The beryllium bronchoalveolar lavage lymphocyte proliferation test: indicator of beryllium sensitization, inflammation or both?

CONTEXT: We had available records on over 300 workers evaluated with the beryllium bronchoalveolar lavage lymphocyte proliferation test (BeBALLPT) at three expert chronic beryllium disease (CBD) diagnostic centers. OBJECTIVE: The objective was to describe the contribution of the BeBALLPT to classification of workers with respect to beryllium sensitization (BeS) and beryllium-induced lung inflammation. METHODS: Company records were used to identify beryllium workers who had undergone diagnostic bronchoscopy with BeBALLPT. Clinical, work and smoking information was abstracted from electronic and paper databases. We analyzed factors influencing BeBALLPT outcome, and its relation to blood-determined BeS and granulomatous inflammation. RESULTS: Positive BeBALLPTs contributed evidence of BeS in subjects without prior positive beryllium blood lymphocyte proliferation tests (BeBLPTs) and of pulmonary inflammation in persons without granulomata evident on lung biopsy. Positive BeBALLPTs were associated with positive BeBLPTs and more strongly with granulomata. The rate of both positive BeBALLPT and granulomata increased with time worked through 4 years and were lower in smoking subjects. The false negative rate of the BeBALLPT was 20%. CONCLUSION: A positive BeBALLPT is closely linked to the presence of granulomata on lung biopsy and can be considered as an indicator of lung inflammation in addition to BeS. The ability to use BeBALLPT as a substitute for the more risky lung biopsy is limited by the BeBALLPT false negative rate and lack of information on the false positive rate. It is not recommended that a positive BeBALLPT be considered sufficient evidence for both lung inflammation and BeS.

Occupational Cohort Time Scales.

PURPOSE: This study explores how highly correlated time variables (occupational cohort time scales) contribute to confounding and ambiguity of interpretation. METHODS: Occupational cohort time scales were identified and organized through simple equations of three time scales (relational triads) and the connections between these triads (time scale web). The behavior of the time scales was examined when constraints were imposed on variable ranges and interrelationships. RESULTS: Constraints on a time scale in a triad create high correlations between the other two time scales. These correlations combine with the connections between relational triads to produce association paths. High correlation between time scales leads to ambiguity of interpretation. CONCLUSIONS: Understanding the properties of occupational cohort time scales, their relational triads, and the time scale web is helpful in understanding the origins of otherwise obscure confounding bias and ambiguity of interpretation.

Bias from using occupational smoking prevalence to adjust occupational incidence cohort lung cancer mortality rates.

OBJECTIVE: To describe how smoking correction factors based on comparing worker smoking prevalence with population smoking prevalence are biased if applied to an occupational incidence cohort. METHODS: Relative rates of smoking for shorter-tenure workers derived from occupational cohort lung cancer studies were applied to incidence and prevalence population tenure distributions to calculate relative smoking estimates. RESULTS: High smoking rates in short-tenure workers have little effect on prevalent worker rates (relative smoking estimates, 1.04 and 1.02) and much larger effect in occupational incidence populations (relative smoking estimates, 1.58 and 1.21), which have a much higher proportion of short tenure-workers. CONCLUSIONS: Smoking correction estimates derived from surveys of smoking habits in prevalent workers may introduce bias when applied to incidence workers because of very different proportions of short-tenure workers (length-time biased sampling).

Migration of Beryllium via Multiple Exposure Pathways among Work Processes in Four Different Facilities.

Inhalation of beryllium is associated with the development of sensitization; however, dermal exposure may also be important. The primary aim of this study was to elucidate relationships among exposure pathways in four different manufacturing and finishing facilities. Secondary aims were to identify jobs with increased levels of beryllium in air, on skin, and on surfaces; identify potential discrepancies in exposure pathways, and determine if these are related to jobs with previously identified risk. Beryllium was measured in air, on cotton gloves, and on work surfaces. Summary statistics were calculated and correlations among all three measurement types were examined at the facility and job level. Exposure ranking strategies were used to identify jobs with higher exposures. The highest air, glove, and surface measurements were observed in beryllium metal production and beryllium oxide ceramics manufacturing jobs that involved hot processes and handling powders. Two finishing and distribution facilities that handle solid alloy products had lower exposures than the primary production facilities, and there were differences observed among jobs. For all facilities combined, strong correlations were found between air-surface (rp ≥ 0.77), glove-surface (rp ≥ 0.76), and air-glove measurements (rp ≥ 0.69). In jobs where higher risk of beryllium sensitization or disease has been reported, exposure levels for all three measurement types were higher than in jobs with lower risk, though they were not the highest. Some jobs with low air concentrations had higher levels of beryllium on glove and surface wipe samples, suggesting a need to further evaluate the causes of the discrepant levels. Although such correlations provide insight on where beryllium is located throughout the workplace, they cannot identify the direction of the pathways between air, surface, or skin. Ranking strategies helped to identify jobs with the highest combined air, glove, and/or surface exposures. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file describing the forms of beryllium materials encountered during production and characteristics of the aerosols by process areas.].

Implications of common and special variation for occupational health: examples from beryllium manufacturing.

OBJECTIVE: Common variation is a statistical process-control term for variability associated with usual operating conditions. Special variation occurs when usual operating conditions are disrupted. The objective was to explore the implications for preventive occupational medicine practice of common and special variation in air-level exposure. METHODS: Illustrations are derived from US and UK beryllium facility databases. RESULTS: Special variation may be missed in finite sampling sets, giving a very inaccurate indication of the highest air levels experienced on the job. Depending on the toxicologic model, failure to assess special variation influences the meaningfulness of aspects of occupational prevention, from medical surveillance through risk management. CONCLUSIONS: Jobs and tasks should be characterized for special variation in addition to traditional air sampling. Both special variation and common variation should be considered in occupational medicine preventive practice.

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.

Sensitization and chronic beryllium disease at a primary manufacturing facility, part 3: exposure-response among short-term workers.

OBJECTIVES: Exposure-response relations for beryllium sensitization (BeS) and chronic beryllium disease (CBD) using aerosol mass concentration have been inconsistent, although process-related risks found in most studies suggest that exposure-dependent risks exist. We examined exposure-response relations using personal exposure estimates in a beryllium worker cohort with limited work tenure to minimize exposure misclassification. METHODS: The population comprised workers employed in 1999 with six years or less tenure. Each completed a work history questionnaire and was evaluated for immunological sensitization and CBD. A job-exposure matrix was combined with work histories to create individual estimates of average, cumulative, and highest-job-worked exposure for total, respirable, and submicron beryllium mass concentrations. We obtained odds ratios from logistic regression models for exposure-response relations, and evaluated process-related risks. RESULTS: Participation was 90.7% (264/291 eligible). Sensitization prevalence was 9.8% (26/264), with 6 sensitized also diagnosed with CBD (2.3%, 6/264). A general pattern of increasing sensitization prevalence was observed as exposure quartile increased. Both total and respirable beryllium mass concentration estimates were positively associated with sensitization (average and highest job), and CBD (cumulative). Increased sensitization prevalence was identified in metal/oxide production, alloy melting and casting, and maintenance, and for CBD in melting and casting. Lower sensitization prevalence was observed in plant-area administrative work. CONCLUSIONS: Sensitization was associated with average and highest job exposures, and CBD was associated with cumulative exposure. Both total and respirable mass concentrations were relevant predictors of risk. New process-related risks were identified in melting and casting and maintenance.

Solubility and chemistry of materials encountered by beryllium mine and ore extraction workers: relation to risk.

OBJECTIVE: Beryllium mine and ore extraction mill workers have low rates of beryllium sensitization and chronic beryllium disease relative to the level of beryllium exposure. The objective was to relate these rates to the solubility and composition of the mine and mill materials. METHOD: Medical surveillance and exposure data were summarized. Dissolution of BeO, ore materials and beryllium hydroxide, Be(OH)(2) was measured in synthetic lung fluid. RESULT: The ore materials were more soluble than BeO at pH 7.2 and similar at pH 4.5. Be(OH)(2) was more soluble than BeO at both pH. Aluminum dissolved along with beryllium from ore materials. CONCLUSION: Higher solubility of beryllium ore materials and Be(OH)(2) at pH 7.2 might shorten particle longevity in the lung. The aluminum content of the ore materials might inhibit the cellular immune response to beryllium.

Dissolution and nanoparticle generation behavior of Be-associated materials in synthetic lung fluid using inductively coupled plasma mass spectroscopy and flow field-flow fractionation.

Various Be-containing micro-particle suspensions were equilibrated with simulated lung fluid (SLF) to examine their dissolution behavior as well as the potential generation of nanoparticles. The motivation for this study was to explore the relationship between dissolution/particle generation behaviors of Be-containing materials relevant to Be-ore processing, and their epidemiologically indicated inhalation toxicities. Limited data suggest that BeO is associated with higher rates of beryllium sensitization (BS) and chronic beryllium disease (CBD) relative to the other five relevant materials studied: bertrandite-containing ore, beryl-containing ore, frit (a processing intermediate), Be(OH)2 (a processing intermediate), and silica (control). These materials were equilibrated with SLF at two pH values (4.5 and 7.2) to reflect inter- and intra-cellular environments in lung tissue. Concentrations of Be, Al, and Si in SLF increased linearly during the first 20 days of equilibration, and then rose slowly, or in some cases reached a maximum, and subsequently decreased. Relative to the other materials, BeO produced relatively low Be concentration in solution at pH 7.2; and relatively high Be concentration in solution at pH 4.5 during the first 20 days of equilibration. For both pH values, however, the Be concentration in SLF normalized to Be content of the material was lowest for BeO, demonstrating that BeO was distinct among the four other Be-containing materials in terms of its persistence as a source of Be to the SLF solution. Following 149 days of equilibration, the SLF solutions were fractionated using flow-field flow fractionation (FlFFF) with detection via ICP-MS. For all materials, nanoparticles (which were formed during equilibration) were dominantly distributed in the 10-100 nm size range. Notably, BeO produced the least nanoparticle-associated Be mass (other than silica) at both pH values. Furthermore, BeO produced the highest Be concentrations in the size range corresponding to < 3 kDa (determined via centrifugal ultrafiltration), indicating that in addition to persistence, the BeO produced the highest concentrations of truly dissolved (potentially ionic) Be relative to the other materials. Mass balance analysis showed reasonable sample recoveries during FFF fractionation (50-100%), whereas recoveries during ICP-MS (relative to acidified standards) were much lower (5-10%), likely due to inefficiencies in nebulizing and ionizing the nanoparticles.

Evaluation of a preventive program to reduce sensitization at a beryllium metal, oxide, and alloy production plant.

OBJECTIVE: We evaluated a workplace preventive program's 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.

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.

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 program's 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 facility's small workforce prevents a definitive conclusion about the program's efficacy. These findings have implications for other copper-beryllium facilities, where program components may merit application.

Exposure to beryllium and occurrence of lung cancer: findings from a cox proportional hazards analysis of data from a retrospective cohort mortality study.

OBJECTIVE: The objective was to assess highly confounded patterns in a standardized mortality ratio (SMR) analysis of lung cancer in beryllium worker cohorts. METHODS: We used Cox proportional hazards single- and multi-variate models to assess confounding and the SMR patterns. RESULTS: We confirmed the lack of association of lung cancer with time worked. We could not confirm the original study's finding of lung cancer highly associated with earlier plants and or with workers hired in the 1940s compared to the 1950s. The pattern of higher rates of lung cancer with increasing latency was attenuated when covariates were added to the model. We could not exclude that the lower SMR and hazard ratios for workers hired in the 1960s might be related to assumed lower beryllium exposures. CONCLUSION: The patterns observed provide little support for an association of lung cancer with beryllium work factors. This result is likely due to the absence in the original study of a significant overall excess of lung cancer after smoking adjustment.

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.

Empirical evaluation of complex epidemiologic study designs: workplace exposure and cancer.

OBJECTIVE: To test whether a frequently used cohort-nested case-control study design exaggerated exposure-response relationships because of unrecognized study design bias. Our aim was to evaluate empirically the performance of this complex study design. METHODS: We applied the design from one such study to a closely related cohort using randomly selected probands as cases. Values for average exposures were assigned to probands equal to, greater than, and less than those assigned to controls (matches). RESULTS: Under certain lag scenarios, the nested study design produced higher average exposure in probands compared with their matches, even when this was clearly not the case. CONCLUSIONS: Empirical evaluation demonstrated that the study design produced a biased case-control lagged exposure difference under the null hypothesis and could not distinguish qualitatively between null and alternate hypotheses. Empirical evaluation provided a useful check on results generated from a complex study design. It gave useful insight into the behavior of the index study design that was not otherwise readily deducible.

Exposure to beryllium and occurrence of lung cancer: a reexamination of findings from a nested case-control study.

OBJECTIVE: Our aim was to reanalyze a nested case-control study of beryllium and lung cancer because we identified analysis and study design issues that could have led to the elevated odds ratios obtained in the study. METHODS: We reanalyzed the data using nontransformed exposure metrics instead of log-transformed metrics used in the publication. We identified and examined effects on estimated odds ratios of imbalances between cases and controls caused by the control selection method. RESULTS: This reanalysis found no elevated odds ratios for any exposure variable. CONCLUSION: : Our conclusions differ from the authors' interpretation that the findings are due to a causal relationship between beryllium exposure and lung cancer. Our alternative explanation is that they may be due to methodological problems that could have been controlled by closer matching of controls to cases. CLINICAL SIGNIFICANCE: This study challenges conclusions made from a large case-control study concerning beryllium-lung cancer associations. Occupational medicine practitioners may want to integrate findings from this study into advice they give beryllium-exposed workers concerned about lung cancer.

Exposure pathway assessment at a copper-beryllium alloy facility.

Controlling beryllium inhalation exposures to comply with regulatory levels (2 micro g m(-3) of air) does not appear to prevent beryllium sensitization and chronic beryllium disease (CBD). Additionally, it has proven difficult to establish a clear inhalation exposure-response relationship for beryllium sensitization and CBD. Thus, skin may be an important route of exposure that leads to beryllium sensitization. A 2000 survey had identified prevalence of sensitization (7%) and CBD (4%) in a beryllium alloy facility. An improved particulate migration control program, including dermal protection in production areas, was completed in 2002 at the facility. The purpose of this study was to evaluate levels of beryllium in workplace air, on work surfaces, on cotton gloves worn by employees over nitrile gloves, and on necks and faces of employees subsequent to implementation of the program. Over a 6 day period, we collected general area air samples (n = 10), wipes from routinely handled work surfaces (n = 252), thin cotton glove samples (n = 113) worn by employees, and neck wipes (n = 109) and face wipes (n = 109) from the same employees. In production, production support and office areas geometric mean (GM) levels of beryllium were 0.95, 0.59 and 0.05 micro g per 100 cm(2) on work surfaces; 42.8, 73.8 and 0.07 micro g per sample on cotton gloves; 0.07, 0.09 and 0.003 micro g on necks; and 0.07, 0.12 and 0.003 micro g on faces, respectively. Correlations were strong between beryllium in air and on work surfaces (r = 0.79), and between beryllium on cotton gloves and on work surfaces (0.86), necks (0.87) and faces (0.86). This study demonstrates that, even with the implementation of control measures to reduce skin contact with beryllium as part of a comprehensive workplace protection program, measurable levels of beryllium continue to reach the skin of workers in production and production support areas. Based on our current understanding of the multiple exposure pathways that may lead to sensitization, we support prudent control practices such as use of protective gloves to minimize skin exposure to beryllium salts and fine particles.