David C. Deubner

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. Conclusions: 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.

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.

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.

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.

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.

Genetic screening in the workplace.

T he mapping and sequencing of the human genome has resulted in an explosion of information, which has led in several instances to improved capability for detecting diseases or increased susceptibility to disease, treatment of diseases, and the identification of individuals at increased risk for adverse reactions to pharmaceuticals and environmental or workplace chemicals. Some genetic tests are already commercially available, for example, tests which screen for variations in genes that metabolize certain pharmaceuticals and others that identify individuals at increased risks of specific types of cancer. Genetic screening∗ offers the prospect of a new era for prevention and treatment and a growing array of effective new interventions.1,2 Genetic screening has also been accompanied by some misunderstanding, mistrust, and fear that it could be used inappropriately. Indeed, certain previous uses of genetic screening have been inconsistent with good ethical standards and sound scientific practice and have led some to advocate that genetic screening be treated as a separate category with special safeguards. Passage of the Genetic Information Nondiscrimination Act (GINA) of 2008 formalized many of these concerns, thereby establishing strict restrictions and guidelines for the use of such testing in occupational settings.3,4,5 Historically, the American College of Occupational and Environmental Medicine (ACOEM) has taken the position that genetic screening was not conceptually different from other types of medical testing or screening and that adherence to existing ethical standards, good scientific practices, and laws regulating medical confidentiality protected the rights of the individual appropriately, while allowing the new information to be used to further safeguard the health of individuals in the workplace and elsewhere. From a scientific perspective, ACOEM still regards genetic screening as conceptually similar to