Christine R. Schuler

Enhanced preventive programme at a beryllium oxide ceramics facility reduces beryllium sensitisation among new workers

Background: A 1998 survey at a beryllium oxide ceramics manufacturing facility found that 10% of workers hired in the previous 6 years had beryllium sensitisation as determined by the beryllium lymphocyte proliferation test (BeLPT). In response, the facility implemented an enhanced preventive programme to reduce sensitisation, including increased respiratory and dermal protection and particle migration control. Aim: To assess the programme’s effectiveness in preventing sensitisation. Methods: In 2000, the facility began testing newly hired workers for beryllium sensitisation with the BeLPT at time of hire and during employment. The sensitisation rate and prevalence for workers hired from 2000 to 2004 were compared with that for workers hired from 1993 to 1998, who were tested in the 1998 survey. Facility environmental conditions for both time periods were evaluated. Results: Newly hired workers in both cohorts worked for a mean of 16 months. Of the 97 workers hired from 2000 to 2004 with at least one employment BeLPT result, four had abnormal results at time of hire and one became sensitised during employment. Of the 69 workers hired from 1993 to 1998 and tested in 1998, six were found to be sensitised. The sensitisation rate for the 2000–4 workers was 0.7–2.7/1000 person-months of employment, and that for the 1993–8 workers was 5.6/1000 person-months, at least 2.1 (95% confidence interval (CI) 0.6 to 8.4) and up to 8.2 (95% CI 1.2 to 188.8) times higher than that for the 2000–4 workers. The sensitisation prevalence for the 2000–4 workers was 1% and that for the 1993–8 workers was 8.7%, 8.4 (95% CI 1.04 to 68.49) times higher than that for the 2000–4 workers. Airborne beryllium levels for production workers for the two time periods were similar. Conclusions: A comprehensive preventive programme reduced beryllium sensitisation in new workers during the first years of employment, despite airborne beryllium levels for production workers that were similar to pre-programme levels.

Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease

Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs primarily in workers who are exposed to beryllium dust or fumes. Although exposure to beryllium is a necessary factor in the pathobiology of CBD, alleles that code for a glutamic acid residue at the 69th position of the HLA-DPβ1 gene have previously been found to be associated with CBD. To date, 43 HLA-DPβ1 alleles that code for glutamic acid 69 (E69) have been described. Whether all of these E69 coding alleles convey equal risk of CBD is unknown. The present study demonstrates that, on the one hand, E69 alleloforms of major histocompatibility complex class II antigen-presenting proteins with the greatest negative surface charge convey the highest risk of CBD, and on the other hand, irrespective of allele, they convey equal risk of beryllium sensitization (BeS). In addition, the data suggest that the same alleles that cause the greatest risk of CBD are also important for the progression from BeS to CBD. Alleles convey the highest risk code for E26 in a constant region and for E69, aspartic acid 55 (D55), E56, D84 and E85 in hypervariable regions of the HLA-DPβ1 chain. Together with the calculated high binding affinities for beryllium, these results suggest that an adverse immune response, leading to CBD, is triggered by chemically specific metal–protein interactions.

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.

An Official American Thoracic Society Statement: Diagnosis and Management of Beryllium Sensitivity and Chronic Beryllium Disease

RATIONALE Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). OBJECTIVES The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. METHODS Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. MAIN RESULTS The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP β chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. CONCLUSIONS Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.

Evaluation of a Preventive Program to Reduce Sensitization at a Beryllium Metal, Oxide, and Alloy Production Plant

Objective: We evaluated a workplace preventive programs effectiveness, which emphasized skin and respiratory protection, workplace cleanliness, and beryllium migration control in lowering beryllium sensitization. Methods: We compared sensitization prevalence and incidence rates for workers hired before and after the program using available cross sectional and longitudinal surveillance data. Results: Sensitization prevalence was 8.9% for the Pre-Program Group and 2.1% for the Program Group. The sensitization incidence rate was 3.7/1000 person-months for the Pre-Program Group and 1.7/1000 person-months for the Program Group. After making adjustments for potential selection and information bias, sensitization prevalence for the Pre-Program Group was 3.8 times higher (95% CI = 1.5 to 9.3) than the Program Group. The sensitization incidence rate ratio comparing the Pre-Program Group to the Program Group was 1.6 (95% CI = 0.8 to 3.6). Conclusions: This preventive program reduced the prevalence of but did not eliminate beryllium sensitization.

Efficacy of a Program to Prevent Beryllium Sensitization Among New Employees at a Copper-Beryllium Alloy Processing Facility

Objectives. In 2000, 7% of workers at a copper-beryllium facility were beryllium sensitized. Risk was associated with work near a wire annealing/pickling process. The facility then implemented a preventive program including particle migration control, respiratory and dermal protection, and process enclosure. We assessed the programs efficacy in preventing beryllium sensitization. Methods. In 2000, the facility began testing new hires (program workers) with beryllium lymphocyte proliferation tests (BeLPTs) at hire and at intervals during employment. We compared sensitization incidence rates (IRs) and prevalence rates for workers hired before the program (legacy workers) with rates for program workers, including program worker subgroups. We also examined trends in BeLPTs from a single laboratory. Results. In all, five of 43 legacy workers (IR=3.8/1,000 person-months) and three of 82 program workers (IR=1.9/1,000 person-months) were beryllium sensitized, for an incidence rate ratio (IRR) of 2.0 (95% confidence interval [CI] 0.5, 10.1). Two of 37 pre-enclosure program workers (IR=2.4/1,000 person-months) and one of 45 post-enclosure program workers (IR=1.4/1,000 person-months) were beryllium sensitized, for IRRs of 1.6 (95% CI 0.3, 11.9) and 2.8 (95% CI 0.4, 66.2), respectively, compared with legacy workers. Test for trend in prevalence rates was significant. Among 2,159 first-draw BeLPTs during 95 months, we identified seven months when high numbers of redraws were required, with one possible misclassification in this facility. Conclusions. Fewer workers became sensitized after implementation of the preventive program. However, low statistical power due to the facilitys small workforce prevents a definitive conclusion about the programs efficacy. These findings have implications for other copper-beryllium facilities, where program components may merit application.

Chronic Beryllium Disease, HLA-DPB1, and the DP Peptide Binding Groove

Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequency-matched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1–4.5) to 3.9 (2.6–5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8–4.6), p < 0.0001; GD versus GG, 2.1 (1.5–2.8), p < 0.0001; LL versus GG, 3.2 (1.8–5.6), p < 0.0001; GL versus GG, 2.8 (2.1–3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.

Cumulative sensitization and disease in a beryllium oxide ceramics worker cohort.

Objective:We followed a cohort of 136 beryllium oxide ceramics workers from 1992 to 2003, including those who left employment, for beryllium sensitization and chronic beryllium disease (CBD). Methods:We invited the cohort’s participation in current worker surveys in 1992, 1998, 2000, and 2002–2003, and in former worker surveys in 2000–2001 and 2003. We calculated 11-year cumulative incidences (after 1992 initial survey) of sensitization and CBD, both crude and corrected for interval censoring; and period prevalences (including 1992 findings), crude and corrected. Results:In 1992, point prevalences were 6% sensitized and 4% CBD. We obtained follow-up on 83% of 128 not sensitized in 1992. Crude cumulative incidences for sensitization and CBD were 13% and 9%, respectively; corrected were 15% and 11%. Crude period prevalences for sensitization and CBD were 16% and 11%, respectively; corrected were 20% and 14%. Corrected period prevalences for pre-1992 machining work were 30% and 20%. Conclusions:With repeated testing over 11 years, total sensitization and CBD in this cohort were triple initial 1992 survey results.

TNF-?? Polymorphisms in Chronic Beryllium Disease and Beryllium Sensitization

Objective: Tumor necrosis factor-alpha (TNF-&agr;) 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-&agr; gene located at -308 and -238 called TNF-&agr;-308*02 and TNF-&agr;-238*02. Methods: TNF-&agr;-308 and TNF-&agr;-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-&agr;-308*02 or TNF-&agr;-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-&agr;-308*02 or TNF-&agr;-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-&agr; alleles and either chronic beryllium disease or sensitization to beryllium.

Association between IL-1A single nucleotide polymorphisms and chronic beryllium disease and beryllium sensitization.

Objective: To determine if single nucleotide polymorphisms (SNPs) in interleukin (IL) IL-1A, IL-1B, IL-1RN, IL-2, IL-9, and IL-9R were associated with chronic beryllium disease (CBD) and beryllium sensitization (BeS). Methods: Forty SNPs in six IL genes were evaluated in 85 individuals with CBD, 61 individuals with BeS, and 730 individuals without BeS or CBD (nonsensitized) using a 5′ nuclease polymerase chain reaction assay. Logistic regression was used to evaluate the association between IL SNPs, CBD, and BeS, adjusting for plant-site and HLA-DPB1Glu69 in additive, dominant, and recessive inheritance models. Results: IL-1A-1142, IL-1A-3769, and IL-1A-4697 were significantly associated with CBD in both the additive and dominant models compared to individuals with BeS or the nonsensitized. Conclusions: These results indicate that genetic variations in the IL-1A gene may play a role in the development of CBD but not BeS.