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.     

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.     

Chronic beryllium disease: uncommon disease, less common diagnosis.

Chronic beryllium disease (CBD) is typically considered only when occupational exposure to beryllium is a certainty; however, CBD has also occurred in occupational and environmental settings where exposure was unexpected. When the etiology of a case of granulomatous pulmonary disease is not determined, sarcoidosis is the "diagnosis of exclusion." This diagnosis does not communicate much information about the patient's prognosis, the disease's etiology, or even what disease etiologies were specifically excluded. Some cases of CBD have been called sarcoidosis, allowing exposure to continue for the patient and (at times) other individuals. The granulomatous changes of sarcoidosis are thought to result from an abnormal immune response. While the etiologic agents that can initiate this response are largely unknown, the immunopathogenesis of CBD has been well described, and laboratory methods are available in a few centers that can (if used) identify beryllium hypersensitivity. The potential for exposure and disease to be widely separated in time and location makes it important for health-care and environmental health professionals to be aware of these new diagnostic methods.     

TNF-alpha polymorphisms in chronic beryllium disease and beryllium sensitization

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine involved in normal immune functions. The aim of this study was to investigate if there is an association between chronic beryllium disease or beryllium sensitization and two variants of the TNF-alpha gene located at -308 and -238 called TNF-alpha-308*02 and TNF-alpha-238*02. METHODS: TNF-alpha-308 and TNF-alpha-238 genotyping was conducted in a large, population-based cohort consisting of 886 beryllium workers (92 individuals with chronic beryllium disease, 64 who were beryllium sensitized, and 730 individuals without sensitization or disease). RESULTS: The odds of chronic beryllium disease in the presence of at least one TNF-alpha-308*02 or TNF-alpha-238*02 allele was not significant (OR=1.0; 95% CI=0.7, 1.7 and OR=0.8; 95% CI=0.4, 1.6). This was true regardless of whether a worker was homozygous or heterozygous for TNF-alpha-308*02 or TNF-alpha-238*02. Similarly, neither allele was associated with sensitization (P>0.05). CONCLUSIONS: Unlike an earlier report, there was no association between these specific TNF-alpha alleles and either chronic beryllium disease or sensitization to beryllium.     

Chronic beryllium disease and cancer risk estimates with uncertainty for beryllium released to the air from the Rocky Flats Plant.

Beryllium was released into the air from routine operations and three accidental fires at the Rocky Flats Plant (RFP) in Colorado from 1958 to 1989. We evaluated environmental monitoring data and developed estimates of airborne concentrations and their uncertainties and calculated lifetime cancer risks and risks of chronic beryllium disease to hypothetical receptors. This article discusses exposure-response relationships for lung cancer and chronic beryllium disease. We assigned a distribution to cancer slope factor values based on the relative risk estimates from an occupational epidemiologic study used by the U.S. Environmental Protection Agency (EPA) to determine the slope factors. We used the regional atmospheric transport code for Hanford emission tracking atmospheric transport model for exposure calculations because it is particularly well suited for long-term annual-average dispersion estimates and it incorporates spatially varying meteorologic and environmental parameters. We accounted for model prediction uncertainty by using several multiplicative stochastic correction factors that accounted for uncertainty in the dispersion estimate, the meteorology, deposition, and plume depletion. We used Monte Carlo techniques to propagate model prediction uncertainty through to the final risk calculations. We developed nine exposure scenarios of hypothetical but typical residents of the RFP area to consider the lifestyle, time spent outdoors, location, age, and sex of people who may have been exposed. We determined geometric mean incremental lifetime cancer incidence risk estimates for beryllium inhalation for each scenario. The risk estimates were < 10(-6). Predicted air concentrations were well below the current reference concentration derived by the EPA for beryllium sensitization.     

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.     

Immunotoxicology of beryllium lung disease

Beryllium induces non-caseating granulomatous inflammation in humans exposed to the metal dust or fumes in both occupational and non-occupational settings. The resulting condition, chronic beryllium disease (CBD), affects principally the lungs, lymphatics, and skin and continues to plague modern industry. Beryllium exerts several important immunotoxic effects, including induction of a beryllium-antigen specific adaptive immune response and the triggering of inflammatory and innate immune responses. Genetic susceptibility plays a role in CBD adaptive immune responses, mainly mediated through single nucleotide polymorphisms in HLA-DP and, to a lesser extent, HLA-DR. The adaptive response is characterized by influx and proliferation of CD4+ central and effector memory T cells expressing Th1 cytokines. Insights into the immunopathogenesis of CBD have implications for the understanding of other immune-mediated granulomatous disorders and for metal antigen behavior.     

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.     

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.     

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.     

Ultrafine beryllium number concentration as a possible metric for chronic beryllium disease risk

Beryllium is a lightweight metal which causes a chronic granulomatous lung disease among workers who become sensitized to it. Recent research has shown a persistence of the disease despite efforts at control with mean exposures below the Occupational Safety and Health Administration (OSHA) occupational exposure limit of 2 microg/m3. Results of our current research confirm a previous finding in certain plants that particle number concentrations are higher in areas where historical estimate of risk showed a high risk of disease despite relatively lower mass concentrations. By providing side-by-side measurements of both particle number and mass, this research adds support to the proposal that particle number rather than particle mass may be more reflective of target organ dose and subsequently a more appropriate measure of exposure for chronic beryllium disease. Our evidence also shows that particle mass exposure measurements and particle number exposure measurements were not correlated.     

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.     

Measurement of beryllium in lung tissue of a chronic beryllium disease case and cases with sarcoidosis

BACKGROUND: The clinical features of chronic beryllium disease (CBD) are similar to many other chronic lung diseases. In particular, it may be difficult to distinguish it from pulmonary sarcoidosis since the two conditions may be very alike in clinical, pathological and radiological features. Aim To determine if the amount of beryllium found in the lungs could be used to differentiate CBD from sarcoidosis and controls. METHODS: Analyses for beryllium in the autopsied lung tissues of 29 cases and controls were carried out. The cases included one CBD, three confirmed sarcoidosis and 25 controls. Blocks of formalin-fixed tissues were analysed by an atomic absorption spectrophotometer equipped with a graphite furnace. A method for analysis of beryllium in air was modified to permit tissue analysis. RESULTS: The CBD case had a much higher average beryllium level, but some individual results were similar to controls and patients with sarcoidosis. CONCLUSION: The CBD case had beryllium levels within the range of values reported in the literature. The differentiation between CBD and sarcoidosis could not be made with reasonable assurance based only on the analytic result. Occupational history is very important in making a diagnosis of CBD, along with the analysis of tissues. Tissue analysis helped confirm the diagnosis of compensatable CBD in this particular case.     

HLA-DPB1 and chronic beryllium disease: a HuGE review

The human leukocyte antigen (HLA) complex is a series of genes located on chromosome 6 that are important in normal immune function. Susceptibility to chronic beryllium disease, a granulomatous lung disease that appears in workers exposed to beryllium, is modified by genetic variants of the HLA-DP subregion. Evaluation of HLA-DPB1 sequence motifs in current and former beryllium workers implicated a glutamic acid residue at position 69 (HLA-DPB1(Glu69)) in chronic beryllium disease. This finding has since been extended to specific HLA-DPB1(Glu69) alleles. Specific job tasks have also been implicated in degree of risk, and in this paper the authors explore gene-environment interaction. The utility of this genetic information for prospective, current, and former beryllium workers must be weighed against the potential for employment and insurance discrimination. Continued research in the beryllium-exposed population will be important for improving personal risk assessment and identifying high-risk genes associated with disease progression.