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Managing Health Effects of Beryllium Exposure 3 Epidemiologic and Clinical Studies of Beryllium Sensitization and Chronic Beryllium Disease It is well established that beryllium causes sensitization (beryllium sensitization, BeS) and chronic beryllium disease (CBD). This chapter assesses the risk of those conditions posed by occupational exposure to beryllium. We first review the epidemiologic literature on BeS and CBD and then present the current clinical description of CBD with diagnostic, testing, and management approaches. Chapter 4 presents what is known about the pathogenesis and mode of action of CBD, genetic factors that confer susceptibility to it, and animal models for studying CBD. EPIDEMIOLOGIC LITERATURE Exposure to airborne beryllium-containing particles can cause two distinct types of pulmonary disease: a pneumonitis referred to as acute beryllium disease and a chronic granulomatous disease called CBD. Acute beryllium disease, first reported in the 1940s, was observed in beryllium workers and was characterized by the onset of severe respiratory symptoms, usually over several weeks. Chest radiographic descriptions were those of initial diffuse haziness followed by lung infiltrates and nodules. Most patients recovered over several months with appropriate treatment and removal from exposure, but the condition recurred on renewed exposure (Van Ordstrand et al. 1945). Autopsy results in seven fatal cases showed pulmonary edema, mononuclear cell exudate, fibrosis, nodules, and one case of well-defined granulomas (Dutra 1948). The incidence of acute beryllium disease decreased after respiratory exposure to beryllium was controlled (Van Ordstrand et al. 1945). The mechanism may be a toxic pneumonitis,
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Managing Health Effects of Beryllium Exposure although immune or hypersensitivity responses are also possible. Acute beryllium disease has been reported only rarely in the last several decades. CBD, however, despite substantial reductions in beryllium respiratory exposures, continues to occur in exposed workers. The pathogenesis of CBD involves a lymphocyte-mediated immune response (delayed hypersensitivity) to beryllium that leads to noncaseating granulomatous lesions. CBD affects primarily the lungs, although granulomas can occur in other organs, such as skin, liver, and spleen. BeS precedes the development of CBD and since the late 1980s has been detected by in vitro challenge of lymphocytes with beryllium salts in the beryllium lymphocyte proliferation test (BeLPT). In the older literature, patients with CBD typically presented with respiratory symptoms, fatigue, and chest-radiographic and lung-function abnormalities. Since the BeLPT has been available, screening of workers with it has enabled diagnosis of CBD often when they have minimal or no symptoms. That has shifted the clinical spectrum of CBD toward less severe cases. The recent epidemiologic literature on BeS and CBD and their clinical presentation, diagnosis, and management are reviewed below. In the United States, acute beryllium disease was first reported in the early 1940s by Van Ordstrand et al. (1943); the first reports of CBD were by Hardy and Tabershaw (1946). Cases were observed in industrial plants that were refining and manufacturing beryllium metal and beryllium alloys and in plants manufacturing fluorescent light bulbs. By 1948, the known cases totaled more than 400, and the basic clinical features of the disease were understood. It was established that the risk of disease among beryllium workers was variable and generally rose with the intensity of airborne exposure (Machle et al. 1948; see Chapter 2 for more information). From the late 1940s into the 1960s, clusters of CBD cases were identified around beryllium refineries in Ohio and Pennsylvania, and outbreaks in family members of beryllium-factory workers were presumably from exposure to contaminated clothing (Hardy 1980). Although there was a relationship between the air concentration of beryllium and the risk of CBD in areas close to the factories, the disease rates outside the plants were higher than expected and not very different from the rate of CBD in the workforce (Eisenbud et al. 1949; Lieben and Metzner 1959). The prevalence of CBD in workers exposed during the 1940s and 1950s has been estimated at 1-10% (Eisenbud and Lisson 1983) although there is considerable uncertainty because most of the studies in that era did not use well-defined cohorts, modern diagnostic methods, or have adequate followup. Sterner and Eisenbud (1951) first proposed an immunologic mechanism of CBD in 1951. Their evidence was largely circumstantial, but their inference was correct. They based their hypothesis on several pieces of evidence: the highly variable incidence in different groups of workers, the surprising occurrence in neighborhoods whose exposure appeared to be low, the sometimes rapid onset of disease after exposure, and the failure to observe an association between the amount of beryllium in lung autopsy specimens and the extent of lung damage.
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Managing Health Effects of Beryllium Exposure From the 1940s through the 1960s, the Atomic Energy Commission (AEC) was the primary user of beryllium in the U.S. economy. In 1949, AEC’s occupational hygienists recommended an air standard of 2 µg/m3 as an 8-h time-weighted average and a 30-min peak standard of 25 µg/m3 (Eisenbud 1982). Before the widespread application of the BeLPT, it appeared that strict adherence to those standards might adequately protect workers from CBD. However, it is now clear that CBD can occur in factories that have beryllium aerosol concentrations consistently below 2 µg/m3 (Kreiss et al. 2007). The development of the BeLPT changed case-finding tools used in CBD epidemiologic studies from chest radiography and spirometry to the identification of BeS with a blood test followed up with clinical examination. That change made it difficult to compare findings from the clinical and epidemiologic literature before and after BeLPT development. With reductions in exposure in many beryllium workplaces, the widespread use of the BeLPT has meant that in recent years CBD has often been diagnosed when there has been less severe evidence of disease. There appears to be a consensus in the field that a case series of CBD identified in exposed workers with the BeLPT and confirmed with biopsies provides more specificity in diagnosis than such tools as chest radiography and spirometry. In its review of the epidemiologic evidence, the committee decided to focus primarily on the epidemiologic studies of CBD that included the use of the BeLPT. The committee took into account the results of the older epidemiologic studies, clinical studies, and case series that described clinically diagnosed CBD in the pre-BeLPT era to inform other sections of this chapter (see sections on “Presentation and Diagnosis of and Testing for Chronic Beryllium Disease” and “Progression and Management of Chronic Beryllium Disease”). In a recent review, Kreiss et al. (2007) summarized 12 studies (with overlapping populations) in which CBD prevalence was assessed cross-sectionally and ranged from 0.1% to nearly 8% (Table 3-1 is a modification of a table of Kreiss et al.). The higher prevalence of BeS and CBD in the facilities studied by Kreiss et al. (1989, 1997), Henneberger et al. (2001), Newman et al. (2001), and Rosenman et al. (2005) is at least partly explained by higher airborne concentrations of beryllium in those facilities. The newer epidemiologic studies have benefited from the ability to detect BeS with the BeLPT, and their results indicate that in general the prevalence of BeS is higher than that of clinically confirmed CBD although the difference varies widely. The differing ratios of BeS to CBD among studies are probably affected by the extent of followup of former workers, the time elapsed since initial exposure, and the physical form and intensity of exposure. It is difficult to estimate the “background” risk of CBD. Although there is nonoccupational exposure to beryllium in soils, air, food, and water, the committee knows of no studies that have attempted to identify cases from “natural” sources. There have been case reports of CBD in people with incidental or inconsequential exposure to beryllium, but such reports are of little use in estimat-
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Managing Health Effects of Beryllium Exposure TABLE 3-1 Summary of Recent Epidemiologic Studies of Chronic Beryllium Disease Reference Study Type Prevalence Exposure-Response Relationship?a Comments BeS CBD Mining and extraction Deubner et al. 2001a Cross-sectional 4.0% 1.3% No Beryllium-metal processing, alloy production Kreiss et al. 1997 Cross-sectional 9.4% 4.6% No Newman et al. 2001 Longitudinal 9.4% 5.5% No Kelleher et al. 2001 Case-control N/A N/A Yes Rosenman et al. 2005 Cross-sectional 14.6% 7.6% No Beryllia ceramics Kreiss et al. 1993a Cross-sectional 1.6% 1.8% No Kreiss et al. 1996 Cross-sectional 5.9% 4.4% Yes Henneberger et al. 2001 Cross-sectional 9.9% 5.3% Yes Cummings et al. 2007 Longitudinal N/A N/A Yes Beryllium-copper alloy processing, distribution Schuler et al. 2005 Cross-sectional 6.5% 3.9% No Stanton et al. 2006 Cross-sectional 1.1% 1.1% No Workers in three distribution centers Nuclear-weapons industry Rocky Flats nuclear-weapons facility Kreiss et al. 1989 Cross-sectional 11.8% 7.8% No Production, research and development machinists only
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Managing Health Effects of Beryllium Exposure Reference Study Type Prevalence Exposure-Response Relationship?a Comments Kreiss et al. 1993b Cross-sectional 1.9% 1.7% No Stratified random sample with probable beryllium exposure Stange et al. 1996b Longitudinal 2.4% 0.7% No Current, former workers Stange et al. 2001 Longitudinal 4.5% 1.6% No Current, former workers (including workers in Stange et al. 1996b) Sackett et al. 2004 Cross-sectional 0.8% 0.1% No Decontamination, decommissioning workers only Viet et al. 2000 Case-control N/A N/A Yes Current, former workers Hanford Nuclear Reservation, Oak Ridge Reservation, Savannah Riversite Welch et al. 2004 Cross-sectional 1.4% 0.1% No Construction-trade workers aNo, no evidence of exposure-response relationship provided inpaper; Yes, evidence of increased prevalence or risk with increasing exposure. Source: Adapted from Kreiss et al. 2007. Adapted table printed with permission; copyright 2007, Annual Review of Public Health.
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Managing Health Effects of Beryllium Exposure ing background risk. It is also likely that many cases of CBD are mistakenly diagnosed as sarcoidosis; without a known source of exposure and lacking a BeLPT, there is no way to distinguish these CBD cases from sarcoidosis. Natural History of Beryllium Lung Disease The committee found it useful to summarize the main pathologic processes that lead to CBD in a simplified schematic (Figure 3-1). The steps in the scheme may be described as follows: Step 1—Sensitization: It is presumed that sensitization precedes CBD. It is unclear whether BeS can resolve or go away, inasmuch as the reversion of an abnormal BeLPT to normal could occur for a number of reasons, such as recruitment of beryllium-responsive cells to the lung, variability in the BeLPT, or development of immune tolerance. In general, immune responses and the ability to detect them vary over time. A beryllium dose to the immune system is necessary for sensitization, but the shape of the dose-response curve (represented by curve 1 in the figure) is not known. There are probably different curves for different subpopulations distinguished by genotypes and possibly other host factors. Some fraction of the population may be incapable of sensitization no matter what their beryllium dose is, but this is not known. The time during which exposure is relevant to the risk of sensitization also is not known. Studies suggest that the incubation period for sensitization can be as short as a few months of exposure (Kelleher et al. 2001; Cummings et al. 2007; Donovan et al. 2007). The exposure period before ascertainment of sensitization was found by Madl et al. (2007) to be highly variable, ranging from 0.2 to 22 years with a median of 2.0 years. Finally, it is likely that there are different dose-response curves depending on the physicochemical form of beryllium, particularly with respect to solubility and particle size; however, the data are sparse, and it is not now possible to estimate separate curves for different types of beryllium. Step 2—Incidence: The likelihood of developing CBD depends on factors such as time, beryllium dose (as represented in the figure by curve 2), and host factors. As with sensitization, the shape of the dose-response curve for CBD incidence (the epidemiologic term for first onset of disease) is not known. It is likely to be different from the relationship in the first step (curve 1) and probably also has genetic determinants that result in different dose-response relationships (or beryllium potencies) in different subpopulations. The genetic polymorphisms that act in this stage may differ from the ones that act in the first stage (see Chapter 4). Step 3—Progression: Some, perhaps many, of the surveillance-identified cases of CBD will not have any impairment in function, at least on initial diagnosis. (The condition is sometimes called “subclinical CBD.” However, the
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Managing Health Effects of Beryllium Exposure FIGURE 3-1 Simplified schematic of natural history of beryllium sensitization (BeS) and chronic beryllium disease (CBD). Some time after initial exposure, normal workers may become sensitized through exposure-response process represented by curve 1. Once they are sensitized, further exposure may lead to CBD (curve 2). Progression of CBD may also occur; third exposure-response relationship contributes to this process (curve 3). Host susceptibility is probably important at all three steps. p(BeS+) = probability of BeS, p(CBD) = probability of CBD. committee considers it part of the spectrum of CBD, which can range from disease with no apparent functional impairment to severe lung disease. Some cases of surveillance-identified CBD can progress to more severe disease, as discussed later.) Again, some dose-response curve probably underlies the progression, but little is known about it; the relevant period, an appropriate exposure metric, and relative potencies of different physicochemical forms are all unknown. The recent literature on BeS and CBD in different sectors of the beryllium industry is summarized briefly below. The division into sectors may be useful because it corresponds roughly to the physicochemical forms of beryllium to which workers are exposed. There are a number of methodologic issues and differences between the epidemiologic studies, including study design, number of study participants, how exposure was quantified, diversity of physicochemical form of beryllium, genetic susceptibility to CBD, and the healthy-worker effect. The section “Challenges in Interpreting the Epidemiologic Literature on Beryllium Disease” later in this chapter elaborates on some of the challenges to understanding CBD risk and how they limit the interpretability of the epidemiologic studies.
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Managing Health Effects of Beryllium Exposure Beryllium Mining and Extraction There is some information on the risk of CBD in workers in beryllium mining and extraction. In the United States, beryllium ore is mined in a single facility in Utah; substantial mineral resources also exist in China, Russia, and elsewhere. The U.S. facility has been studied twice: by Rom et al. (1983), who reported on worker-health surveys in 1979 and 1982, and more recently by Deubner et al. (2001a). The Rom et al. study used an early version of the BeLPT, and its results are difficult to interpret. The Deubner et al. study appears to provide a more reliable assessment of the risk in mining and extraction. Bertrandite ore (containing an average of 0.23% beryllium) is mined at the Utah facility, and an extraction mill at the same site produces beryllium hydroxide, which is shipped elsewhere to be made into beryllium oxide ceramics and beryllium metal. The same facility produces beryllium hydroxide from beryl ore (3.6-5.0% beryllium) that is mined abroad. A medical-surveillance study in 1996 included the BeLPT (Deubner et al. 2001a). Of the 87 workers in the facility, 75 (86%) were tested; 12 refused. The single worker found to have CBD had had substantial exposure to beryllium in another facility. Three beryllium-sensitized workers had worked only in the facility under study. It is not possible from the data given to conclude that there is no risk in mining and extraction. The paper does not permit an analysis that separates mine workers from mill workers, so it is not possible to estimate the prevalence or risk of sensitization separately for the two activities—mining, in which exposure is exclusively to highly dilute ores, and extraction, in which beryllium salts are present. It appears that there may be a lower risk of sensitization in mining and extraction than in other phases of production, but confidence in this finding is limited by the small numbers, limited participation, and inability to separate exposures in mining and in extraction. Beryllium-Metal Processing and Alloy Production The beryllium-metal processing and alloy-production facilities have provided important data on risks of BeS and CBD and the relationships between the two (Kreiss et al. 1997; Kelleher et al. 2001; Newman et al. 2001; Rosenman et al. 2005; Madl et al. 2007). The relevant studies involved cross-sectional screening of a working population, and each found both BeS and CBD (Table 3-1). Rosenman et al. (2005) studied a large group (1,351) of former workers of a beryllium-processing plant more than 25 years after the end of exposure. Exposure reconstruction was used to assign beryllium-exposure histories to all cohort members, who were offered medical screening, including BeLPT. Those with BeS were invited to a further workup, including bronchoalveolar lavage for BeLPT testing of lavage fluid and histologic evaluation for granulomas. The overall prevalence of BeS (6.9%) and prevalence of definite or probable CBD (7.6%) were higher than in other studies although historical exposure at this
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Managing Health Effects of Beryllium Exposure plant was also higher than more recent exposure in other plants that were studied. The authors compared workers with BeS and CBD with nonsensitized workers with respect to several exposure metrics and found only limited evidence of an exposure-response relationship. The findings were weakened, however, by substantial losses to followup, refusals to participate in medical monitoring, and limited exposure data. The exposure-response findings are probably biased by the healthy-worker effect and exposure misclassification. The study by Newman et al. (2001) is valuable because the same population was studied in a later case-control analysis (Kelleher et al. 2001) to investigate exposure-risk relationships that go beyond the prevalence data presented in most studies. The two studies were conducted in a beryllium-metal machining facility that experienced an index CBD case in 1995. The plant opened in 1969, and extensive environmental measurements were taken throughout the plant’s history. Beginning in 1995, BeLPT screening of all workers was conducted, with retesting 2 years later. All 235 eligible workers were tested in 1995-1997, and 15 (6.4%) were beryllium-sensitized. Of the 15 sensitized workers, 12 completed clinical evaluations, and nine were found to have CBD. The onset of sensitization was sometimes very short—3 months or less in four of the 15. To investigate exposure-response relationships, seven workers with BeS and 13 with CBD were compared with 206 at-risk workers who had neither condition in a case-control analysis (Kelleher et al. 2001). Exposure of cases and controls was assessed by using personal exposure data that had been gathered with a size-selective impactor in the breathing zone. Cumulative and average lifetime exposures were calculated for particles of two sizes: less than 6 µm and less than 1 µm. There was evidence that case subjects were more highly exposed than controls in terms of both total exposure and in the two size ranges. For example, cumulative exposure to particles smaller than 1 µm was associated with the prevalence of BeS or CBD when prevalence was compared in three exposure groups. In comparison with those who had low cumulative exposure (less than 0.09 µg/m3), the odds ratio (OR) in those with medium exposure (0.09-1.87 µg/m3) was 1.85, and the OR in those with high exposure (over 1.87 µg/m3) was 2.46. Confidence intervals were rather wide because of the small numbers of cases, but a trend was clear. More recently, Madl et al. (2007) evaluated exposure-response relationships between beryllium exposure and BeS and CBD in workers in the same metal-machining plant that was studied by Kelleher et al. (2001). A number of indexes of beryllium exposure were estimated for each of the nine workers who were identified as beryllium-sensitized and 18 as having CBD since 1995. Many air sampling measurements were available for these workers, and five exposure metrics were estimated for each of the 27 cases; each metric represented a slightly different assumption about which aspect of an exposure profile is most important in predicting risk. For example, three of the five metrics attempted to estimate the time-weighted-average exposure in the year of highest exposure of each worker. Another approximated an overall average lifetime exposure of
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Managing Health Effects of Beryllium Exposure each worker. Unlike Kelleher et al., Madl et al. did not include a formal epidemiologic study design that might have permitted investigation of exposure-response relationships. Probably the most straightforward approach would have been a nested case-control study, drawing controls from the at-risk population of the plant and using incidence-density sampling. Without a comparison population, it is not possible to use the results to investigate the possibility of a threshold of exposure below which there is no risk, nor can one estimate the risk at different exposures. The results do provide one important insight that is not limited by the lack of a comparison population: BeS and CBD developed in some workers after air exposure that was below 0.2 µg/m3. More detailed predictions of the distribution of exposure magnitudes leading to disease cannot be supported by the data, given the small number of workers with BeS and CBD and the lack of a comparison population. Other studies have suggested that BeS or CDB can occur at exposure below 0.2 µg/m3. Kelleher et al. (2001) reported that eight of 20 workers with BeS or CBD in a beryllium-machining facility had individual lifetime-weighted (LTW) exposure of less than 0.2 µg/m3, whereas none of the workers with LTW exposure below 0.02 µg/m3 had BeS or CBD. In a study of beryllium exposure in an aluminum smelter (see description below), Taiwo et al. (2008) found two workers with CBD whose mean beryllium exposure was 0.16 and 0.04 µg/m3. In summary, the literature on beryllium-metal processing and alloy production provide many of the available data on BeS and CBD. Beryllium Oxide Ceramics Beryllium oxide–ceramics production workers in two facilities have been studied: one that produced ceramics until 1975 (Kreiss et al. 1993a), and a second that still produces ceramics (Kreiss et al. 1996; Henneberger et al. 2001; Cummings et al. 2007). Those studies are among the best sources of evidence of the risk of BeS after low exposure. The plant that still produces ceramics has monitored workers closely for the onset of sensitization (and for CBD in those who become sensitized) over about 10 years. The facility has also engaged in increasingly elaborate control procedures in an attempt to eliminate the risk of sensitization. BeS screening with the BeLPT was first conducted in 1992, when eight (5.9%) of 136 screened workers were found to be sensitized. Six of the eight had CBD as evidenced by granulomas in biopsied lung tissue. The highest risk was in machining, which had higher average mass concentrations of beryllium in air than other jobs. At the initial 1992 screening, the prevalence of BeS was higher in machinists (14.3%) than in all other workers (1.2%). After the survey, the company undertook engineering controls to reduce airborne exposures over the period 1993-1996. Employment increased in 1996, and a second BeLPT screening was conducted in 1998. A detailed assessment of airborne exposures was carried out at the same time. Overall, 15 (9.9%) of 151 screened workers had BeS in 1998.
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Managing Health Effects of Beryllium Exposure Those results are best understood by looking separately at two groups: long-term workers who had been employed before the first screening in 1992 and short-term workers who were hired after it. The short-term workers had experienced only recent exposure to beryllium, and their exposure-risk experience was less likely to have been biased by loss to followup than that of the long-term workers. But the prevalence of BeS was similar in the two groups: 10.4% in 77 long-term workers and 9.5% in 74 short-term workers. The investigators observed that short-term workers with “low” mean exposure (0.05-0.28 µg/m3) had a lower prevalence of sensitization (5%) than those with higher exposure (0.29-4.4 µg/m3; 14%). That fairly large difference in prevalence was based on very small numbers: 39 workers with low exposure and 35 with high exposure. Concluding that additional ventilation controls had not reduced the prevalence of sensitization, the company embarked on a second, much more elaborate control strategy, including respiratory protection, reduction in skin contact, stricter control of airborne exposure, and improved housekeeping practices. From 2000 on, as new workers were hired, they received baseline sensitization tests so that the incidence of sensitization could be quantified prospectively. Cummings et al. (2007) assessed the effectiveness of the post-2000 exposure-control program by comparing the incidence of sensitization in workers hired from 2000 to 2004 with the incidence in those hired from 1993 to 1998. From 2000 to 2004, 126 workers were hired, and most contributed a baseline result and at least one postbaseline test result. The results were compared with those of the 69 workers tested in the 1998 survey. The two groups of workers were of similar mean age (37 and 35 years, respectively), and both had mean tenures of 16 months. The incidence of BeS in those hired in 2000-2004 was 0.7 worker per 1,000 person-months, and the incidence in the group hired earlier was 5.6 workers per 1,000 person-months. Although that is a large difference, it was based on very small numbers: one worker in 1,480 person-months and six workers in 1,081 person-months, respectively. It appears from the Cummings et al. paper that an extensive control program—including scrupulous attention to skin contact, inhalation exposure, and dust control throughout the facility—was effective in reducing (but not eliminating) the risk of sensitization. Comparison of the first (1992) and second (1998) surveys suggested that engineering control of airborne exposure alone was not sufficient to eliminate the risk of sensitization (Henneberger et al. 2001). Taiwo et al. (2008) recently reported findings from a voluntary beryllium-surveillance program for aluminum-smelter workers with low beryllium exposure (median concentration, 0.05 µg/m3). BeS was found in two (0.27%) of 734) of the workers on the basis of two abnormal BeLPT results. On further evaluation, probable CBD was diagnosed in the two workers; attempts to obtain lung tissue with bronchoscopy were unsuccessful. Although it was a low prevalence, probable CBD was detected in a group of workers in whom it previously was not suspected and who do not routinely undergo surveillance.
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Managing Health Effects of Beryllium Exposure A clinical evaluation for CBD generally includes a careful occupational history to assess exposure to beryllium, medical history, BeLPT testing, and medical evaluation with a focus on the lung. This evaluation generally includes spirometry, measurement of lung volume and diffusion capacity, chest radiography, and, if clinically indicated, high-resolution computed tomography (HRCT) of the chest. For a person with evidence of BeS and abnormalities that suggest the presence of interstitial lung disease, many clinicians would recommend bronchoscopy with BAL and transbronchial biopsy. In the setting of surveillance-detected BeS in a worker with no other evidence of pulmonary disease, caution should be taken in evaluating the histopathologic findings in lung biopsies to avoid misclassifying workers as having CBD. Common histopathologic findings in CBD include nonnecrotizing granulomas and mononuclear-cell infiltrates. Presentation of CBD ranges from the presence of histologic changes in lung biopsies consistent with CBD, but without symptoms, radiographic abnormalities, or decrements in pulmonary-function tests to end-stage lung disease with severe dyspnea, pulmonary-function decrements, radiographic abnormalities, hypoxemia, and cor pulmonale. Between the extremes, there may be mild to severe changes in one or more of the tests. The symptoms, radiographic changes, and pulmonary-function test findings are nonspecific for CBD, so other explanations need to be considered. (Normal pulmonary-function test results in a person who has CBD can reflect substantial declines for that patient, which may be apparent only if serial pulmonary-function test results are available with a true baseline for the person.) HRCT can detect abnormalities consistent with CBD when a chest radiograph or lung function appears normal. Thus, it can be difficult to determine whether mild disease is truly “subclinical” or constitutes a clinically significant effect; the term subclinical CBD has been used (Kriebel et al. 1988; Newman 1996) but not clearly defined. Other terms have also been used, such as early CBD (Rossman 1996) and surveillance CBD (Pappas and Newman 1993). For this report, CBD is used to refer to the full spectrum of CBD, as is done with other diseases (such as sarcoidosis and silicosis) that may be present despite the absence of detectable functional abnormalities or symptoms. The committee decided not to use the term subclinical CBD but to refer to CBD identified through screening as surveillance-identified CBD. Histopathology The largest study of the histopathology of CBD examined 124 cases of CBD from the Beryllium Case Registry (Freiman and Hardy 1970), which included workers in various industries (such as extraction and smelting, alloy production and processing, nuclear-weapons production, fluorescent-lamp manufacturing, and ceramic production). Patterns of diffuse noncaseating granulomas and various degrees of mononuclear-cell interstitial infiltrates were described in the lung-biopsy specimens obtained from open lung biopsies or autopsy material
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Managing Health Effects of Beryllium Exposure from those workers. Moderate to marked interstitial cellular infiltration was present in 80% (99 of 124) of the cases, and granulomas were absent or poorly formed in 44% (55 of 124). Some 20% (25 of 124) of the CBD cases had slight or absent cellular infiltration and well-formed granulomas, and this group appeared to have a better prognosis than those with more cellular infiltration. No relationships were identified between the histologic pattern and the character of the industrial exposure or the timing of the illness. Giant cells, asteroid bodies in giant cells, and calcific inclusions were also noted. About half the cases had accompanying moderate to advanced interstitial fibrosis. More recent studies have confirmed the histopathologic pattern of noncaseating granulomas, mononuclear-cell (lymphocytic) interstitial infiltrates, and less commonly interstitial fibrosis in lung specimens from transbronchial biopsies of patients with CBD (Newman et al.1989). Granulomas may not be detected in transbronchial biopsies, and a lymphocytic infiltrate may be the primary finding. The pathologic findings are not specific for CBD and may occur in other lung diseases, including sarcoidosis and hypersensitivity pneumonitis. In addition to noncaseating granulomas in the lung, extrapulmonary granulomas have been described in skin, liver, lymph nodes, and muscle in patients with CBD (Stoeckle et al. 1969). Bronchoscopy, Bronchoalveolar Lavage, and Biopsy Bronchoscopy with BAL and transbronchial biopsy is generally recommended for diagnosing CBD but is not without risk. Risks posed by bronchoscopy (such as oversedation, bleeding, and pneumothorax) vary with the individual patient’s circumstances and are considered on an individual basis, as discussed in Chapter 7. Transbronchial lung biopsies are performed to determine the presence of nonnecrotizing granulomas and mononuclear-cell interstitial infiltrates; fibrosis may also be seen. The granulomas are histologically indistinguishable from those due to other granulomatous disorders, such as sarcoidosis and a granulomatous response to infection (without caseation). BAL fluid is usually obtained by washing the middle lobe or lingula, and the fluid is sent for analysis of total and differential cell counts (to identify the presence of lymphocytosis), for culturing (to exclude infection as a cause of granulomatous changes), and to a specialized laboratory for a BeLPT of the BAL cells (rapid processing of the fluid with a specialized technique is needed) (Rossman et al. 1988; Newman et al. 1989). BAL in CBD typically shows lymphocytosis (Rossman et al. 1988; Newman et al. 1989); the percentage of BAL lymphocytes may correlate with physiologic and radiographic disease severity. In some subjects with BeS and biopsyconfirmed CBD, BAL has shown normal percentages of lymphocytes (Newman et al. 2005). Because of the association between cigarette-smoking and increases in alveolar macrophages, cigarette-smoking may obscure BAL lymphocytosis.
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Managing Health Effects of Beryllium Exposure In addition, nicotine has been shown to inhibit lymphocyte proliferation (Kalra et al. 2000). Pulmonary-Function Testing Results of pulmonary-function testing in patients with CBD are variable; they include restrictive, obstructive, mixed-pattern, or isolated impairment in lung diffusion capacity. Milder cases can have minimal or no physiologic abnormalities. Sensitive physiologic measures have been reported to be increased ratio of dead space to tidal volume (VD/VT) on exercise testing (Pappas and Newman 1993) and an increased alveolar-arterial oxygen (A-a) gradient on exercising (Daniloff et al. 1997); both reflect impaired gas exchange, but neither is specific for CBD. Increased A-a gradient on exercising has also shown good correlation with HRCT-scan indications of CBD (Daniloff et al. 1997). In more advanced cases, decreased DLCO, restriction, airflow obstruction, and arterial hypoxemia may be present alone or in combination. An early report from Andrews et al. (1969) of 41 patients studied for an average of 23 years after initial beryllium exposure showed a restrictive defect (20%); reduced diffusing capacity, normal lung volumes and airflow rates but reduced DLCO (36%); and an obstructive defect, which could have included mixed obstruction and restriction (39%); and normal pulmonary-function tests (5%). The authors reported that the obstructive pattern occurred in both smokers and nonsmokers and was associated with peribronchial granulomas. In a report of 12 patients with new diagnoses of CBD, pulmonary-function abnormalities were mild (Newman et al. 1989). One patient had restriction, and two former smokers had mild obstruction. Of the 12 patients, 11 had diffusing capacity that was normal when corrected for lung volume. Gas exchange on maximal exercise was normal in six of the nine patients tested. Another study of 21 patients with CBD (defined as beryllium exposure, consistent biopsy results, and abnormal BeLPT results) identified through screening at their plants showed that 14 had normal pulmonary-function test results and 10 had normal physiologic measures on maximal exercise (Pappas and Newman 1993). Four had airflow obstruction, two had mixed obstruction and restriction, and one had abnormal DLCO). The 11 with abnormal exercise physiologic results showed increased VD/VT on exercise, abnormal gas exchange, or both. A comparison group of 15 CBD patients referred because of symptoms or radiographic abnormalities showed similar results, although fewer of them had normal pulmonary-function test results and exercise physiologic results. Chest Radiography Radiographic findings in CBD were first described as diffuse densities and hilar adenopathy (Weber et al. 1965; Stoeckle et al. 1969; Hasan and Kazemi
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Managing Health Effects of Beryllium Exposure 1974). Contraction of lobes with hyperinflation of adjacent lobes, calcifications in parenchymal densities and hilar nodes, pneumothorax, cysts, bullae, and linear scars were also described in advanced cases. More recent studies of CBD that used the International Labour Organization classification system have described mainly diffuse, symmetric small opacities that were rounded, irregular, and of mixed patterns (Aronchick et al. 1987; Newman et al. 1994). Hilar adenopathy (always associated with interstitial abnormalities) was observed in 35-40% of people who had abnormal chest radiographs. Less common plain-film findings included coalescence of small opacities, linear scars, emphysematous bullae, retraction, distortion of lung architecture, and pleural thickening. Of those with biopsy-proven noncaseating granulomas, 46% had normal chest radiographs (Newman et al. 1994). The radiographic features of CBD are nonspecific and occur in other lung diseases, including sarcoidosis. HRCT of the chest is more sensitive than plain chest radiography in identifying abnormalities in patients with CBD. However, in 25% of patients with biopsy-proven noncaseating granulomas, HRCT scans have not shown signs consistent with CBD (Newman et al. 1994). The most common HRCT findings in CBD are nodules and septal thickening. Other findings include ground-glass attenuation, pleural irregularity, bronchial-wall thickening, and hilar and mediastinal adenopathy. Honeycombing has been reported in clinically severe cases (Newman et al. 1994). The HRCT appearances of CBD are nonspecific and occur in other lung diseases, including sarcoidosis. In a study by Daniloff et al. (1997), there was a significant correlation between HRCT changes and impaired gas exchange on exercise. Additional and New Tests Newer tests and approaches for improving the diagnosis of CBD and elucidating disease progression are being developed but are not in regular clinical use. For example, measuring neopterin concentrations in peripheral blood has been proposed as a diagnostic adjunct that may correlate with CBD severity or progression (Harris et al. 1997; Maier et al. 2003a). A beryllium-stimulated neopterin test has been reported to have a sensitivity of 80-90% and a specificity of 87-100% (Maier et al. 2003a). Beryllium-specific T-cell cytokines (interferon-gamma and interleukin-2) that are detected in vitro in peripheral blood proliferation assays (Pott et al. 2005) have been proposed to differentiate BeS from CBD (Tinkle et al. 1997). Progression and Management of Chronic Beryllium Disease As noted earlier, CBD has a clinical spectrum that can range from evidence of BeS and granulomas of the lung without clinically significant symptoms or deficits in lung function to end-stage lung disease. Little has been pub-
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Managing Health Effects of Beryllium Exposure lished on the progression of CBD from no apparent functional impairment to functionally significant lung disease. The risk factors and time course have not been clearly delineated. Possible risk factors for progression that have not been systematically assessed include magnitude and type of beryllium exposure (including particle size and solubility), exposure duration, concurrent exposure to other lung toxicants, smoking, race, sex, life stresses, combat, surgery, and genetic factors (Newman 1996). Newman (1996) emphasized the need for prospective studies of the natural history of BeS and surveillance-identified CBD. Because of the highly variable rate of progression and presentation of signs and symptoms, Rossman (1996) recommended an annual assessment of CBD patients, including a history, physical examination, chest radiography, pulmonary-function tests, and exercise-physiology tests. In a cohort of 55 patients with BeS followed for 1-11 years, 17 (31%) developed CBD in an average of 3.8 years (range, 1-9.5 years) (Newman et al. 2005). Eleven of the 17 who progressed to CBD had at least one followup evaluation after CBD was diagnosed to determine progression. Average followup from CBD diagnosis to the most recent evaluation was 4.7 years. One of the 11 received oral steroid therapy 2 years after CBD was diagnosed. Longer followup will be needed to determine outcome in those with surveillance-detected CBD on a long-term basis. Clinical management of CBD is modeled on the management of sarcoidosis. Oral corticosteroid treatment is initiated in patients who have evidence of progressive disease, although progressive disease is not well defined. In advanced cases of CBD (with respiratory symptoms and deteriorating pulmonary function that are considered as probably due to CBD), standard clinical practice includes the use of corticosteroids. In cases of CBD without physiologic impairment, whose diagnosis is usually based on transbronchial biopsy, the general approach is periodic re-evaluation, typically every 1-2 years, to look for deterioration in symptoms, pulmonary-function test results, or in chest radiographs. The decision to institute treatment with corticosteroids or other anti-inflammatory agents is made case by case. Older reports, which appeared when beryllium concentrations were higher, indicated that deterioration can be rapid after the development of clinical disease. Hardy and Tabershaw (1946) followed 17 cases in young workers (age at symptom onset, 20-38 years) and described progression to death in five patients within 1-2 years. Improvement was noted in several workers, but the others had continuing disease that progressed rapidly in many cases. In some cases, exacerbation and remission were described. In others, a stable condition that lasted for years was followed by deterioration. Deterioration was described as worsening dyspnea, worsening lung function, worsening radiographic abnormalities, and in some cases the signs and symptoms of pulmonary hypertension and cor pulmonale. One patient returned to normal (with regard to symptoms and radiographic findings) after treatment with adrenocorticotropin (Stoeckle et al. 1969). A more recent report of siblings with CBD showed clinical features similar to those reported earlier with progressive worsening of disease over 6 years despite steroid treatment (Tarlo et al. 2001). Since the report was published, one
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Managing Health Effects of Beryllium Exposure sibling has died, and the other has become oxygen-dependent. A third co-worker also has end-stage lung disease and has been assessed for heart-lung transplantation (case presentation at International Beryllium Meeting in Montreal 2005), and a fourth worker identified in the last year also has clinical disease requiring steroid therapy despite a BeLPT surveillance program (S. Tarlo, University of Toronto, personal communication, April 23, 2007). No studies have measured the effect of removal from exposure to beryllium on sensitization or CBD. Other occupational diseases that result from immunologic sensitization to an occupational agent include hypersensitivity pneumonitis and occupational asthma. In both, the outcome is worse with continued exposure after disease develops. However, it is difficult to extrapolate those results to beryllium disease because both of the other conditions typically result in symptoms and pulmonary-function changes within hours after exposure. In addition, CBD has different clinical characteristics from either of the other diseases. Older cases of CBD in people who had not been removed from exposure appear to have more severe disease compared with those who developed CBD more recently. However, it is not known whether that is due to the higher exposure concentrations of beryllium in former years, higher total pulmonary load of beryllium, or longer exposure after sensitization or onset of disease. It is unlikely that large cohorts of workers who are found to be sensitized to beryllium or have CBD will continue to work with beryllium exposure, and a research study to randomize workers to continue or avoid exposure would likely be considered unethical because of the potential severity of CBD. Therefore, the current clinical practice of a strong recommendation to remove CBD patients from exposure (Mapel and Coultas 2002 [p. 182, Box 10.1]; Cowie et al. 2005; Kreiss 2005; Maier et al. 2006) is appropriate. Offering it to those with BeS would also be prudent. There is an absence of published data on possible modification of risk of sensitization and disease by demographic variables or differences in baseline health status. CBD that is diagnosed before there is any loss of pulmonary function would not generally need treatment with corticosteroids; however, removal from exposure to prevent progression of disease is an important rationale for early detection of CBD. The committee recognizes that, as with many such occupational restrictions, implementation can be difficult because of economic or other job-related concerns for individual workers and their families. The diagnosis of CBD or BeS may be associated with psychosocial stress or loss of income. A case presentation at the 2005 International Beryllium Disease Conference in Montreal described a young man with surveillance-identified disease that resulted in job loss, major reactive depression, and unemployment (S. Tarlo, University of Toronto, personal communication, April 23, 2007). Although there are few published data on the psychosocial and economic consequences of a diagnosis of BeS or CBD, the committee recognizes the challenges of case management when there are potential psychosocial and economic implications. The committee believes that implementation of a comprehensive beryllium exposure- and disease-management program that includes appropriate
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Managing Health Effects of Beryllium Exposure worker education and counseling and medical-removal protection against lost wages (see Chapter 7) can minimize such potential adverse consequences. A more extensive examination of those issues lies outside the current scope of work. Extrapulmonary Disease Like sarcoidosis, CBD can have extrapulmonary manifestations; they are less common than in sarcoidosis, but few studies have systematically characterized them. As noted above, skin lesions used to be reported in workers exposed to beryllium salts (Kreiss et al. 2007) but much less commonly in workers exposed to beryllium-metal particles and dusts. Reported cutaneous manifestations of beryllium exposure include dermal granulomas and irritant and allergic contact dermatitis (Curtis 1951; Vilaplana et al. 1992; Berlin et al. 2003). The prevalence of those beryllium-related skin conditions appears to be relatively low, but epidemiologic studies have focused primarily on BeS and CBD. Medical Surveillance of Beryllium-Exposed Workers with the Beryllium Lymphocyte Proliferation Test Any test that is used in medical surveillance should have acceptable sensitivity, specificity, and predictive value. A diagnosis of BeS is usually followed by additional diagnostic testing for CBD with attendant risk and expense, so such a diagnosis must have an acceptable positive predictive value (PPV). Not all abnormal BeLPT results are confirmed by a second test on the same person or even on the same blood sample. Stange et al. (2004) reported on variation between laboratories when blood samples were split and sent to two laboratories simultaneously. The range of agreement on abnormal results was 26.2-61.8%, depending on the laboratories being compared; even between the laboratories with the highest agreement, 38.2% of abnormal BeLPT results were not confirmed by a second laboratory. Most guidelines for diagnosis of BeS require a confirmation of an abnormal BeLPT result with a second abnormal result; this reduces sensitivity while raising specificity. It is theoretically possible that someone could have a confirmed abnormal BeLPT result but not be sensitized to beryllium, but there is no other test to measure sensitization to beryllium, so it is not possible to identify such cases confidently. The available evidence suggests that false positives are rare. For example, of 458 employees at Rocky Flats who were either new hires or employees with no known exposure to beryllium, none had a confirmed abnormal result (Stange et al. 2004). Silveira et al. (2003) combined data on three sites and found no confirmed abnormal results in over 1,000 people with no identified exposure. Donovan et al. (2007) reported that six (1.1%) of the new hires had confirmed abnormal BeLPT results, but all six had 18-50 days of exposure to beryllium between the initial positive test and a confirmatory BeLPT, and this leaves open the possibility that sensitization occurred
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Managing Health Effects of Beryllium Exposure after exposure began; the same study reported that a peak in the prevalence of confirmed abnormal BeLPT results occurred 4-8 months after the beginning of employment. Because CBD has occurred in nonoccupational groups of people who lived near factories and cases can occur at very low levels of exposure, an apparent false positive may occur in a person who has nonoccupational exposure. The essential question is how well the BeLPT predicts CBD; the answer can only be approximated. The usefulness of a screening test can be described according to its sensitivity, its specificity, its PPV, and its negative predictive value. Sensitivity is a measure of how well the test detects true positives, and specificity is a measure of how well it detects true negatives. The PPV is a measure of how many of those who test positive have the underlying condition; it is the ratio of true positives to all positives. A test with very good sensitivity and specificity may not have a good PPV if the disease prevalence is low in the population being screened. For example, if we use a test whose sensitivity is 99.9% and whose specificity is 99.9% in a population of 1,000,000 of whom 1% have the disease, we will detect 9,990 cases and miss 10 cases. However, we will also have 990 false positives and a PPV of 91%. As the specificity of the test declines or the underlying prevalence of disease declines, so does the PPV. Middleton et al. (2008) used the data from Stange et al. (2004) to estimate the PPV of a single or confirmed abnormal BeLPT result. They calculated that a confirmed abnormal result would have a PPV of 0.968 in a population with a 1% prevalence of BeS, and a single abnormal result would have a PPV of 0.383 in the same population. Middleton et al. estimate a PPV of 0.872 for a single abnormal result when the prevalence of BeS is 10%, but in most settings a single unconfirmed abnormal result has little value because of a low PPV for BeS. Borak et al. (2006) argues that the PPV of the BeLPT is not high enough to meet current criteria for a good screening test. Their analysis of the PPV of the BeLPT for BeS is based on the use of a single test; current practice is to confirm a single abnormal test, and as Middleton et al. (2008) state, the PPV of the BeLPT can improve from 0.383 to 0.968 when a single abnormal BeLPT result is confirmed with a second abnormal result. There are fewer data on which estimate the PPV of a confirmed abnormal BeLPT result for CBD. In one study that specifically addressed a beryllium-exposed population, Deubner et al. (2001b) calculated the PPV of the blood BeLPT in the Brush-Wellman workforce and reported that a single unconfirmed result had a PPV of 39% for CBD, a confirmed abnormal result had a PPV of 45% for CBD, and a split sample reported as abnormal in two laboratories had a PPV of 40% for CBD. Those values would decline as the prevalence of CBD declined. The ratio of people with CBD to all sensitized people (with and without CBD) is the PPV of the BeLPT. The PPV was 35% in the Rocky Flats workers described by Stange et al. (2004); about one-third of those who were sensitized also had CBD. The PPV varied between subgroups of the Rocky Flats workers; it was 14% in workers with fewer than 5 years of employment at Rocky
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Managing Health Effects of Beryllium Exposure Flats and increased to 65% in workers with more than 20 years of work at the facility. The BeLPT is integral to any screening program. No alternative tests have been adequately validated to be put into practice outside research settings. The U.S. Air Force asked the committee to comment on five questions about the BeLPT. Each question is addressed below. What is the value of a borderline or a true-positive BeLPT result in predicting CBD? A borderline BeLPT result in combination with a positive result is generally indicative of sensitization. If a borderline result is not preceded or followed by a positive result, the subject is not considered sensitized. An algorithm for interpreting BeLPT results is presented in Appendix B, and the role of a borderline result is defined in the algorithm. The committee considers a true-positive (or confirmed abnormal) blood BeLPT result to be a predictor of CBD in workers with known exposure to beryllium, but there are insufficient data to predict the risk of progression accurately. What is the utility of the BeLPT in worker surveillance? The BeLPT identifies BeS in exposed workers. When used to identify at-risk populations, rather than as a screening or diagnostic test, the BeLPT has been shown to be valuable for identifying facilities or jobs that pose risk. Medical surveillance with the BeLPT has been able to detect BeS risk better than traditional air sampling because BeS can occur at low air concentrations of beryllium. 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 for 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 bronchoalveolar lavage, transbronchial biopsy, and possibly other tests (see Chapter 7). 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? Some studies have reported that CBD is diagnosed in up to 50% or more of screened workers who have positive BeLPT results, and the conversion rate from BeS to CBD has been estimated to be 6-8% per year (Newman et al. 2005). However, the conversion rate was based on only one cohort of workers. Although those with positive BeLPT results are at increased risk for CBD, the available evidence is insufficient to make quantitative predictions about the magnitude of the risk.
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Managing Health Effects of Beryllium Exposure Is there a standardized method for achieving consistent test results in different laboratories? No standardized method is used in laboratories in the Unites States. As described above, Brousseau et al. showed that concordance in results between laboratories improved when testing procedures were closely matched (when such variables as dose, time, and controls were standardized). Concordance in laboratory testing and analysis and a standard testing algorithm should reduce variation between laboratories but will not address issues of the sensitivity and specificity of the test. CONCLUSIONS Epidemiologic studies have shown that BeS and CBD occur in settings where airborne exposure to beryllium is below the current standard of 2 µg/m3 but do not indicate clearly how much lower such a standard would have to be to be protective. Studies have shown that the risk of CBD in workers depends on the industry and the process, but the available data are inadequate for estimating specific risks related to different forms of beryllium exposure. Thus, the committee concludes that it is not possible to estimate a chronic inhalation-exposure level that is likely to prevent BeS and CBD in settings where beryllium has the potential for being aerosolized. Existing medical-management programs designed to keep air, surface, and skin exposure as low as feasible have been successful in substantially reducing BeS and CBD in various beryllium industries. RECOMMENDATIONS In the absence of sufficient data to establish a chronic inhalation level for beryllium that is unlikely to result in BeS or CBD, the committee recommends that an exposure- and disease-management program be implemented by the U.S. Air Force 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 possible, 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 exposure to the lowest feasible level. Important aspects of the exposure- and disease-management program are discussed in Chapter 7. The Air Force should evaluate the feasibility of requiring concordance in testing procedures between laboratories performing its BeLPTs, and the committee recommends the use of an algorithm for interpreting BeLPT results (see Appendix B). As noted several times in this chapter, there remain many important questions about BeS and CBD, including host and exposure risk factors and the natural history of BeS and CBD. Research to address these questions will be assisted by the Air Force developing a centralized surveillance database (see Chapter 7),
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Managing Health Effects of Beryllium Exposure which would include workplace and exposure data and clinical information obtained as part of the beryllium exposure- and disease-management program. In addition to facilitating evaluation of the effectiveness of the program over time, the database could be appropriately designed to be used as a resource by researchers.