance and biomonitoring. It will also comment on the utility of the beryllium lymphocyte proliferation test (BeLPT). Specifically, the committee will determine the value of the borderline or a true positive test in predicting CBD, its utility in worker surveillance, further followup tests needed for workers with positive BeLPT (such as thin-slice computed-tomography, bronchoscopy and biopsy), the likelihood of developing CBD after a true positive test, and a standardized method to achieve consistent test results in different laboratories. The committee will consider whether there are more suitable tests that would be more accurate as screening or surveillance tools. The committee will also identify data gaps relevant to risk assessment of beryllium alloys and make recommendations for further research. COMMITTEE’S APPROACH To accomplish its first task, the committee held two meetings in February and April 2007. The meetings involved data-gathering sessions that were open to the public. The committee heard presentations from the U.S. Air Force and from researchers in the government and academe who were involved in beryllium research (see Preface for list of speakers). The committee also reviewed a large body of scientific literature on beryllium. The primary health concerns related to beryllium—sensitization, CBD, and lung cancer—make up the bulk of the literature. A much smaller database was found on other toxicity end points, such as reproductive and developmental effects. This report provides a survey of the literature on beryllium that was available by the end of April 2007. The purpose is to identify areas on which to focus a more critical review. In the second report, the committee will expand upon the first report by providing a more critical analysis of the literature (including any new publications), establishing exposure-based health-protection standards, and evaluating tests for screening and surveillance of workers.

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Health Effects of Beryllium Exposure: A Literature Review ORGANIZATION OF THE REPORT The remainder of this report is organized in four chapters. Chapter 2 reviews exposure factors important for assessing health risks associated with beryllium. It includes a review of the exposure assumptions that underlie existing exposure standards, consideration of exposures in natural and anthropogenic settings, and an examination of how physiochemical characteristics and particle sizes are associated with risk of disease. Chapter 3 provides an overview of the scientific literature on beryllium sensitization and CBD, including what is known about pathogenesis, mode of action, and genetic susceptibility. Chapter 4 focuses on the evidence of beryllium’s carcinogenic potential. Other health end points, such as reproductive and developmental effects, are reviewed in Chapter 5.