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 exposed to high concentrations of beryllium have been reported to have acute beryllium disease, a pneumonitis-like lung condition, often reversible upon removal from exposure and supportive respiratory care. There was a decrease in incidence of acute beryllium disease in the 1940s when respiratory exposure to beryllium became better controlled in the workplace. Beryllium can also induce a condition known as chronic beryllium disease (CBD), a systemic granulatomous 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’s Committee on Toxicology (COT) conduct an independent evaluation of the scientific literature on beryllium, provide risk estimates for cancer and noncancer health end points, and make recommendations about specific tests for surveillance and biomonitoring of workers. The request specified that two reports be produced to accomplish those tasks (see Box S-1). The first is to provide a review of the scientific literature on beryllium, and the second will expand more critically on the review in considering the maximum chronic inhalation exposure levels that are unlikely to produce adverse health effects, in estimating carcinogenic risks, and in providing guidance on testing methods for surveillance and monitoring of worker populations and other specific issues detailed in the statement of task. In response to the U.S. Air Force request, COT convened the Committee on Beryllium Alloy Exposures, which prepared this first report. The report identifies the available toxicologic, epidemiologic, and other literature on beryllium that is most relevant for addressing the statement of task, focusing primarily on beryllium sensitization, CBD, and cancer.
Statement of Task for 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 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 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 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.
SENSITIZATION AND CHRONIC BERYLLIUM DISEASE
Clinical and Epidemiologic Studies
It is well established that beryllium can cause sensitization and CBD. Sensitization is an immune response, not a disease, and does not have any symptoms. It is usually detected with the beryllium lymphocyte proliferation test (BeLPT), an in vitro test that measures lymphocyte proliferation in peripheral blood cells or bronchoalveolar lavage (BAL) cells. CBD is a systemic granulomatous disorder that affects mainly the lungs. It can present with a variety of other effects that may include respiratory symptoms, radiographic abnormalities, and deficits in lung function. Since its pathogenesis involves a beryllium-specific, cell-mediated immune response, CBD cannot occur without sensitization.
Epidemiologic studies performed on cohorts of workers exposed to various forms of beryllium in different industries have indicated that sensitization and CBD can occur after exposure to beryllium even at concentrations below the current occupational exposure limit of 2 μg/m3. The studies have also shown that the incidence of CBD in workers depends on the industry or process, as well as the job category, and that sensitization does not always progress to CBD. There is growing evidence that skin exposure can contribute to sensitization and development of CBD.
Progression to CBD appears to be influenced not only by the magnitude of beryllium exposure but also by the physiochemical properties of the form of beryllium (such as composition and particle size), the genotype and phenotype of the exposed person, and probably the route of exposure. Other possible risk factors that have not been systematically addressed include smoking status, race, sex, concurrent exposures, and other environmental stressors. There is little published information on the rate of progression from asymptomatic immunologic sensitization to CBD.
Beryllium Lymphocyte Proliferation Test
In the BeLPT, a test for sensitization to beryllium, mononuclear cells derived from peripheral blood or 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 CBD and for medical surveillance of workers. For example, a positive BeLPT result differentiates
between CBD and other lung diseases, such as sarcoidosis and chronic obstructive pulmonary disease. When the test is used on a population basis, rather than as a screening or diagnostic test, it is reportedly more useful than traditional air sampling in identifying facilities and areas in a given facility that have substantial beryllium exposure. Screening of healthy exposed workers with the BeLPT has also enabled the detection of beryllium sensitization in asymptomatic workers and earlier diagnosis of CBD.
In its second report, the committee will discuss aspects of the use of the BeLPT in routine surveillance and medical monitoring, including the value of the BeLPT in predicting CBD, protocols for further followup tests after a positive BeLPT result, the likelihood of developing CBD after a true positive test, and a standardized method for achieving consistent test results in different laboratories.
Several animal models of CBD have been studied, including models in mice, dogs, and monkeys. Some immunologic and pulmonary effects similar to those in CBD have been induced in the animal models, but the nature and course of the disease were not exactly the same as in human CBD. For example, the beryllium-induced disease in animals appears to regress when exposure is stopped, whereas in humans it progresses. In general, the exposure that was required to produce the disease in animals was greater by several orders of magnitude than the exposure that has been implicated in human CBD. In addition, it is now clear from animal and human data that susceptibility to CBD has a genetic component. Efforts are under way to create humanized mouse models that might be useful in clarifying the interactions of beryllium with specific target molecules in tissues that may lead to sensitization and progression to CBD in humans.
Influence of Physiochemical Properties
Metal processing operations produce beryllium particles that can be inhaled or deposited on the skin. Differences in the number, composition, structure, size, and surface area of the particles affect their deposition in the lung and their bioavailability. In general, the respirable fraction of beryllium aerosols (particles less than 10 μm in diameter) is a better indicator of exposure than is total mass. However, recent research indicates that surface area and dissolution rate in the lungs also contribute to the rate of release of beryllium ions. How all the relevant factors are combined to achieve a rate of release sufficient to activate T lymphocytes and to initiate and sustain a granulomatous response remains to be elucidated.
As noted above, only a fraction of people who are exposed to beryllium become sensitized, and only some of those who are sensitized develop CBD. Attempts to identify the genetic components involved in susceptibility have centered mainly on investigating polymorphisms of the major histocompatibility complex (MHC) class II and proinflammatory genes. Research has indicated that an allele of the HLA-DP gene containing glutamic acid at the 69th position of the β chain (HLA-DPβGlu69) is the most important marker of susceptibility to CBD. However, the presence of that marker alone does not necessarily confer susceptibility, nor is its absence a guarantee of nonsusceptibility. T-cell receptor expression, inflammation-related genes, and other potential modifier genes also appear to play roles in disease progression.
It is clear from the committee’s review that the data on beryllium sensitization and CBD will be critical in its consideration of acceptable chronic inhalation exposure levels. The key datasets and uncertainties associated with exposure estimates, genetic susceptibility, and forms of beryllium exposure will be detailed in the committee’s second report.
CANCER AND OTHER EFFECTS
There is evidence from many controlled studies that exposure to beryllium can cause lung cancer in rats. 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 classifications by such agencies as the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the National Toxicology Program. After the cancer classifications were formed, critiques and alternative analyses of the epidemiologic investigations took place. In its second report, the committee will consider the collective evidence in determining whether any of the available studies are appropriate for establishing carcinogenic risk estimates.
In studies of health end points other than CBD and cancer, adverse effects have generally been observed only at doses higher than the lowest doses that induce CBD or cancer.