Summary

Beryllium is an important metal that is used in a number of industries—including the defense, aerospace, automotive, medical, and electronics industries—because of its exceptional strength, stability, and heat-absorbing capability. It is found in a variety of technologies, including nuclear devices, satellite systems, missile systems, radar systems, bushings and bearings in aircraft and heavy machinery, x-ray machines used for mammography, cellular-telephone components, computer components, and connectors for fiber optics.

Since the early 1940s, beryllium has been recognized as posing an occupational hazard in manufacturing and production settings. Workers in the 1940s exposed to high concentrations of beryllium were reported to develop acute beryllium disease, an acutely toxic, pneumonitis-like lung condition. Cases of acute beryllium disease have been rarely reported in recent decades as respiratory exposure to beryllium has become better controlled in the workplace. Beryllium can also induce a condition known as chronic beryllium disease (CBD), a disease primarily affecting the lungs that is caused by a specific immune response to beryllium. An 8-h occupational guideline for limiting exposure to beryllium to 2 µg/m3 has been in place since 1949. That guideline was successful in practically eliminating acute beryllium disease, but the risk of CBD persists.

To help 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 that the National Research Council conduct an independent evaluation of the scientific literature on beryllium, and make judgments about potential health risks. The request specified that two reports be produced to accomplish those tasks (see Box S-1). The first report, issued in 2007, provided a review of the scientific literature on beryllium. That review is expanded in this, the second report, in which the committee also considers the maximum chronic inhalation exposure to beryllium that is unlikely to produce adverse health effects, discusses carcinogenic risks, and describes testing methods for surveillance and monitoring of worker populations.



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Summary Beryllium is an important metal that is used in a number of industries— including the defense, aerospace, automotive, medical, and electronics indus- tries—because of its exceptional strength, stability, and heat-absorbing capabil- ity. It is found in a variety of technologies, including nuclear devices, satellite systems, missile systems, radar systems, bushings and bearings in aircraft and heavy machinery, x-ray machines used for mammography, cellular-telephone components, computer components, and connectors for fiber optics. Since the early 1940s, beryllium has been recognized as posing an occupa- tional hazard in manufacturing and production settings. Workers in the 1940s exposed to high concentrations of beryllium were reported to develop acute be- ryllium disease, an acutely toxic, pneumonitis-like lung condition. Cases of acute beryllium disease have been rarely reported in recent decades as respira- tory exposure to beryllium has become better controlled in the workplace. Beryl- lium can also induce a condition known as chronic beryllium disease (CBD), a disease primarily affecting the lungs that is caused by a specific immune re- sponse to beryllium. An 8-h occupational guideline for limiting exposure to be- ryllium to 2 µg/m3 has been in place since 1949. That guideline was successful in practically eliminating acute beryllium disease, but the risk of CBD persists. To help 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 that the National Research Council conduct an in- dependent evaluation of the scientific literature on beryllium, and make judg- ments about potential health risks. The request specified that two reports be pro- duced to accomplish those tasks (see Box S-1). The first report, issued in 2007, provided a review of the scientific literature on beryllium. That review is ex- panded in this, the second report, in which the committee also considers the maximum chronic inhalation exposure to beryllium that is unlikely to produce adverse health effects, discusses carcinogenic risks, and describes testing meth- ods for surveillance and monitoring of worker populations. 3

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4 Managing Health Effects of Beryllium Exposure BOX S-1 Statement of Task of the Committee on Beryllium Alloy Exposures In its first report, the committee will provide an independent review of the toxicologic, epidemiologic, and other relevant data on beryllium. It will review both carcinogenic and noncarcinogenic effects. In its second report, the committee will estimate chronic inhalation exposure levels for military personnel and civilian contractor workers that are unlikely to produce ad- verse 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 results (such as thin-slice computed-tomography bronchoscopy and biopsy), the likelihood of developing CBD after a true positive test, and a standardized method for achieving consistent test results in different labora- tories. The committee will consider whether there are more suitable tests that would be more accurate as screening or surveillance tools. The com- mittee will also identify data gaps relevant to risk assessment of beryllium alloys and make recommendations for further research. The primary health effects of interest in connection with beryllium are be- ryllium sensitization (BeS), CBD, and lung cancer. After critically reviewing the available literature on those outcomes, the committee concluded that available scientific information does not enable the identification of an inhalation expo- sure that is unlikely to lead to BeS or CBD. The best approach for protecting the Air Force’s workforce from the effects of beryllium exposure is to establish a beryllium exposure- and disease-management program. The program should be designed to reduce exposure to beryllium to the lowest feasible level and should include a medical-surveillance program for identifying and following affected workers. The committee also found that uncertainties in the epidemiologic evi- dence limit the ability to derive quantitative carcinogenic risk estimates associ- ated with current magnitudes of beryllium exposure. How the committee came to those conclusions and recommendations is elaborated below. BERYLLIUM SENSITIZATION AND CHRONIC BERYLLIUM DISEASE It is well established that beryllium can cause sensitization and CBD. BeS is an immune response triggered by beryllium exposure in susceptible people. It

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5 Summary is not a disease, but it is a predictor of CBD in workers with known exposure to beryllium. CBD is a systemic granulomatous disorder that affects mainly the lungs. CBD has a clinical spectrum that can range from asymptomatic disease with no deficits in lung function or radiographic abnormalities to end-stage lung disease. Asymptomatic cases are usually identified when workers in a beryl- lium-surveillance program test positive for BeS and followup medical evalua- tions reveal lung granulomas or other evidence of disease. Only a fraction of people who are exposed to beryllium become sensitized, and only some of those who are sensitized develop CBD. A number of factors appear to influence sus- ceptibility to sensitization and development of CBD, including magnitude of exposure, physicochemical properties of beryllium, route of exposure, and host factors. The committee was asked to consider the toxicity of different forms of be- ryllium because the Air Force uses beryllium alloys in its aerospace applications and the exposure scenarios probably differ from settings in which beryllium is mined, manufactured, or processed. The committee found that the physico- chemical properties of the different forms of beryllium may affect their deposi- tion in lungs and their bioavailability and may be important factors in the devel- opment and course of CBD. However, there are insufficient data from the epidemiologic and toxicologic literature to draw firm conclusions about the rela- tive chronic toxicity of different forms. Thus, the committee considered risks posed by beryllium exposure broadly to include all forms of beryllium. The immunopathogenic mechanisms underlying BeS and progression to CBD have been investigated largely through clinical studies and experiments focused on the human immune system. Attempts to develop animal models of CBD have had little success. Acute toxicity may be somewhat similar in animals and humans, but immunologic mechanisms underlying BeS and progression to CBD are not well represented by animal models. For example, the beryllium- induced immunologic disease in laboratory animals appears to regress when exposure is stopped, whereas in humans it persists or progresses. Thus, it is not possible to rely on animal models to determine potential human health effects of low-dose chronic beryllium exposures in workers. It is clear from animal and human data that susceptibility to BeS and CBD has genetic components. Attempts to identify the genetic components of suscep- tibility have centered mainly on investigating polymorphisms of the major histo- compatibility complex class II and proinflammatory genes. Alleles of the HLA- DP gene containing glutamic acid at the 69th position of the β chain (HLA- DPβGlu69) appear to be the most important markers of susceptibility to CBD. However, the presence of that marker alone does not necessarily confer suscep- tibility, nor is its absence a guarantee of nonsusceptibility. In addition to expo- sure, T-cell receptor expression, inflammation-related genes, and other potential modifier genes may play roles in sensitization and disease progression. Efforts are under way to create humanized mouse models with specific human alleles associated with a range of BeS and CBD risk.

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6 Managing Health Effects of Beryllium Exposure Epidemiologic studies have shown that detection of BeS and CBD occurs in settings where airborne exposure to beryllium is below the current occupa- tional standard of 2 µg/m3, but they have not given a clear indication of how much lower the standard would have to be set to be fully protective. It has also been hypothesized that skin exposure to beryllium may contribute to BeS and CBD. Thus, the committee concludes that the available data are insufficient for estimating an inhalation exposure magnitude that will prevent BeS and CBD in settings where beryllium has the potential for being aerosolized. Beryllium in- dustries have succeeded in reducing the prevalence of BeS and CBD by estab- lishing exposure- and disease-management programs to minimize exposure and to monitor workers for adverse health effects. Recommendation: In the absence of sufficient evidence to establish a chronic inhalation level for beryllium that that is unlikely to result in BeS or CBD, the committee recommends that the Air Force implement an exposure- and disease-management program to protect its workers. The program should involve industrial-hygiene assessments to identify potentially exposed workers, to eliminate as many job tasks involving exposure to beryllium particles as pos- sible, and to minimize the number of workers performing those tasks; screening of potentially exposed workers for BeS; medical management of BeS and CBD; and stringent engineering and work-practice controls to keep beryllium expo- sure as low as is feasible. Important aspects of the recommended exposure- and disease-management program are shown in Figure S-1. The program should evolve as more is learned about exposure and disease prevalence in the Air Force. BERYLLIUM LYMPHOCYTE PROLIFERATION TEST The beryllium lymphocyte proliferation test (BeLPT) is an in vitro test of BeS that will be integral to any beryllium-related screening program. No alterna- tive tests of sensitization or biomarkers of exposure have been adequately vali- dated to be put into practice outside research settings. In the BeLPT, mononuclear cells derived from peripheral blood or bron- choalveolar-lavage (BAL) fluid are challenged with beryllium salts in vitro. A response is considered positive if beryllium induces proliferation of sensitized lymphocytes. The test is used both for diagnostic evaluation of patients who present with possible CBD and for medical surveillance of workers. For exam- ple, the BeLPT is a tool that can help to differentiate CBD from other interstitial granulomatous lung diseases, such as sarcoidosis and chronic hypersensitivity pneumonitis. When the test is used to identify at-risk populations, rather than as an individual screening or diagnostic test, it is useful for identifying facilities, areas in a given facility, and job tasks that have risk for CBD. Screening of healthy exposed workers with the BeLPT has also enabled the detection of BeS

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7 Summary FIGURE S-1 Beryllium exposure and disease management program. in such workers and has enabled earlier diagnosis of CBD. Despite some issues regarding the reproducibility, sensitivity, and specificity of the BeLPT, the committee judged it to be an adequate assay for use in a surveillance program. The committee was asked by the Air Force to comment on five questions about the BeLPT. The questions and the committee’s answers are presented below. • What is the value of a borderline or true-positive BeLPT result in predicting CBD? A borderline test result in combination with a positive test result is generally considered indicative of sensitization. If a borderline result is not preceded or followed by a positive result, the tested person is considered nonsensitized. The committee considers a true-positive (or confirmed abnormal) blood BeLPT result to be a predictor of CBD in a worker with known exposure to beryllium, but there are insufficient data for accurate prediction of risk of progression. • What is the utility of the BeLPT in worker surveillance? The BeLPT identifies BeS in exposed workers. When used to identify at-risk popula- tions, rather than as a screening or diagnostic test, the BeLPT has been shown to be useful for identifying facilities or jobs that pose risk. Medical surveillance with the BeLPT has been able to detect risk of CBD better than traditional air sampling because BeS can occur at low air concentrations and possibly from

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8 Managing Health Effects of Beryllium Exposure skin exposure. The committee stresses, however, that BeLPT screening should not be used as the first line of defense against exposure. • What followup tests should be performed on workers with positive BeLPT results? Workers with positive BeLPT results should undergo further medical evaluation, which should generally include a medical and occupational questionnaire, pulmonary-function tests that include lung volumes and carbon monoxide diffusing capacity, and high-resolution computed tomography of the chest when indicated. After review of the test results, consideration should be given to performing bronchoscopy with BAL, transbronchial biopsy, and possi- bly other tests. In the clinical setting, the decision to perform those examinations is made case by case. • What is the likelihood of developing CBD after a true-positive test result? Some studies have reported that CBD is diagnosed in up to 50% or more of screened workers who have true-positive BeLPT results, and the conversion rate from BeS to CBD has been estimated to be 6-8% per year. However, the estimated conversion rate was based on a single cohort of workers. Although those with positive BeLPT results are at an increased risk for CBD, the available evidence is insufficient to make quantitative predictions about the magnitude of the risk. • Is there a standardized method for achieving consistent test results in different laboratories? No standardized method is used in laboratories in the United States. Preliminary results of a study in Canada showed that concordance in results between laboratories improved when testing procedures were closely matched (e.g., when such variables as dose, times, and controls were standard- ized). Concordance in laboratory testing and analysis and a standardized testing algorithm should reduce variation between laboratories but will not address is- sues regarding the sensitivity and specificity of the test. CANCER There is evidence from inhalation-exposure studies that beryllium can cause lung cancer in laboratory animals. Epidemiologic studies have reported increases in lung-cancer risk in two worker cohorts exposed to beryllium. Those studies were instrumental in forming the basis of the current cancer classifica- tions of the International Agency for Research on Cancer, the U.S. Environ- mental Protection Agency, and the National Toxicology Program. New studies and reanalyses of data performed since those assessments have not added sub- stantially to understanding of the carcinogenicity of beryllium or of the dose- response relationship between beryllium exposure and lung cancer. The commit- tee agrees with the other agencies that the balance of the evidence supports a conclusion that beryllium is likely a human carcinogen.

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9 Summary The committee was asked to develop carcinogenic risk estimates for dif- ferent magnitudes of inhalation exposure to beryllium; however, the committee judged that the available human and animal data are inadequate to support a dose-response analysis with low-dose extrapolation to current exposure magni- tudes. A useful cancer dose-response assessment cannot be conducted until more information is available on existing or new worker cohorts regarding complete work history, possible exposure to other carcinogens, and exposure history. Fur- thermore, carcinogenic risk estimates would be of limited utility in light of the committee’s recommendation that the Air Force implement an exposure- and disease-management program to reduce exposure to beryllium to the lowest fea- sible magnitude to prevent BeS and CBD.