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Title: Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry

Abstract

Beryllium sensitisation (BeS) and chronic beryllium disease (CBD) are caused by exposure to beryllium with susceptibility affected by at least one well-studied genetic host factor, a glutamic acid residue at position 69 (E69) of the HLA-DPb chain (DPbE69). However, the nature of the relationship between exposure and carriage of the DPbE69 genotype has not been well studied. The goal of this study was to determine the relationship between DP{beta}E69 and exposure in BeS and CBD. Current and former workers (n=181) from a US nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, Tennessee, USA), were enrolled in a case-control study including 35 individuals with BeS and 19 with CBD. HLA-DPB1 genotypes were determined by PCR-SSP. Beryllium exposures were assessed through worker interviews and industrial hygiene assessment of work tasks. After removing the confounding effect of potential beryllium exposure at another facility, multivariate models showed a sixfold (OR 6.06, 95% CI 1.96 to 18.7) increased odds for BeS and CBD combined among DP{beta}E69 carriers and a fourfold (OR 3.98, 95% CI 1.43 to 11.0) increased odds for those exposed over an assigned lifetime-weighted average exposure of 0.1 {micro}g/m{sup 3}. Those with both risk factors had higher increased odds (ORmore » 24.1, 95% CI 4.77 to 122). DP{beta}E69 carriage and high exposure to beryllium appear to contribute individually to the development of BeS and CBD. Among workers at a beryllium-using facility, the magnitude of risk associated with either elevated beryllium exposure or carriage of DP{beta}E69 alone appears to be similar.« less

Authors:
 [1];  [2];  [1];  [2];  [2];  [1];  [1];  [1];  [3];  [3];  [3];  [4];  [1];  [2]
  1. National Jewish Health, Denver, CO (United States). Hollis Lab.
  2. (United States)
  3. Oak Ridge Associated Univ., Oak Ridge, TN (United States)
  4. Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO (United States)
Publication Date:
Research Org.:
Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Health, Safety, and Security (HSS)
OSTI Identifier:
1030816
Report Number(s):
11-OEWH-1905
Journal ID: ISSN 1351-0711; OEMEEM; TRN: US201124%%476
DOE Contract Number:
AC05-06OR23100
Resource Type:
Journal Article
Resource Relation:
Journal Name: Occupational and Environmental Medicine; Journal Volume: 68; Journal Issue: 11
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; BERYLLIUM; DISEASES; GENETICS; GENOTYPE; GLUTAMIC ACID; NUCLEAR WEAPONS; PRODUCTION; RESIDUES; Y-12 PLANT; beryllium, genetics, chronic beryllium disease

Citation Formats

Van Dyke, M. V., Colorado State Univ., Fort Collins, CO, Martyny, John W., Colorado State Univ., Fort Collins, CO, Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO, Mroz, M. M., Silveira, L. J., Strand, M., Cragle, D. L., Tankersley, W. G., Wells, S. M., Newman, L. S., Maier, L. A., and Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO. Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry. United States: N. p., 2011. Web. doi:10.1136/oem.2010.064220.
Van Dyke, M. V., Colorado State Univ., Fort Collins, CO, Martyny, John W., Colorado State Univ., Fort Collins, CO, Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO, Mroz, M. M., Silveira, L. J., Strand, M., Cragle, D. L., Tankersley, W. G., Wells, S. M., Newman, L. S., Maier, L. A., & Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO. Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry. United States. doi:10.1136/oem.2010.064220.
Van Dyke, M. V., Colorado State Univ., Fort Collins, CO, Martyny, John W., Colorado State Univ., Fort Collins, CO, Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO, Mroz, M. M., Silveira, L. J., Strand, M., Cragle, D. L., Tankersley, W. G., Wells, S. M., Newman, L. S., Maier, L. A., and Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO. 2011. "Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry". United States. doi:10.1136/oem.2010.064220.
@article{osti_1030816,
title = {Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry},
author = {Van Dyke, M. V. and Colorado State Univ., Fort Collins, CO and Martyny, John W. and Colorado State Univ., Fort Collins, CO and Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO and Mroz, M. M. and Silveira, L. J. and Strand, M. and Cragle, D. L. and Tankersley, W. G. and Wells, S. M. and Newman, L. S. and Maier, L. A. and Univ. of Colorado Denver School of Medicine and Colorado School of Public Health, Denver, CO},
abstractNote = {Beryllium sensitisation (BeS) and chronic beryllium disease (CBD) are caused by exposure to beryllium with susceptibility affected by at least one well-studied genetic host factor, a glutamic acid residue at position 69 (E69) of the HLA-DPb chain (DPbE69). However, the nature of the relationship between exposure and carriage of the DPbE69 genotype has not been well studied. The goal of this study was to determine the relationship between DP{beta}E69 and exposure in BeS and CBD. Current and former workers (n=181) from a US nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, Tennessee, USA), were enrolled in a case-control study including 35 individuals with BeS and 19 with CBD. HLA-DPB1 genotypes were determined by PCR-SSP. Beryllium exposures were assessed through worker interviews and industrial hygiene assessment of work tasks. After removing the confounding effect of potential beryllium exposure at another facility, multivariate models showed a sixfold (OR 6.06, 95% CI 1.96 to 18.7) increased odds for BeS and CBD combined among DP{beta}E69 carriers and a fourfold (OR 3.98, 95% CI 1.43 to 11.0) increased odds for those exposed over an assigned lifetime-weighted average exposure of 0.1 {micro}g/m{sup 3}. Those with both risk factors had higher increased odds (OR 24.1, 95% CI 4.77 to 122). DP{beta}E69 carriage and high exposure to beryllium appear to contribute individually to the development of BeS and CBD. Among workers at a beryllium-using facility, the magnitude of risk associated with either elevated beryllium exposure or carriage of DP{beta}E69 alone appears to be similar.},
doi = {10.1136/oem.2010.064220},
journal = {Occupational and Environmental Medicine},
number = 11,
volume = 68,
place = {United States},
year = 2011,
month = 4
}
  • Five workers at a precious metal refinery developed granulomatous lung disease between 1972 and 1985. The original diagnosis was sarcoidosis, but 4 of the workers were subsequently proved to have hypersensitivity to beryllium by in vitro proliferative responses of lymphocytes obtained by bronchoalveolar lavage. Review of medical records of coworkers and extensive industrial hygiene surveillance of the plant demonstrated that 4 cases occurred in the furnace area where air concentrations of beryllium fume were consistently below the permissible exposure limit of 2 micrograms/M3. A single case has been recognized from parts of the refinery where exposures to cold beryllium dustmore » often exceeded the standard by as much as 20-fold. These data demonstrate that chronic beryllium disease still occurs and confirm the importance of specific immunologic testing in patients suspected of having sarcoidosis but with potential exposure to beryllium. The data raise concern about the adequacy of modern industrial controls, especially in the setting of exposure to highly respirable beryllium fumes.« less
  • To study the prevalence of beryllium sensitization (BeS) and chronic beryllium disease (CBD) in a cohort of workers from a nuclear weapons research and development facility. We evaluated 50 workers with BeS with medical and occupational histories, physical examination, chest imaging with HRCT (N=49), and pulmonary function testing. Forty of these workers also underwent bronchoscopy for bronchoalveolar lavage (BAL) and transbronchial biopsies. The mean duration of employment at the facility was 18 yrs and the mean latency (from first possible exposure) to time of evaluation was 32 yrs. Five of the workers had CBD at the time of evaluation (basedmore » on histology or HRCT); three others had evidence of probable CBD. These workers with BeS, characterized by a long duration of potential Be exposure and a long latency, had a low prevalence of CBD.« less
  • Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. The authors describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and they apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP{beta}1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity ({approximately}94%) butmore » low specificity ({approximately}70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD valuations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.« less
  • Workers employed in 15 utilities that generate nuclear power in the United States have been followed for up to 18 years between 1979 and 1997. Their cumulative dose from whole-body ionizing radiation has been determined from the dose records maintained by the facilities themselves and the REIRS and REMS systems maintained by the Nuclear Regulatory Commission and the Department of Energy, respectively. Mortality in the cohort from a number of causes has been analyzed with respect to individual radiation doses. The cohort displays a very substantial healthy worker effect, i.e. considerably lower cancer and noncancer mortality than the general population.more » Based on 26 and 368 deaths, respectively, positive though statistically nonsignificant associations were seen for mortality from leukemia (excluding chronic lymphocytic leukemia) and all solid cancers combined, with excess relative risks per sievert of 5.67 (95% confidence interval (CI) -2.56, 30.4) and 0.596 (95% CI -2.01, 4.64), respectively. These estimates are very similar to those from the atomic bomb survivors study, though the wide confidence intervals are also consistent with lower or higher risk estimates. A strong positive and statistically significant association between radiation dose and deaths from arteriosclerotic heart disease including coronary heart disease was also observed in the cohort, with an ERR of 8.78 (95% CI 2.10, 20.0). While associations with heart disease have been reported in some other occupational studies, the magnitude of the present association is not consistent with them and therefore needs cautious interpretation and merits further attention. At present, the relatively small number of deaths and the young age of the cohort (mean age at end of follow-up is 45 years) limit the power of the study, but further follow-up and the inclusion of the present data in an ongoing IARC combined analysis of nuclear workers from 15 countries will have greater power for testing the main hypotheses of interest.« less
  • With the advent of in vitro immunologic testing, we can now detect exposed individuals who are sensitized to beryllium and those who have chronic beryllium disease (CBD) with lung pathology and impairment. Earlier detection and more accurate diagnostic tools raise new questions about the natural history of sensitization and granulomatous disease. Preliminary data suggest that early detection identifies people who are sensitized to beryllium and that these individuals are at risk for progressing into clinical disease. This article discusses the historical, recent, and ongoing studies germane to our understanding of CBD natural history, including the immunologic and inflammatory basis ofmore » the disease, the environmental and host risk factors for disease progression, biological markers of disease severity and activity that may help predict outcome, and the implications for broad-based workplace screening to identify patients at the earliest stages of beryllium sensitization and disease. 29 refs., 2 figs.« less