The beryllium lymphocyte proliferation test: Relevant issues in beryllium health surveillance

BACKGROUND: The beryllium lymphocyte proliferation test (Be-LPT) measures beryllium-specific cellular immune response, and is useful in medical surveillance of beryllium sensitivity and chronic beryllium disease (CBD). METHODS: Current and former employees (n = 12,194) of 18 United States Department of Energy (DOE) sites were tested for beryllium sensitization at four laboratories with Be-LPT expertise. Beryllium sensitized individuals were offered evaluations for CBD. The sensitivity, specificity, and positive predictive value (PPV) of the Be-LPT were determined, as was inter- and intra-laboratory agreement. RESULTS: False positives were calculated to be 1.09%, with a laboratory range of 0.00-3.35% for the 10-year investigation. Be-LPTs performed on inter-laboratory split blood specimens from sensitized individuals showed a false negative rate of 31.7%. The intra-laboratory repeatability of abnormal Be-LPT results ranged from 80.4-91.9%. The sensitivity of the Be-LPT was determined to be 0.683, with a specificity of 0.969. The PPV of one abnormal Be-LPT was 0.253. CONCLUSIONS: The Be-LPT is efficacious in medical surveillance of beryllium-exposed individuals. The PPV of the Be-LPT is comparable to other widely accepted medical tests. Confirmation of an abnormal result is recommended to assure appropriate referral for CBD medical evaluation.     

Sensitization and chronic beryllium disease among workers in copper-beryllium distribution centers

OBJECTIVE: Little is known about the risk of sensitization and chronic beryllium disease (CBD) among workers performing limited processing of copper-beryllium alloys downstream of the primary beryllium industry. In this study, we performed a cross-sectional survey of employees at three copper-beryllium alloy distribution centers. METHODS: One hundred workers were invited to be tested for beryllium sensitization using the beryllium blood lymphocyte proliferation test (BeLPT); a sensitized worker was further evaluated for CBD. Available beryllium mass concentration air sampling data were obtained for characterization of airborne exposure. RESULTS: One participant, who had exposure to other forms of beryllium, was found to be sensitized and to have CBD, resulting in a prevalence of sensitization/CBD of 1% for all tested. CONCLUSIONS: The overall prevalence of beryllium sensitization and CBD for workers in these three copper-beryllium alloy distribution centers is lower than for workers in primary beryllium production facilities.     

Process-related risk of beryllium sensitization and disease in a copper-beryllium alloy facility

BACKGROUND: Chronic beryllium disease (CBD), which primarily affects the lungs, occurs in sensitized beryllium-exposed individuals. At a copper-beryllium alloy strip and wire finishing facility we performed a cross-sectional survey to examine prevalences of beryllium sensitization and CBD, and relationships between sensitization and CBD and work areas/processes. METHODS: Current employees (185) were offered beryllium lymphocyte proliferation testing (BeLPT) for sensitization, clinical evaluation for CBD (if sensitized), and questionnaires. We obtained historical airborne beryllium measurements. RESULTS: Participation was 83%. Prevalences of sensitization and CBD were 7% (10/153) and 4% (6/153), respectively; this included employees with abnormal BeLPTs from two laboratories, four diagnosed with CBD during the survey, and one each diagnosed preceding and following the survey. Potential BeLPT laboratory problems were noted; one laboratory was twice as likely to have reported an abnormal result (P < 0.05, all tests), and five times as likely to have reported a borderline or uninterpretable result (P < 0.05, first blood draw and all tests). CBD risk was highest in rod and wire production (P < 0.05), where air levels were highest. CONCLUSIONS: Sensitization and CBD were associated with an area in which beryllium air levels exceeded 0.2 microg/m3, and not with areas where this level was rarely exceeded. Employees at this copper-beryllium alloy facility had similar prevalences of sensitization and CBD as workers at facilities with higher beryllium air levels.     

Chronic beryllium disease and sensitization at a beryllium processing facility

We conducted a medical screening for beryllium disease of 577 former workers from a beryllium processing facility. The screening included a medical and work history questionnaire, a chest radiograph, and blood lymphocyte proliferation testing for beryllium. A task exposure and a job exposure matrix were constructed to examine the association between exposure to beryllium and the development of beryllium disease. More than 90% of the cohort completed the questionnaire, and 74% completed the blood and radiograph component of the screening. Forty-four (7.6%) individuals had definite or probable chronic beryllium disease (CBD), and another 40 (7.0%) were sensitized to beryllium. The prevalence of CBD and sensitization in our cohort was greater than the prevalence reported in studies of other beryllium-exposed cohorts. Various exposure measures evaluated included duration; first decade worked; last decade worked; cumulative, mean, and highest job; and highest task exposure to beryllium (to both soluble and nonsoluble forms). Soluble cumulative and mean exposure levels were lower in individuals with CBD. Sensitized individuals had shorter duration of exposure, began work later, last worked longer ago, and had lower cumulative and peak exposures and lower nonsoluble cumulative and mean exposures. A possible explanation for the exposure-response findings of our study may be an interaction between genetic predisposition and a decreased permanence of soluble beryllium in the body. Both CBD and sensitization occurred in former workers whose mean daily working lifetime average exposures were lower than the current allowable Occupational Safety and Health Administration workplace air level of 2 microg/m3 and the Department of Energy guideline of 0.2 microg/m3.     

Beryllium health effects in the era of the beryllium lymphocyte proliferation test

The beryllium lymphocyte proliferation test (BeLPT) has revolutionized our approach to the diagnosis, screening, and surveillance of beryllium health effects. Based on the development of a beryllium-specific cell-mediated immune response, the BeLPT has allowed us to define early health effects of beryllium, including beryllium sensitization (BeS), and chronic beryllium disease (CBD) at a subclinical stage. The use of this test as a screening tool has improved our understanding of these health effects. From a number of studies it is apparent that BeS precedes CBD and develops after as little as 9 weeks of beryllium exposure. CBD occurs within 3 months and up to 30 years after initial beryllium exposure. Exposure-response variables have been associated with BeS/CBD, including work as a machinist, chemical or metallurgical operator, laboratory technician, work in ceramics or beryllium metal production, and years of beryllium exposure. Recent studies have found BeS and CBD in workplaces in which the majority of exposures were below the 2 microg/m3 OSHA time-weighted average (TWA). Ideally, the BeLPT would be used in surveillance aimed at defining other risk-related processes, determining exposure variables which predict BeS and CBD, and defining the exposure level below which beryllium health effects do not occur. Unfortunately, the BeLPT can result in false negative tests and still requires an invasive procedure, a bronchoscopy, for the definitive diagnosis of CBD. Thus, research is needed to establish new tests to be used alone or in conjunction with the BeLPT to improve our ability to detect early beryllium health effects.     

Screening for beryllium disease among construction trade workers at Department of Energy nuclear sites

BACKGROUND: To determine whether current and former construction workers are at significant risk for occupational illnesses from work at the Department of Energy's (DOE) nuclear weapons facilities, screening programs were undertaken at the Hanford Nuclear Reservation, Oak Ridge Reservation, and the Savannah River Site. METHODS: Medical examination for beryllium disease used a medical history and a beryllium blood lymphocyte proliferation test (BeLPT). Stratified and multivariate logistic regression analyses were used to explore the risk of disease by age, race, sex, trade, duration of DOE employment, reported work in buildings where beryllium was used, and time since last DOE site employment. RESULTS: Of the 3,842 workers included in this study, 34% reported exposure to beryllium. Overall, 2.2% of workers had at least one abnormal BeLPT test, and 1.4% were also abnormal on a second test. Regression analyses demonstrated increased risk of having at least one abnormal BeLPT to be associated with ever working in a site building where beryllium activities had taken place. CONCLUSIONS: The prevalence of beryllium sensitivity and chronic beryllium disease (CBD) in construction workers is described and the positive predictive value of the BeLPT in a population with less intense exposure to beryllium than other populations that have been screened is discussed. The BeLPT findings and finding of cases of CBD demonstrate that some of these workers had significant exposure, most likely, during maintenance, repair, renovation, or demolition in facilities where beryllium was used.     

Exposure-response analysis for beryllium sensitization and chronic beryllium disease among workers in a beryllium metal machining plant

The current occupational exposure limit (OEL) for beryllium has been in place for more than 50 years and was believed to be protective against chronic beryllium disease (CBD) until studies in the 1990s identified beryllium sensitization (BeS) and subclinical CBD in the absence of physical symptoms. Inconsistent sampling and exposure assessment methodologies have often prevented the characterization of a clear exposure-response relationship for BeS and CBD. Industrial hygiene (3831 personal lapel and 616 general area samples) and health surveillance data from a beryllium machining facility provided an opportunity to reconstruct worker exposures prior to the ascertainment of BeS or the diagnosis of CBD. Airborne beryllium concentrations for different job titles were evaluated, historical trends of beryllium levels were compared for pre- and postengineering control measures, and mean and upper bound exposure estimates were developed for workers identified as beryllium sensitized or diagnosed with subclinical or clinical CBD. Five approaches were used to reconstruct historical exposures of each worker: industrial hygiene data were pooled by year, job title, era of engineering controls, and the complete work history (lifetime weighted average) prior to diagnosis. Results showed that exposure metrics based on shorter averaging times (i.e., year vs. complete work history) better represented the upper bound worker exposures that could have contributed to the development of BeS or CBD. Results showed that beryllium-sensitized and CBD workers were exposed to beryllium concentrations greater than 0.2 microg/m3 (95th percentile), and 90% were exposed to concentrations greater than 0.4 microg/m3 (95th percentile) within a given year of their work history. Based on this analysis, BeS and CBD generally occurred as a result of exposures greater than 0.4 microg/m3 and maintaining exposures below 0.2 microg/m3 95% of the time may prevent BeS and CBD in the workplace.     

The association between HLA-DPB1Glu69 and chronic beryllium disease and beryllium sensitization

BACKGROUND: Several case-control studies have found an association between chronic beryllium disease (CBD) and HLA-DPB1 gene variants. However, the relationship between HLA-DPB1 and beryllium sensitization, and whether the presence of one or two HLA-DPB1(Glu69) alleles is differentially associated with CBD and beryllium sensitization have not been completely resolved. METHODS: Restriction fragment length polymorphism (RFLP) analysis was used to address these questions in a large population-based cohort consisting of 884 beryllium workers (90 with CBD, 64 beryllium sensitized). RESULTS: HLA-DPB1(Glu69) was associated with both CBD (OR = 9.4; 95% CI = 5.4, 16.6) and sensitization (OR = 3.3, 95% CI = 1.9, 5.9). Further, workers with CBD and sensitization were more likely to be homozygous HLA-DPB1(Glu69) compared to workers without disease or sensitization (P < 0.001). CONCLUSIONS: Follow-up of this cohort, scrutiny of HLA-DPB1 haplotypes, and evaluation of gene-environment and gene-gene interactions will be important for fully understanding the immunogenetic nature of this occupational disease.     

Variability, predictive value, and uses of the beryllium blood lymphocyte proliferation test (BLPT): preliminary analysis of the ongoing workforce survey

The beryllium blood lymphocyte proliferation test (BLPT) is used as a medical surveillance tool for assessment of persons at risk for developing clinical and subclinical chronic beryllium disease (CBD). Three laboratories, coded "A," "B," and "C," were used to perform the BLPTs, which involved two simultaneous tests on a split specimen. The intra-laboratory agreement analysis compared the first and the second test performed by the same laboratory. The interlaboratory agreement analysis compared test results performed by different laboratories on the same sample. The level of agreement was expressed as a kappa statistic. The positive predictive value (PPV) analysis compared BLPT results against the results of a bronchoscopy used to detect CBD. The data included 5483 records representing 3081 samples from 1510 persons. Intra-laboratory agreement was fair to moderate, with kappa values between 0.3 and 0.6. Inter-laboratory agreement was moderate (kappa = 0.5) for Labs A and B, moderate (kappa = 0.6) for Labs B and C, and poor (kappa = 0.2) for Labs A and C. A single unconfirmed abnormal test had a PPV for CBD of 39 percent, a confirmed (based on subsequent testing) abnormal test had a PPV for CBD of 45 percent, and a first-time double abnormal test had a PPV for CBD of 49 percent. Substantial inter- and intralaboratory disagreement exists between and within major laboratories that conduct this test.     

Illness Absences Among Beryllium Sensitized Workers

Objectives. This study examined absence rates among US Department of Energy workers who had beryllium sensitization (BeS) or were diagnosed with chronic beryllium disease (CBD) compared with those of other workers.Methods. We used the lymphocyte proliferation test to determine beryllium sensitivity. In addition, we applied multivariable logistic regression to compare absences from 2002 to 2011 between workers with BeS or CBD to those without, and survival analysis to compare time to first absence by beryllium sensitization status. Finally, we examined beryllium status by occupational group.Results. Fewer than 3% of the 19 305 workers were BeS, and workers with BeS or CBD had more total absences (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.18, 1.46) and respiratory absences (OR = 1.51; 95% CI = 1.24, 1.84) than did other workers. Time to first absence for all causes and for respiratory conditions occurred earlier for workers with BeS or CBD than for other workers. Line operators and crafts personnel were at increased risk for BeS or CBD.Conclusions. Although not considered “diseased,” workers with BeS have higher absenteeism compared with nonsensitized workers.The US Department of Energy (DOE) oversees a unique industrial complex in which diverse activities in research, production, and dismantlement have the potential for workplace exposures to a variety of chemical hazards. The Illness and Injury Surveillance Program (IISP) began in 1990, in response to the DOE’s legislative mandate1,2 to monitor the health of its workers. By 2011, there were 15 sites encompassing 164 000 workers participating in the IISP. All workers absent 5 or more consecutive workdays (or 40 hours) were included in the IISP. The 5-day calendar requirement corresponds with the DOE Order 5480.8 that requires workers absent 5 workdays report to the site’s occupational medicine clinic to be pronounced “fit for duty” before returning to work. A worker could have multiple absences in a given year. The IISP database contains worker health information, including dates and medical condition related to an absence from work, demographic data, and job titles. Annual site-specific surveillance reports were produced from 1992 through 2010, and worker health summaries3,4 presented analyses of IISP data over time and from multiple sites.Beryllium is a lightweight, strong, hard silver-gray metallic element with many industrial applications. Beryllium has been used extensively in the DOE complex in its nuclear operations. Although the potential for exposure in the current workplace is far less than from early operations, federal regulations5 require DOE sites to: (1) determine whether employees are at risk for chronic beryllium disease (CBD), (2) implement CBD prevention programs, and 3) report health and exposure data to the Beryllium-Associated Worker Registry (BAWR).The BAWR, established in 2002, collects information on all DOE workers potentially at risk for occupational exposure to beryllium. It covers 27 DOE contractor facilities and contains information on 28 429 workers tested for beryllium sensitization (BeS). Medical information in the BAWR database includes the results and dates of all beryllium lymphocyte proliferation tests (BeLPTs). The BeLPT is a blood test that measures the proliferation of lymphocytes exposed to beryllium in vitro. The BeLPT result is said to be abnormal when lymphocytes proliferate more rapidly in the presence of beryllium than in the absence of beryllium. A worker is classified as having BeS if there are (1) 2 or more abnormal BeLPTs, (2) 1 abnormal BeLPT and 2 or more borderline BeLPTs, or (3) an abnormal BeLPT from cells collected from a bronchoalveolar lavage. The abnormal or borderline BeLPTs do not have to be sequential for a worker to be considered sensitized. A worker with an abnormal BeLPT is removed from further work with beryllium.CBD, a disease of the lungs caused by inhaling beryllium powder or fumes, is characterized by granuloma formation in and eventual scarring of lung tissue. While BeS is not a disease, a worker sensitized to beryllium is at increased risk for CBD. If a worker has been diagnosed with CBD, the diagnostic information and date are included in the BAWR.A site’s participation in the IISP was independent of the use of beryllium at the site. The site occupational medical department assigned a unique pseudo-identifier to each worker, which allowed the records in the IISP and the BAWR to be linked. The IISP and BAWR electronic data files do not contain any personal identifiers to protect the workers’ identities. A worker may not opt out of either registry. The de-identified records are stored in 2 independent databases maintained at the Oak Ridge Associated Universities, a contractor to the DOE Office of Environment, Health, Safety, and Security. Investigators have found that alterations in gas exchange and the pulmonary vascular bed occur early in beryllium disease.6 In a study of early pulmonary function test abnormalities, 21 patients with BeS had similar baseline chest x-rays, pulmonary function, and exercise tolerance as nonsensitized individuals. However, measurable physiologic abnormalities were found at the time of diagnosis in 12 (57%) of these individuals. We postulated that physiological abnormalities could lead to prolonged absences attributed to illnesses among workers with BeS or CBD. The objective of this analysis was to determine if illness absence rates differed among workers with BeS or CBD compared with workers who were BeLPT normal. Access to data from the IISP and the BAWR provided a unique opportunity to conduct this investigation and allowed a quantitative examination of this relationship.A second objective of this investigation was to determine if workers in certain occupational groups were more likely to have BeS or CBD than other workers. Job titles were organized into 7 occupational groups: administrative support, professionals, line operators, crafts, technical support, service, and security and fire. Line operators and craft workers were determined a priori to have highest potential exposure to beryllium. Line operators were most likely to be involved in machining and grinding beryllium or beryllium alloy parts; craft workers, which included laborers, were also at higher risk for exposure to beryllium because of work assignments in areas where beryllium activities were present. Occupational groups were defined in the IISP so it was not possible to refine analyses by specific job titles, and specific job tasks could vary from site to site.Several studies compared BeS and CBD occurrence among occupational groups. Compared with workers in other job categories, machinists had the highest BeS rates (4.7%).7 In a study of 55 monitored workers with BeS, 17 individuals who developed CBD were more likely to have been machinists.8 In a case-control study, those with BeS and CBD were more likely to have worked as machinists than were controls (odds ratio [OR] = 4.4; 95% confidence interval [CI] = 1.1, 17.5).9 Workers in the rod and wire production area of a plant using copper-beryllium alloys had significantly higher prevalence of BeS (10%) or CBD (6%) than did workers in other areas of the plant with lower beryllium air levels (P < .05).10 Construction workers at 3 DOE sites where beryllium activities occurred were at increased risk for at least 1 abnormal BeLPT from activities (maintenance, repair, renovation, and demolition) conducted at those buildings.11 The risk of BeS was elevated among individuals working in a Nevada Test Site building where beryllium parts were machined (OR = 2.52; 95% CI = 1.02, 6.19).12 Workers who machined or ground copper-beryllium alloys appeared at increased risk for BeS compared with workers with low potential beryllium exposure (OR = 2.6; 95% CI = 0.23, 29.9).13     

A Reconsideration of Acute Beryllium Disease

Context

Although chronic beryllium disease (CBD) is clearly an immune-mediated granulomatous reaction to beryllium, acute beryllium disease (ABD) is commonly considered an irritative chemical phenomenon related to high exposures. Given reported new cases of ABD and projected increased demand for beryllium, we aimed to reevaluate the patho physiologic associations between ABD and CBD using two cases identified from a survey of beryllium production facility workers.

Case Presentation

Within weeks after exposure to beryllium fluoride began, two workers had systemic illness characterized by dermal and respiratory symptoms and precipitous declines in pulmonary function. Symptoms and pulmonary function abnormalities improved with cessation of exposure and, in one worker, recurred with repeat exposure. Bronchoalveolar lavage fluid analyses and blood beryllium lymphocyte proliferation tests revealed lymphocytic alveolitis and cellular immune recognition of beryllium. None of the measured air samples exceeded 100 μg/m³, and most were < 10 μg/m³, lower than usually described. In both cases, lung biopsy about 18 months after acute illness revealed noncaseating granulomas. Years after first exposure, the workers left employment because of CBD.

Discussion

Contrary to common understanding, these cases suggest that ABD and CBD represent a continuum of disease, and both involve hypersensitivity reactions to beryllium. Differences in disease presentation and progression are likely influenced by the solubility of the beryllium compound involved.

Relevance to Practice

ABD may occur after exposures lower than the high concentrations commonly described. Prudence dictates limitation of further beryllium exposure in both ABD and CBD.     

Serum neopterin in chronic beryllium disease

We evaluated serum neopterin as a biomarker of chronic beryllium disease (CBD), for use in conjunction with the beryllium lymphocyte proliferation test (BeLPT) in workplace screening. Serum neopterin levels were determined by radioimmunoassay, and we compared levels in three groups: CBD (n = 86), beryllium sensitized (BeS) (n = 22), and normal (Nor) (n = 20). Those in the diseased group underwent pulmonary function tests, bronchoalveolar lavage (BAL), and maximal exercise testing. We correlated neopterin levels with results of these clinical parameters of disease severity. To evaluate the optimum sensitivity, specificity, and neopterin cut-off value, receiver operator characteristic (ROC) curves were generated. The median serum neopterin level in CBD was significantly higher than in BeS or in Nor [median 1.45, 25^th, 75^th percentiles (1.00, 2.7) ng/ml, 0.82 (0.67, 1.16) ng/ml, and 0.92 (0.86, 1.16) ng/ml, respectively] (P < 0.05). In CBD, we observed statistically significant associations between neopterin and measures of gas exchange and BAL cellularity. Using a neopterin value of 1.27 ng/ml, test specificity is 88%. In those workers with an abnormal BeLPT, serum neopterin has high positive predictive value (92%), and can identify disease, helping to distiudistinguish it from BeS without the risks of biopsy. Am. J. Ind. Med. 32:21-26, 1997. © 1997 Wiley-Liss, Inc.     

Beryllium sensitization, chronic beryllium disease, and exposures at a beryllium mining and extraction facility

In this study, we examine beryllium sensitization, chronic beryllium disease (CBD), and workplace exposures at a beryllium mining (mine) and extraction facility (mill) in Delta, Utah. Historical airborne beryllium data collected between 1970-1999 included general area (GA), breathing zone (BZ), and personal lapel (LP) measurements and calculations of job-specific quarterly daily-weighted averages (DWVAs). We compared GA, BZ, and DWA data to airborne beryllium data from a mixed beryllium products facility and a beryllium ceramics facility located in Elmore, Ohio and Tucson, Arizona, respectively. At the Delta facility, jobs involving beryllium hydrolysis and wet-grinding activities had the highest air concentrations; annual median GA concentrations were less than 0.3 microg/m3 or both areas. Annual median GA sample concentrations ranged from 0.1-0.4 microg/m(-3) at Delta. These levels were generally lower than Elmore (0.1-1.0 microg/m3) and were comparable to the Tucson facility (0.1-0.4 microg/m3). Median BZ concentrations were higher, whereas DWAs were lower at the Delta facility than at the other two facilities. Among the 87 employees at the Delta facility, 75 participated in the medical survey; there were three persons sensitized, one with CBD. The individual with CBD previously worked at the Elmore facility for 10 years. Cumulative CBD incidence rates were significantly lower at the Delta facility: 0.3 percent compared to 2.0 percent for Elmore and 2.5 percent for the Tucson facility. Sensitization and CBD prevalence rates determined from cross-sectional surveys for the Delta facility were lower than but not significantly different from rates at the other two facilities. There was no sensitization or CBD among those who worked only at the mine where the only exposure to beryllium results from working with bertrandite ore. Although these results are derived from a small sample, this study suggests that the form of beryllium may affect the likelihood of developing CBD. Specifically, exposure to beryl and bertrandite ore dusts or to beryllium salts, in the absence of exposure to beryllium oxide particulates appears to pose a lower risk for developing CBD.     

Efficacy of serial medical surveillance for chronic beryllium disease in a beryllium machining plant

There is limited information on the use of the blood beryllium lymphocyte proliferation test (BeLPT) at regular intervals in medical surveillance. Employees of a beryllium machining plant were screened with the BeLPT biennially, and new employees were screened within 3 months of hire. Of 235 employees screened from 1995 to 1997, a total of 15 (6.4%) had confirmed abnormal BeLPT results indicating beryllium sensitization; nine of these employees were diagnosed with chronic beryllium disease. Four of the 15 cases were diagnosed within 3 months of first exposure. When 187 of the 235 employees participated in biennial screening in 1997 to 1999, seven more had developed beryllium sensitization or chronic beryllium disease, increasing the overall rate to 9.4% (22 of 235). The blood BeLPT should be used serially in beryllium disease surveillance to capture new or missed cases of sensitization and disease. Beryllium sensitization and chronic beryllium disease can occur within 50 days of first exposure in modern industry.     

Beryllium-stimulated neopterin as a diagnostic adjunct in chronic beryllium disease

BACKGROUND: The diagnosis of chronic beryllium disease (CBD) relies on the beryllium lymphocyte proliferation test (BeLPT) to demonstrate a Be specific immune response. This test has improved early diagnosis, but cannot discriminate beryllium sensitization (BeS) from CBD. We previously found high neopterin levels in CBD patients' serum and questioned whether Be-stimulated neopterin production by peripheral blood cells in vitro might be useful in the diagnosis of CBD. METHODS: CBD, BeS, Be exposed workers without disease (Be-exp) normal controls and sarcoidosis subjects were enrolled. Peripheral blood mononuclear cells (PBMN) were cultured in the presence and absence of beryllium sulfate. Neopterin levels were determined from cell supernatants by enzyme linked immunosorbent assay (ELISA). Clinical evaluation of CBD subjects included chest radiography, pulmonary function testing, exercise testing, and the BeLPT. RESULTS: CBD patients produced higher levels of neopterin in both unstimulated and Be-stimulated conditions compared to all other subjects (P < 0.0001). Unstimulated neopterin mononuclear cell levels overlapped among groups, however, Be-stimulated neopterin levels in CBD showed little overlap. Using a neopterin concentration of 2.5 ng/ml as a cutoff, Be-stimulated neopterin had a sensitivity of 80% and specificity of 100% for CBD and was able to differentiate CBD from BeS. Be-stimulated neopterin was inversely related to measures of pulmonary function, exercise capacity, and gas exchange. CONCLUSIONS: Neopterin may be a useful diagnostic adjunct in the non-invasive assessment of CBD, differentiating CBD from BeS. Further studies will be required to determine how it performs in workplace screening.     

Beryllium sensitization and disease among long-term and short-term workers in a beryllium ceramics plant

OBJECTIVE: Workers at a beryllium ceramics plant were tested for beryllium sensitization and disease in 1998 to determine whether the plant-wide prevalence of sensitization and disease had declined since the last screening in 1992; an elevated prevalence was associated with specific processes or with high exposures; exposure-response relationships differed for long-term workers hired before the last plant-wide screening and short-term workers hired since then. METHODS: Current workers were asked to complete a questionnaire and to provide blood for the beryllium lymphocyte proliferation test (BeLPT). Those with an abnormal BeLPT were classified as sensitized, and were offered clinical evaluation for beryllium disease. Task- and time-specific measurements of airborne beryllium were combined with individual work histories to compute mean, cumulative, and peak beryllium exposures for each worker. RESULTS: The 151 participants represented 90% of 167 eligible workers. Fifteen (9.9% of 151) had an abnormal BeLPT and were split between long-term workers (8/77 = 10.4%) and short-term workers (7/74 = 9.5%). Beryllium disease was detected in 9.1% (7/77) of long-term workers but in only 1.4% (1/74) of short-term workers (P = 0.06), for an overall prevalence of 5.3% (8/151). These prevalences were similar to those observed in the earlier survey. The prevalence of sensitization was elevated in 1992 among machinists, and was still elevated in 1998 among long-term workers (7/40 = 18%) but not among short-term workers (2/36 = 6%) with machining experience. The prevalence of sensitization was also elevated in both groups of workers for the processes of lapping, forming, firing, and packaging. The data suggested a positive relationship between peak beryllium exposure and sensitization for long-term workers and between mean, cumulative, and peak exposure and sensitization for short-term workers, although these findings were not statistically significant. Long-term workers with either a high peak exposure or work experience in forming were more likely to have an abnormal BeLPT (8/51 = 16%) than the other long-term workers (0/26, P = 0.05). All seven sensitized short-term workers either had high mean beryllium exposure or had worked longest in forming or machining (7/55 = 13% versus 0/19, P = 0.18). CONCLUSIONS: A plant-wide decline in beryllium exposures between the 1992 and 1998 surveys was not matched by a decline in the prevalence of sensitization and disease. Similar to findings from other studies, beryllium sensitization/disease was associated with specific processes and elevated exposures. The contrast in disease prevalence between long-term and short-term workers suggests that beryllium sensitization can occur after a short period of exposure, but beryllium disease usually requires a longer latency and/or period of exposure. The findings from this study motivated interventions to more aggressively protect and test workers, and new research into skin exposure as a route of sensitization and the contribution of individual susceptibility.     

Chronic beryllium disease: a hypersensitivity disorder

Chronic beryllium disease (CBD) is one of two pulmonary syndromes caused by environmental exposure to beryllium. Acute beryllium disease was first described in 1943 and is an acute toxic reaction to beryllium. CBD was first described in 1946 and the pathogenesis of this disorder was not fully appreciated until the development of fiberoptic bronchoscopy allowed sampling of bronchoalveolar lung cells. Because CBD was associated with a delayed skin test reaction to beryllium, occurred in only 1-5 percent of individuals, was not associated with a clear-cut dose-response curve, and was associated with a granulomatous reaction, a hypersensitivity to beryllium was suspected as the cause. The hypothesis that CBD was due to hypersensitivity was not proven until the 1980s when samples of bronchoalveolar cells obtained by bronchoscopy demonstrated that not only did every individual with CBD have lymphocytes that could respond to beryllium (lymphocyte proliferation assay), but, also, that there was an accumulation of these cells at the site of active disease. The immunological reaction in CBD was associated with CD4+ lymphocytes responding to a beryllium-influenced but unknown peptide(s) that was (were) presented by HLA molecules on antigen-presenting cells. Genetic studies also demonstrated an association of CBD with HLA-DPB1 alleles that contain glutamine at position 69 in up to 97 percent of subjects with CBD but also 30-40 percent of controls. The understanding that CBD is a hypersensitivity disorder has had important implications for the diagnosis, screening, and environmental control precautions necessary for its prevention.     

Beryllium Exposure Control Program at the Cardiff Atomic Weapons Establishment in the United Kingdom

The Cardiff Atomic Weapons Establishment (AWE) plant, located in Cardiff, Wales, United Kingdom, used metallic beryllium in their beryllium facility during the years of operation 1961-1997. The beryllium production processes included melting and casting, powder production, pressing, machining, and heat and surface treatments. As part of Cardiff's industrial hygiene program, extensive area measurements and personal lapel measurements of airborne beryllium concentrations were collected for Cardiff workers over the 36-year period of operation. In addition to extensive air monitoring, the beryllium control program also utilized surface contamination controls, building design, engineering controls, worker controls, material controls, and medical surveillance. The electronic database includes 367,757 area sampling records at 101 locations and 217,681 personal lapel sampling records collected from 194 employees over the period 1981-1997. Similar workplace samples were collected from 1961 to 1980, but they were not analyzed because they were not available electronically. Annual personal mean sampling concentrations for all workers ranged from 0.11 to 0.72 micrograms per cubic meter (microg/m3) with 95th percentiles ranging from 0.22 to 1.89 microg/m3; foundry workers worked in the highest concentration areas with a mean of 0.87 microg/m3 and a 95th percentile of 2.9 microg/m3. Area sampling concentrations, as expected, were lower than personal sampling concentrations. Mean annual area sample concentrations for all locations ranged from 0.02 to 0.32 microg/m3. The area sample 95th percentile concentrations for all years were below 0.5 microg/m3. For the overwhelming majority of samples, airborne beryllium concentrations were below the 2.0 microg/m3 standard. Although blood lymphocyte testing for beryllium sensitization has not been routinely conducted among these workers, this metal beryllium processing facility is the only large scale beryllium facility of its kind to have experienced only one unique a case of clinical chronic beryllium disease (CBD) ascertained by traditional medical monitoring procedures. The treating physician determined that this lung disease was likely caused by a systems reaction resulting from a mound contaminated with beryllium. However, he could not rule out the potential for inhalation exposure. Over the 17 years of measurement data analyzed, on occasion, airborne beryllium concentrations have exceeded 2.0 microg/m3; however, the Cardiff experience demonstrates that strict and consistent adherence to exposure control measures that emphasized airborne and surface levels and appropriate engineering controls, work practices, and use of personal protective equipment appears to have successfully prevented the incidence of clinical CBD with the exception of one unique case.     

Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas

OBJECTIVE: We hypothesized that beryllium (Be) might persist in lung granulomas in patients with chronic beryllium disease (CBD). METHODS: A total of 33 Be-exposed ceramics workers underwent transbronchial biopsy. They were classified based on histopathology and Be-lymphocyte proliferation test as CBD or other categories. Lung tissue sections were analyzed using secondary ion mass spectroscopy. RESULTS: Be was detected in the lungs of all Be-exposed groups. Be levels were increased within the granulomas of patients with CBD compared with the Be levels outside granulomas. Notably, Be was detectable in the lungs of CBD patients who had ceased exposure to Be an average of 9 years previously. CONCLUSIONS: Be was detected in the lungs of all Be-exposed subjects, with the highest levels of persistent Be inside CBD lung granulomas. Be antigen persistence may help explain the chronicity of this granulomatous disorder.     

Introduction to beryllium: uses, regulatory history, and disease

Beryllium is an ubiquitous element in the environment, and it has many commercial applications. Because of its strength, electrical and thermal conductivity, corrosion resistance, and nuclear properties, beryllium products are used in the aerospace, automotive, energy, medical, and electronics industries. What eventually came to be known as chronic beryllium disease (CBD) was first identified in the 1940s, when a cluster of cases was observed in workers from the fluorescent light industry. The U.S. Atomic Energy Commission recommended the first 8-hour occupational exposure limit (OEL) for beryllium of 2.0 microg/m3 in 1949, which was later reviewed and accepted by the American Conference of Governmental Industrial Hygienists (ACGIH), the American Industrial Hygiene Association (AIHA), the American National Standards Institute (ANSI), the Occupational Safety and Health Administration (OSHA), and the vast majority of countries and standard-setting bodies worldwide. The 2.0 microg/m3 standard has been in use by the beryllium industry for more than 50 years and has been considered adequate to protect workers against clinical CBD. Recently, improved diagnostic techniques, including immunological testing and safer bronchoscopy, have enhanced our ability to identify subclinical CBD cases that would have formerly remained unidentified. Some recent epidemiological studies have suggested that some workers may develop CBD at exposures less than 2.0 microg/m3. ACGIH is currently reevaluating the adequacy of the current 2.0 microg/m3 guideline, and a plethora of research initiatives are under way to provide a better understanding of the cause of CBD. The research is focusing on the risk factors and exposure metrics that could be associated with CBD, as well as on efforts to better characterize the natural history of CBD. There is growing evidence that particle size and chemical form may be important factors that influence the risk of developing CBD. These research efforts are expected to provide data that will help identify a scientifically based OEL that will protect workers against CBD.