Managing Health Effects of Beryllium Exposure (2008)

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1 Introduction Beryllium is a low-density metal that is used in various applications in a number of industries—including the automotive, aerospace, defense, medical, and electronics industries—because it is exceptionally strong, is light in weight compared with other metals, has high heat-absorbing capability, and has dimen- sional stability in a wide range of temperatures. The three forms of beryllium- containing materials used in manufacturing processes are beryllium alloys, me- tallic 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 al- loys are the most commonly used and are found in electric connectors and re- lays, 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 (Ko- lanz 2001). Beryllium metal is used in aircraft disk-brake systems, fusion reac- tors, 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, rocket nozzles, crucibles, laser struc- tural components, automotive ignition systems, and radar electronic counter- measure 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 set- tings poses health hazards, primarily in the forms of acute beryllium disease and chronic beryllium disease (CBD). In 1949, the U.S. Atomic Energy Commission 10 

Introduction 11 (now the U.S. Department of Energy [DOE]) recommended the first occupa- tional exposure limit (OEL) for beryllium, 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, the Occupational Safety and Health Administration (OSHA), the American Industrial Hygiene Associa- tion, 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 beryl- lium in relation to other metals. It was assumed that beryllium toxicity was com- parable with that of heavy metals on an atom-for- atom basis. Mercury and lead had occupational exposure limits of around 100 µg/m3, and that value was di- vided 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 had become a rare occurrence and the incidence of CBD had become much lower. 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 indi- cates that particle size, chemical form, concentration, and genetic factors may all play roles 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. OSHA was petitioned in 1999 and 2001 to issue an emer- gency 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. The agency issued a formal request for information in 2002 (67 Fed. Reg. 70700 [2002]). Peer review of OSHA’s health-effects and risk-assessment report is expected to be completed by November 2008 (73 Fed. Reg. 24723 [2008]). Other agencies have taken action in re-evaluating their occupational expo- sure 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 ap- plicable 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. DOE also established two surface-contamination guidelines for beryllium to reduce its accumulation on surfaces and its spread outside specific work areas (10 CFR 850.29-30 [1999]). A beryllium surface guideline was set at 3 µg/100 

12 TABLE 1-1 Selected Exposure Guidelines and Actions Taken on Beryllium Agency Year Guideline or Action Notes and References DOE 1949 OEL, 2 µg/m3 (DWA) DWA averaged from samples over quarterly periods 1999 8-h TWA action level, 0.2 µg/m3 Action level triggers worker-protection measures; issued while OSHA was completing rule-making (64 Fed. Reg. 68854 [1999]). 1999 Surface contamination standard, 0.3 µg/100 cm2 Triggers worker-protection measures, including protective clothing and equipment (10 CFR 850.29-30 [1999]) 1999 Surface contamination standard (for release to the 10 CFR 850.31 (1999) general public or for use in a non-beryllium area), 0.2 µg/100 cm2 2006 Worker safety and health program 71 Fed. Reg. 6858 (2006) 3 ACGIH 1959 TLV, 2 µg/m (8-h TWA) ACGIH 2006 1975 A2 carcinogen (suspected human carcinogen) ACGIH 2006 1997 A1 carcinogen (confirmed human carcinogen) ACGIH 2006 3 1999 TLV, 0.2 µg/m (8-h TWA, inhalable particulate mass, ACGIH 2006 sensitizer; notice to change) 2005 TLV, 0.05 µg/m3 (8-h TWA, inhalable particulate mass, ACGIH 2006 sensitizer, skin exposure; notice of intended change) NIOSH 1972 REL, 2 µg/m3 (8-h TWA) NIOSH 1972 3 1977 REL, 0.5 µg/m (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 PEL, 2 µg/m3 (8-h TWA) PEL adopted from ANSI standard (67 Fed. Reg. 70700 [2002]) 1975 PEL, 1 µg/m3 (8-h TWA; proposed value) Proposed value based on presumption of carcinogenicity; never promulgated (40 Fed. Reg. 48814 [1975]; 67 Fed. Reg. 70700 [2002]) 1999, 2001 OSHA petitioned to issue emergency temporary Petition denied by OSHA, but OSHA stated intent to begin standard data-gathering (67 Fed. Reg. 70700 [2002]) 2002 Request for information issued 67 Fed. Reg. 70700 (2002) 3 AIHA 1964 Hygienic standard, 2 µg/m (8-h TWA) Trucano 1964 3 ANSI 1970 OEL for particles ≤5 µm, 2 µg/m (8-h TWA) ANSI 1970 IARC 1993 Group 1 human carcinogen IARC 1993 3 EPA 1998 RfC, 0.02 µg/m Value based on sensitization and progression to CBD (EPA 1998a) RfD, 0.002 mg/kg-day Value based on intestinal lesions in dogs (EPA 1998a) -3 3 Air unit risk = 2.4 × 10 per µg/m Value based on lung cancer (EPA 1998a) 24-h ambient-air limit (averaged over 30 d), 40 CFR Sec. 61.32 = 0.01 µg/m3 Cal/OSHA 2006 PEL, 0.2 µg/m3 California Labor Code, § 144.6, Title 8, § 5155 Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AIHA, American Industrial Hygiene Association; ANSI, American National Standards Institute; Cal/OSHA, California Occupational Safety and Health Administration; CBD, chronic beryllium dis- ease; 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 concen- tration (inhalation); RfD, reference dose (oral); TLV, Threshold Limit Value; TWA, time-weighted average. 13 

14 Managing Health Effects of Beryllium Exposure cm2 for operational areas where workers may be exposed to beryllium. The sec- ond guideline for the surfaces of equipment and other items to be released to the general public or for use in DOE nonberyllium work areas was set at 0.2 µg/100 cm2. No guidelines were set for skin exposure. In 2005, ACGIH proposed revi- sion to its Threshold Limit Value for beryllium, but it has not yet issued a final determination. 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 (includ- ing 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 progressing to CBD. Observations in 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 apply- ing two uncertainty factors of 3 to account for the poor quality of the exposure assessments in those and 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 (1998a,b) also classifies beryllium as a likely human carcinogen. 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. On the basis of that value, EPA 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. EPA is updating its human health risk assess- ment of beryllium. COMMITTEE’S TASKS To determine the steps necessary to protect its workforce from the adverse effects of exposure to beryllium used in military aerospace applications, the U.S. Air Force requested an independent evaluation of the health risk posed by beryl- lium. An ad hoc committee under the oversight of the National Research Coun- cil’s standing Committee on Toxicology was tasked with writing two reports to address the request. For the first report, which was issued in 2007, the commit- tee was asked to provide an independent review of the toxicologic, epidemi- ologic, and other relevant data on beryllium (NRC 2007). For this, its second report, the committee was asked to estimate levels of chronic inhalation expo- 

Introduction 15 sure of military personnel and civilian contractor workers that are unlikely to produce adverse health effects. The committee was asked to provide estimates of carcinogenic risk posed by various levels of inhalation exposure. Genetic sus- ceptibility among worker subpopulations was to be considered. If sufficient data were available, the committee was to evaluate whether levels of beryllium-alloy exposure should be different from those of exposure to other forms of beryllium because of differences in particle size. The committee was asked to identify spe- cific tests for worker surveillance and biomonitoring and to comment on the utility of the beryllium lymphocyte proliferation test (BeLPT). Specifically, the committee was asked to 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 results (such as thin-slice high- resolution computed tomography, bronchoscopy, and biopsy), the likelihood of developing CBD after a true-positive test, and a standardized method of achiev- ing consistent test results in different laboratories. Consideration was to be given to whether there are more suitable tests that would be more accurate as screen- ing or surveillance tools. The committee was also asked to identify data gaps relevant to risk assessment of beryllium alloys and to make recommendations for further research. COMMITTEE’S APPROACH To accomplish its tasks, the committee held four meetings from February 2007 to February 2008. The meetings included data-gathering sessions that were open to the public. The committee heard presentations from the U.S. Air Force and from researchers in government and academe who were involved in beryl- lium 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. The committee’s first report (NRC 2007) provided a survey of the literature on beryllium that was available at the end of April 2007. The purpose was to identify topics on which to focus a more critical review. In the present report, the literature review has been revised and updated, and the committee draws conclusions about the potential health risks posed by beryllium exposure and makes recommendations for an exposure- management and disease-management program. ORGANIZATION OF THE REPORT The remainder of this report is organized in six chapters. Chapter 2 re- views exposure factors important for assessing health risks associated with be- ryllium. It includes a review of the exposure assumptions that underlie existing exposure standards, consideration of exposures in natural and anthropogenic set- 

16 Managing Health Effects of Beryllium Exposure tings, and an examination of how physiochemical characteristics and particle sizes are associated with risk of disease. Chapter 3 provides an overview of the epidemiologic and clinical literature on beryllium sensitization and CBD. Chap- ter 4 presents information mainly from animal studies on the pathogenesis and mode of action of CBD and information on genetic susceptibility. Chapter 5 focuses on the evidence of beryllium’s carcinogenic potential and considers car- cinogenic risk estimates. Other health end points, such as reproductive and de- velopmental effects, are reviewed in Chapter 6. Finally, Chapter 7 discusses the design of a beryllium exposure- and disease-management program for workers in the Air Force.