HLA-DPB1 E69 genotype and exposure in beryllium sensitisation and disease.

OBJECTIVES: Human leukocyte antigen-DP beta 1 (HLA-DPB1) with a glutamic acid at the 69th position of the ß chain (E69) genotype and inhalational beryllium exposure individually contribute to risk of chronic beryllium disease (CBD) and beryllium sensitisation (BeS) in exposed individuals. This retrospective nested case-control study assessed the contribution of genetics and exposure in the development of BeS and CBD. METHODS: Workers with BeS (n=444), CBD (n=449) and beryllium-exposed controls (n=890) were enrolled from studies conducted at nuclear weapons and primary beryllium manufacturing facilities. Lifetime-average beryllium exposure estimates were based on workers' job questionnaires and historical and industrial hygienist exposure estimates, blinded to genotype and case status. Genotyping was performed using sequence-specific primer-PCR. Logistic regression models were developed allowing for over-dispersion, adjusting for workforce, race, sex and ethnicity. RESULTS: Having no E69 alleles was associated with lower odds of both CBD and BeS; every additional E69 allele increased odds for CBD and BeS. Increasing exposure was associated with lower odds of BeS. CBD was not associated with exposure as compared to controls, yet the per cent of individuals with CBD versus BeS increased with increasing exposure. No evidence of a gene-by-exposure interaction was found for CBD or BeS. CONCLUSIONS: Risk of CBD increases with E69 allele frequency and increasing exposure, although no gene by environment interaction was found. A decreased risk of BeS with increasing exposure and lack of exposure response in CBD cases may be due to the limitations of reconstructed exposure estimates. Although reducing exposure may not prevent BeS, it may reduce CBD and the associated health effects, especially in those carrying E69 alleles.

Beryllium disease among construction trade workers at Department of Energy nuclear sites: A follow-up.

BACKGROUND: Construction workers at U.S. Department of Energy (DOE) nuclear weapons facilities are screened to identify DOE-related occupational illnesses, including beryllium sensitization (BeS) and chronic beryllium disease (CBD). The study objectives were to estimate beryllium disease risks and the CBD claims acceptance rate in the energy workers' benefits program. METHODS: Workers diagnosed with BeS via beryllium lymphocyte proliferation test (BeLPT) included in screening examinations were interviewed about subsequent diagnosis of CBD. We estimated the proportion who developed CBD based on the ratio of CBD cases, based on self-reported compensation claim status, to all workers with BeS interviewed. We used stratified analyses to explore trends in disease frequency by age, race, sex, DOE employment duration, site, trade group, and cigarette smoking history. RESULTS: Between 1998 and 2020, 21,854 workers received a BeLPT; 262 (1.20%) had BeS (two abnormals or one abnormal plus one borderline test); 212 (0.97%) had a single abnormal BeLPT. Of 177 BeS workers interviewed, 35 (19.8%) reported an accepted CBD compensation claim. The claims acceptance rate among BeS workers increased with years of DOE employment, from 8.4% with <5 years to 33.3% for >25 or more years. Five of 68 interviewed workers with a single positive BeLPT reported CBD claim acceptance; an additional CBD case was confirmed by chart review (8.8%). CONCLUSIONS: Years of DOE work predict the risk of developing CBD among those sensitized and getting a claim for CBD accepted. Ongoing surveillance and increased awareness of the risk of beryllium exposure and CBD as an occupational disease among construction workers are needed.

Transplantation for work-related lung disease in the USA.

OBJECTIVES: Work-related lung diseases (WRLDs) are entirely preventable. To assess the impact of WRLDs on the US transplant system, we identified adult lung transplant recipients with a WRLD diagnosis specified at the time of transplant to describe demographic, payer and clinical characteristics of these patients and to assess post-transplant survival. METHODS: Using US registry data from 1991 to 2018, we identified lung transplant recipients with WRLDs including coal workers' pneumoconiosis, silicosis, asbestosis, metal pneumoconiosis and berylliosis. RESULTS: The frequency of WRLD-associated transplants has increased over time. Among 230 lung transplants for WRLD, a majority were performed since 2009; 79 were for coal workers' pneumoconiosis and 78 were for silicosis. Patients with coal workers' pneumoconiosis were predominantly from West Virginia (n=31), Kentucky (n=23) or Virginia (n=10). States with the highest number of patients with silicosis transplant were Pennsylvania (n=12) and West Virginia (n=8). Patients with metal pneumoconiosis and asbestosis had the lowest and highest mean age at transplant (48.8 and 62.1 years). Median post-transplant survival was 8.2 years for patients with asbestosis, 6.6 years for coal workers' pneumoconiosis and 7.8 years for silicosis. Risk of death among patients with silicosis, coal workers' pneumoconiosis and asbestosis did not differ when compared with patients with idiopathic pulmonary fibrosis. CONCLUSIONS: Lung transplants for WRLDs are increasingly common, indicating a need for primary prevention and surveillance in high-risk occupations. Collection of patient occupational history by the registry could enhance case identification and inform prevention strategies.

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.

A novel alternative to environmental monitoring to detect workers at risk for beryllium exposure-related health effects.

The purpose of this study was to describe a methodology for surveillance and monitoring of beryllium exposure using biological monitoring to complement environmental monitoring. Eighty-three Israeli dental technicians (mean age 41.6 ± 1.36 years) and 80 American nuclear machining workers (54.9 ± 1.21 years) were enrolled. Biological monitoring was carried out by analyzing particle size (laser technique) and shape (image analysis) in 131/163 (80.3%) induced sputum samples (Dipa Analyser, Donner Tech, Or Aquiva, Israel). Environmental monitoring was carried out only in the United States (Sioutas impactor, SKC, Inc., Eighty Four, Pa.). Pulmonary function testing performance and induced sputum retrieval were done by conventional methods. Sixty-three Israeli workers and 37 American workers were followed up for at least 2 years. Biological monitoring by induced sputum indicated that a >92% accumulation of <5 µm particles correlated significantly to a positive beryllium lymphocyte proliferation test result (OR 3.8, 95% CI 1.2-11.4, p = 0.015) among all participants. Environmental monitoring showed that beryllium particles were <1 µm, and this small fraction (0.1-1 µ) was significantly more highly accumulated in nuclear machining workers compared to dental technicians. The small fractions positively correlated with induced sputum macrophages (r = 0.21 p = 0.01) and negatively correlated with diffusion lung carbon monoxide single breath (DLCO-SB r = 0.180 p = 0.04) in all subjects. Years of exposure were positively correlated to the number of accumulated particles 2-3 µ in diameter (r = 0.2, p = 0.02) and negatively correlated to forced expiratory volume in one second/forced vital capacity findings (r = -0.18, p = 0.02). DLCO was decreased in both groups after two years of monitoring. Biological monitoring is more informative than environmental monitoring in the surveillance and monitoring of workers in beryllium industries. Induced sputum is a feasible and promising biomonitoring method that should be included in the surveillance of exposed workers.

Beryllium disease among construction trade workers at Department of Energy nuclear sites.

BACKGROUND: A medical surveillance program was developed to identify current and former construction workers at significant risk for beryllium related disease from work at the DOE nuclear weapons facilities, and to improve surveillance among beryllium exposed workers. METHODS: Medical examinations included 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, trade, and reported work in buildings where beryllium was used. After adjusting for covariates, the risk of BeS was significantly higher among boilermakers, roofers, and sheet metal workers, as suggested in the stratified analyses. Workers identified as sensitized to beryllium were interviewed to determine whether they had been subsequently diagnosed with chronic beryllium disease. RESULTS: Between 1998 and December 31, 2010 13,810 workers received a BeLPT through the BTMed program; 189 (1.4%) were sensitized to beryllium, and 28 reported that they had had a compensation claim accepted for CBD. CONCLUSIONS: These data on former construction workers gives us additional information about the predictive value of the blood BeLPT test for detection of CBD in populations with lower total lifetime exposures and more remote exposures than that experienced by current workers in beryllium machining operations. Through this surveillance program we have identified routes of exposures to beryllium and worked with DOE site personnel to identity and mitigate those exposures which still exist, as well as helping to focus attention on the risk for beryllium exposure among current demolition workers at these facilities.

Long-term efficacy of a program to prevent beryllium disease.

BACKGROUND: In 2000, a manufacturer of beryllium materials and products introduced a comprehensive program to prevent beryllium sensitization and chronic beryllium disease (CBD). We assessed the program's efficacy in preventing sensitization 9 years after implementation. METHODS: Current and former workers hired since program implementation completed questionnaires and provided blood samples for the beryllium lymphocyte proliferation test (BeLPT). Using these data, as well as company medical surveillance data, we estimated beryllium sensitization prevalence. RESULTS: Cross-sectional prevalence of sensitization was 0.7% (2/298). Combining survey results with surveillance results, a total of seven were identified as sensitized (2.3%). Early Program workers were more likely to be sensitized than Late Program workers; one of the latter was newly identified. All sensitization was identified while participants were employed. One worker was diagnosed with CBD during employment. CONCLUSIONS: The combination of increased respiratory and dermal protection, enclosure and improved ventilation of high-risk processes, dust migration control, improved housekeeping, and worker and management education showed utility in reducing sensitization in the program's first 9 years. The low rate (0.6%, 1/175) among Late Program workers suggests that continuing refinements have provided additional protection against sensitization compared to the program's early years.

Occupational exposure to beryllium and cancer risk: a review of the epidemiologic evidence.

There is controversy on whether occupational exposure to beryllium causes lung cancer. We conducted a systematic review of epidemiologic studies on cancer among workers exposed to beryllium, including a study of seven U.S. production plants which has been recently updated, a study of patients with beryllium disease (largely overlapping with the former study) and several smaller studies. A small excess mortality from lung cancer was detected in the large cohort, which was partially explained by confounding by tobacco smoking and urban residence. Other potential confounders have not been addressed. The excess mortality was mainly among workers employed (often for a short duration) in the early phase of the manufacturing industry. There was no relation with duration of employment or cumulative exposure, whereas average and maximum exposure were associated with lung cancer risk. The use of lagged exposure variables resulted in associations with lung cancer risk; however, these associations were due to confounding by year of birth and year of hire. The studies of beryllium disease patients do not provide independent evidence and the results from other studies do not support the hypothesis of an increased risk of lung cancer or any other cancer. Overall, the available evidence does not support a conclusion that a causal association has been established between occupational exposure to beryllium and the risk of cancer.

Search for chronic beryllium disease among sarcoidosis patients in Ontario, Canada.

Chronic beryllium disease (CBD) is clinically similar to other granulomatous diseases such as sarcoidosis. It is often misdiagnosed if a thorough occupational history is not taken. When appropriate, a beryllium lymphocyte proliferation tests (BeLPT) need to be performed. We aimed to search for CBD among currently diagnosed pulmonary sarcoidosis patients and to identify the occupations and exposures in Ontario leading to CBD. Questionnaire items included work history and details of possible exposure to beryllium. Participants who provided a history of previous work with metals underwent BeLPTs and an ELISPOT on the basis of having a higher pretest probability of CBD. Among 121 sarcoid patients enrolled, 87 (72%) reported no known previous metal dust or fume exposure, while 34 (28%) had metal exposure, including 17 (14%) with beryllium exposure at work or home. However, none of these 34 who underwent testing had positive test results. Self-reported exposure to beryllium or metals was relatively common in these patients with clinical sarcoidosis, but CBD was not confirmed using blood assays in this population.

Interpreting borderline BeLPT results.

BACKGROUND: The beryllium lymphocyte proliferation test (BeLPT) identifies persons sensitized to beryllium (BeS) and thus at risk for chronic beryllium disease (CBD). BeLPT test results are abnormal (AB), borderline (BL), or normal (NL). This manuscript addresses the predictive value and interpretation of BL BeLPT results. METHODS: The various three-result combinations that meet or exceed a nominal referral criteria of 1 AB + 1 BL are assessed with probability modeling and compared. RESULTS: At 2% prevalence, the three-result combinations that meet or exceed this referral criteria and associated probabilities of BeS are: (a) 1 AB + 1 BL + 1 NL (72%); (b) 3 BL (91%); (c) 2 AB + 1 NL (95%); (d) 1 AB + 2 BL (99%); (e) 2 AB + 1 BL (100%); and (f) 3 AB (100%). CONCLUSION: These results suggest that BL results are meaningful and that three BL results predict BeS across a broad range of population prevalences. An analysis of longitudinal BeLPT results and clinical findings from an actual surveillance program is warranted to confirm the model's predictions.

Risk of beryllium sensitization in a low-exposed former nuclear weapons cohort from the Cold War era.

BACKGROUND: The nuclear weapons industry has long been known as a source of beryllium exposure. METHODS: A total of 1,004 former workers from a nuclear weapons assembly site in the Midwest were screened for sensitization to beryllium (BeS). The screenings were part of the Department of Energy (DOE) Former Worker Program established in 1996. RESULTS: Twenty-three (2.3%) workers were found sensitized to beryllium and this prevalence was comparable to other DOE sites. Occasional, direct exposure to beryllium through machining and grinding of copper-beryllium (Cu-Be) 2% alloy tools was found to increase the risk of sensitization compared to background exposure (OR = 3.83; 95% CI: 1.04-14.03) with a statistically significant trend (P = 0.03) revealing that particular jobs are associated with sensitization. Exposure potential in this study was estimated based on job titles and not personal exposure information. CONCLUSIONS: These results confirm the need to screen workers using beryllium alloy tools in other industries and for consideration of altering work practices.

[Management of occupational health for adverse health effects of beryllium and its compounds in workplaces - Recent trends and issues in Japan].

OBJECTIVES: Beryllium is primarily used in its metallic form, in alloys, or in beryllium oxide ceramics. Its physical and mechanical properties make it useful for many applications across a range of industries. Because beryllium is recognized as a sensitizing and carcinogenic agent, the management of occupational health for workers who may be occupationally exposed to beryllium has long been an important issue in the world. Under these circumstances, the U.S. Occupational Safety and Health Administration (OSHA) had published a rule in January 2017, to prevent the development of chronic beryllium disease and lung cancer. This rule strengthens the regulations governing the use of beryllium and its compounds. With the announcement of the OSHA rule in January 2017, the purpose of this study is to gain insight into the health problems and industrial hygiene associated with the use of beryllium and share the issues related to the management of occupational health for persons working with beryllium in Japan. METHODS: We collected information regarding the beryllium industry, beryllium exposure, beryllium-induced health disorders, OSHA rule of January 2017, and regulations for beryllium use in Japan. After reviewing them, we discussed the issues concerning occupational health management of workers exposed to beryllium in Japan. RESULTS: It has been reconfirmed that in recent years, the most serious health problem due to beryllium exposure is chronic beryllium disease caused by beryllium sensitization. Management of occupational health that emphasizes reduction of beryllium sensitization and early detection of beryllium-sensitized workers is important. CONCLUSIONS: It was suggested that the following should be considered as the issues of management of occupational health of workers exposed to beryllium in Japan: (1) Collect epidemiologic data on health hazards from beryllium exposure in Japan. (2) Review the diagnostic items of special medical check-ups. (3) Review the definition of beryllium and its compounds in the Ordinance on Prevention of Hazards due to Specified Chemical Substances.

Long-term follow-up of beryllium sensitized workers from a single employer.

BACKGROUND: Up to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain. METHODS: Seventy two current and former employees of a beryllium manufacturer, including 22 with pathologic changes of chronic beryllium disease (CBD), and 50 without, with a confirmed positive test were followed-up for 7.4 +/-3.1 years. RESULTS: Beyond predicted effects of aging, flow rates and lung volumes changed little from baseline, while DLCO dropped 17.4% of predicted on average. Despite this group decline, only 8 subjects (11.1%) demonstrated physiologic or radiologic abnormalities typical of CBD. Other than baseline status, no clinical or laboratory feature distinguished those who clinically manifested CBD at follow-up from those who did not. CONCLUSIONS: The clinical outlook remains favorable for beryllium-sensitized individuals over the first 5-12 years. However, declines in DLCO may presage further and more serious clinical manifestations in the future. These conclusions are tempered by the possibility of selection bias and other study limitations.

Prevalence of beryllium sensitization among aluminium smelter workers.

BACKGROUND: Beryllium exposure occurs in aluminium smelters from natural contamination of bauxite, the principal source of aluminium. AIMS: To characterize beryllium exposure in aluminium smelters and determine the prevalence rate of beryllium sensitization (BeS) among aluminium smelter workers. METHODS: A population of 3185 workers from nine aluminium smelters owned by four different aluminium-producing companies were determined to have significant beryllium exposure. Of these, 1932 workers participated in medical surveillance programmes that included the serum beryllium lymphocyte proliferation test (BeLPT), confirmation of sensitization by at least two abnormal BeLPT test results and further evaluation for chronic beryllium disease in workers with BeS. RESULTS: Personal beryllium samples obtained from the nine aluminium smelters showed a range of <0.01-13.00 µg/m(3) time-weighted average with an arithmetic mean of 0.25 µg/m(3) and geometric mean of 0.06 µg/m(3). Nine workers were diagnosed with BeS (prevalence rate of 0.47%, 95% confidence interval = 0.21-0.88%). CONCLUSIONS: BeS can occur in aluminium smelter workers through natural beryllium contamination of the bauxite and further concentration during the refining and smelting processes. Exposure levels to beryllium observed in aluminium smelters are similar to those seen in other industries that utilize beryllium. However, compared with beryllium-exposed workers in other industries, the rate of BeS among aluminium smelter workers appears lower. This lower observed rate may be related to a more soluble form of beryllium found in the aluminium smelting work environment as well as the consistent use of respiratory protection.

[Cytochemical parameters in nasal mucosal and peripheral blood cells in beryllium production workers].

Nasal mucosal and peripheral blood cells from beryllium production workers underwent cytochemical tests for catecholamines and phospholipids and the activity of esterase and lysosomal cationic proteins. The established peripheral blood metabolic changes reflect reduced cell resistance in response to poor occupational factors and may be used in the rapid hygienic assessment of cytotoxicity of toxic substances.

[Diagnostic difficulties of chronic pulmonary berylliosis in France]. / Difficultés diagnostiques de la bérylliose pulmonaire chronique en France.

INTRODUCTION: The epidemiology of chronic beryllium disease (CBD) in France is poorly understood. The aim of this study was to determine the number of prevalent cases of CBD in France between 2010 and 2014. METHODS: We conducted a national survey using a specific questionnaire distributed by the professional pathology services. RESULTS: In total, 33 CBD cases were reported in France, with a diagnosis established between 1982 and 2014. 85% (28/33) of CBD cases resulted from professional exposure and mostly concerned foundry workers (39%). A definite diagnosis defined by the association of an abnormal beryllium lymphocyte proliferation test and of a granulomatous inflammatory response in the lung, was obtained in 29/33 cases (88%). The other cases were probable CBD, defined by a granulomatous lung disease with a beryllium exposure, but without evidence of beryllium sensitisation. The diagnosis of granulomatous disease was confirmed a mean of 4 years after the end of exposure. The median delay between diagnosis of a granulomatous disease and diagnosis of CBD was 2 years (range 0-38 years). A genetic predisposition was found in 14 of 17 tested patients (82%). CONCLUSION: In this study, we report 33 cases of CBD followed in France between 2010 and 2014. The poor understanding of CBD and the exposure leading to it, the late development after the end of exposure, the complexity of the diagnosis and the similarities with sarcoidosis may explain the small number of cases reported.

Beryllium hypersensitivity and chronic beryllium lung disease.

PURPOSE OF REVIEW: This review aims to present the clinician with a synthesis of recent studies that have enhanced our understanding of the epidemiology and pathogenesis of beryllium hypersensitivity (BeH) and chronic beryllium disease (CBD). RECENT FINDINGS: Lower occupational limit levels to beryllium exposure and more stringent preventive measures can decrease the risk for development of BeH and CBD. Beryllium sensitization is determined by a positive beryllium lymphocyte proliferation test (BeLPT). Longitudinal data suggest that BeH progresses to CBD. Together with a comprehensive history the BeLPT may help identify berylliosis in patients erroneously diagnosed to have sarcoidosis. HLA-DPB1-Glu69 marker is associated with increased susceptibility to development of BeH and CBD but poor positive predictive value limits its use; other genetic markers are being investigated. Recent investigations augment our understanding on the role of T-lymphocytes and chemokines in the pathogenesis of beryllium-associated disease. However, the basis for treatment strategies remains scarce. SUMMARY: Our enhanced understanding of beryllium-associated lung disease potentially provides a window to unraveling other granulomatous diseases. However, even more questions beg to be elucidated and additional efforts are needed to translate this body of knowledge into better prevention and treatment.

Recent chronic beryllium disease in residents surrounding a beryllium facility.

RATIONALE: Between 1948 and 1969, cases of community-acquired chronic beryllium disease (CA-CBD) were reported in neighborhoods surrounding beryllium facilities. Further surveillance was not performed in these communities, and additional cases have not been reported. OBJECTIVES: To increase awareness of recently diagnosed cases of CA-CBD in residents surrounding a beryllium facility. METHODS: Medical records were reviewed from individuals in a community surrounding a beryllium manufacturing facility in Reading, Pennsylvania. Definite cases of CBD required (1) an abnormal beryllium lymphocyte proliferation test in blood or bronchoalveolar lavage and (2) biopsy evidence of granulomatous inflammation. Probable cases of CBD either displayed an abnormal blood test to beryllium and radiographic evidence consistent with disease, or met epidemiologic criteria for CBD based on the Beryllium Case Registry criteria. Cases with occupational or potential paraoccupational exposure were excluded. MEASUREMENTS AND MAIN RESULTS: Sixteen cases of potential community-acquired CBD were evaluated. From these, eight cases of community-acquired CBD were identified (five definite and three probable). The cases' initial year of residence began between 1943 and 1953 and continued until 1956-2001. Six of the eight cases required medical treatment and three of the cases died since diagnosis. CONCLUSIONS: Cases of CBD meeting current immunologic diagnostic criteria and attributable to industry-associated environmental exposure were detected among residents of a community surrounding a beryllium manufacturing facility. Most were diagnosed years after exposure cessation. The frequency and extent of beryllium disease in this community are unknown. We anticipate that not only have cases been misdiagnosed in this community but that more cases of CBD will be diagnosed in the future.

Beryllium lymphocyte proliferation test surveillance identifies clinically significant beryllium disease.

BACKGROUND: Workplace surveillance identifies chronic beryllium disease (CBD) but it remains unknown over what time frame mild CBD will progress to a more severe form. METHODS: We examined physiology and treatment in 229 beryllium sensitization (BeS) and 171 CBD surveillance-identified cases diagnosed from 1982 to 2002. Never smoking CBD cases (81) were compared to never smoking BeS patients (83) to assess disease progression. We compared CBD machinists to non-machinists to examine effects of exposure. RESULTS: At baseline, CBD and BeS cases did not differ significantly in exposure time or physiology. CBD patients were more likely to have machined beryllium. Of CBD cases, 19.3% went on to require oral immunosuppressive therapy. At 30 years from first exposure, measures of gas exchange were significantly worse and total lung capacity was lower for CBD subjects. Machinists had faster disease progression as measured by pulmonary function testing and gas exchange. CONCLUSIONS: Medical surveillance for CBD identifies individuals at significant risk of disease progression and impairment with sufficient time since first exposure.

[Genotoxic effects caused in workers by beryllium compounds].

The author represents results of studying genotoxic effects caused in workers by beryllium compounds. Increasing age and length of service apperared to correlate with higher level of chromosomal aberration in peripheral WBC. Findings are that obtaining beryllium and its compounds is associated with changed level of chromosomal damages.