Clinical tool for disease phenotyping in granulomatous lung disease.

BACKGROUND: Exposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function. METHODS: Using a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD. RESULTS: Two factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients. CONCLUSIONS: Using factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity.

Developing effective worker health and safety training materials: hazard awareness, identification, recognition, and control for the salon industry.

OBJECTIVE: In addition to formaldehyde, workers in salons can be exposed to other chemical irritants, sensitizers, carcinogens, reproductive hazards, infectious agents, ergonomic, and other physical hazards. Worker health and safety training is challenging because of current product labeling practices and the myriad of hazards portending risk for a wide variety of health effects. METHODS: Through a Susan B. Harwood Targeted Topic Training grant from the Occupational Safety and Health Administration and assistance from salon development and training partners, we developed, delivered, and validated a health and safety training program using an iterative five-pronged approach. RESULTS: The training was well received and resulted in knowledge gain, improved workplace safety practices, and increased communication about health and safety. CONCLUSIONS: These training materials are available for download from the Occupational Safety and Health Administration's Susan B. Harwood Training Grant Program Web site.

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.

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.

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

OBJECTIVES: 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-DPß chain (DPßE69). However, the nature of the relationship between exposure and carriage of the DPßE69 genotype has not been well studied. The goal of this study was to determine the relationship between DPßE69 and exposure in BeS and CBD. METHODS: 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. RESULTS: 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 DPßE69 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 µg/m(3). Those with both risk factors had higher increased odds (OR 24.1, 95% CI 4.77 to 122). CONCLUSION: DPßE69 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 DPßE69 alone appears to be similar.

Gene-environment interactions influence airways function in laboratory animal workers.

BACKGROUND: Most diseases, including asthma, result from the interaction between environmental exposures and genetic variants. Functional variants of CD14 negatively affect lung function in farm workers and children exposed to animal allergens and endotoxin. OBJECTIVE: We hypothesized that CD14 polymorphisms interact with inhaled endotoxin, mouse allergen, or both to decrease airways function in laboratory animal workers. METHODS: Three hundred sixty-nine Caucasian workers completed a symptom and work exposure questionnaire, skin prick testing, and spirometry. Individual exposure estimates for endotoxin and murine allergen were calculated by weighting task-based breathing zone concentrations by time reported for each task and length of time in the current job. Real-time PCR was used to assess CD14/-1619, -550, and -159 alleles. Multiple linear regression predicting airways function included an interaction term between genotype and exposure. RESULTS: Workers at the highest quartile of the natural log-transformed cumulative endotoxin exposure and with the endotoxin-responsive CD14/-1619 G allele had significantly lower FEV(1) and forced expiratory flow, midexpiratory phase (FEF(25-75)) percent predicted compared with workers with an AA genotype, with no significant differences noted at lower endotoxin levels for either genotype. The gene-environment effect was marked for atopic workers. Laboratory animal allergy, murine allergen exposure, CD14/-159 or -550 genotype, and a gene-exposure interaction term for these genotypes and exposures did not predict changes in lung function. CONCLUSIONS: A significant gene-environment interaction affects airways function in laboratory animal workers. More highly endotoxin-exposed workers with CD14/-1619G alleles have significantly lower FEV(1) and FEF(25-75) percent predicted than those with CD14/-1619AA alleles. Atopic workers are particularly affected by cumulative endotoxin exposures.

Development and piloting of an exposure database and surveillance system for DOE cleanup operations. Department of Energy.

An industrial hygiene exposure database and surveillance system was developed in partnership between National Institute for Occupational Safety and Health (NIOSH)-funded independent investigators and practicing industrial hygienists at the Rocky Flats Environmental Technology Site (RFETS) in Golden, Colo. RFETS is a former U.S. Department of Energy nuclear weapons plant that is now in cleanup phase. This project is presented as a case study in the development of an exposure database and surveillance system in terms that are generalizable to most other industries and work contexts. Steps include gaining organizational support; defining system purpose and scope; defining database elements and coding; planning practical and efficient analysis strategies; incorporating reporting capabilities; and anticipating communication strategies that maximize the probability that surveillance findings will feed back to preventive applications. For each of these topics, the authors describe both general considerations as well as the specific choices made for this system. An important feature of the system is a two-tier task-coding scheme comprising 33 categories of task groups. Examples of grouped analyses of exposure data captured during the system pilot period demonstrate applications to exposure control, medical surveillance, and other preventive measures.

Exposure databases and exposure surveillance: promise and practice.

Based on recent developments in occupational health and a review of industry practices, it is argued that integrated exposure database and surveillance systems hold considerable promise for improving workplace health and safety. A foundation from which to build practical and effective exposure surveillance systems is proposed based on the integration of recent developments in electronic exposure databases, the codification of exposure assessment practice, and the theory and practice of public health surveillance. The merging of parallel, but until now largely separate, efforts in these areas into exposure surveillance systems combines unique strengths from each subdiscipline. The promise of exposure database and surveillance systems, however, is yet to be realized. Exposure surveillance practices in general industry are reviewed based on the published literature as well as an Internet survey of three prominent industrial hygiene e-mail lists. Although the benefits of exposure surveillance are many, relatively few organizations use electronic exposure databases, and even fewer have active exposure surveillance systems. Implementation of exposure databases and surveillance systems can likely be improved by the development of systems that are more responsive to workplace or organizational-level needs. An overview of exposure database software packages provides guidance to readers considering the implementation of commercially available systems. Strategies for improving the implementation of exposure database and surveillance systems are outlined. A companion report in this issue on the development and pilot testing of a workplace-level exposure surveillance system concretely illustrates the application of the conceptual framework proposed.