Results from a Ukrainian-US collaborative study: prevalence and predictors of respiratory symptoms among Ukrainian coal miners.

BACKGROUND: Underground coal mining is an expanding industry in Ukraine, yet little is known about the burden of respiratory disease among Ukrainian miners. METHODS: A Fogarty International Center-supported collaboration between researchers at the University of Illinois and the Institute of Occupational Health in Kyiv, Ukraine formed to improve capacity for conducting and monitoring medical surveillance among Ukrainian coal miners. A cross-sectional survey among a random sample of working and former miners was conducted; demographic, work, and health information were collected using a standardized questionnaire. Weighted prevalence rates were calculated and predictors of respiratory symptoms explored. RESULTS: Improvements in infrastructure, including spirometry and chest radiography testing, transformed medical surveillance among these miners. Results from the health study included that the prevalence of respiratory symptoms was higher among former compared to current miners (shortness of breath 35.6% vs. 5.1%; chronic bronchitis 18.1% vs. 13.9%, respectively). A statistically significant exposure-response relationship was observed between years mining and respiratory symptoms in former miners and between years mining at the coal face and respiratory symptoms among current miners. Evidence of downward bias from the healthy worker survivor effect was observed. CONCLUSIONS: This successful international collaboration built a sustainable infrastructure for conducting workplace medical surveillance and research. The resulting study was the first in the western literature to report on respiratory symptoms in this population; likely underestimation of disease rates due to selection and measurement biases was demonstrated. Efforts should continue to build this collaboration and to characterize and reduce respiratory illness among Ukrainian coal miners.

Development of a fibre size-specific job-exposure matrix for airborne asbestos fibres.

OBJECTIVE: To develop a method for estimating fibre size-specific exposures to airborne asbestos dust for use in epidemiological investigations of exposure-response relations. METHODS: Archived membrane filter samples collected at a Charleston, South Carolina asbestos textile plant during 1964-8 were analysed by transmission electron microscopy (TEM) to determine the bivariate diameter/length distribution of airborne fibres by plant operation. The protocol used for these analyses was based on the direct transfer method published by the International Standards Organization (ISO), modified to enhance fibre size determinations, especially for long fibres. Procedures to adjust standard phase contrast microscopy (PCM) fibre concentration measures using the TEM data in a job-exposure matrix (JEM) were developed in order to estimate fibre size-specific exposures. RESULTS: A total of 84 airborne dust samples were used to measure diameter and length for over 18,000 fibres or fibre bundles. Consistent with previous studies, a small proportion of airborne fibres were longer than >5 microm in length, but the proportion varied considerably by plant operation (range 6.9% to 20.8%). The bivariate diameter/length distribution of airborne fibres was expressed as the proportion of fibres in 20 size-specific cells and this distribution demonstrated a relatively high degree of variability by plant operation. PCM adjustment factors also varied substantially across plant operations. CONCLUSIONS: These data provide new information concerning the airborne fibre characteristics for a previously studied textile facility. The TEM data demonstrate that the vast majority of airborne fibres inhaled by the workers were shorter than 5 mum in length, and thus not included in the PCM-based fibre counts. The TEM data were used to develop a new fibre size-specific JEM for use in an updated cohort mortality study to investigate the role of fibre dimension in the development of asbestos-related lung diseases.

Challenges and Opportunities for Occupational Epidemiology in the Twenty-first Century.

PURPOSE OF REVIEW: There are many opportunities and challenges for conducting occupational epidemiologic studies today. In this paper, we summarize the discussion of a symposium held at the Epidemiology in Occupational Health (EPICOH) conference, Chicago 2014, on challenges for occupational epidemiology in the twenty-first century. RECENT FINDINGS: The increasing number of publications and attendance at our conferences suggests that worldwide interest in occupational epidemiology has been growing. There are clearly abundant opportunities for new research in occupational epidemiology. Areas ripe for further work include developing improved methods for exposure assessment, statistical analysis, studying migrant workers and other vulnerable populations, the use of biomarkers, and new hazards. Several major challenges are also discussed such as the rapidly changing nature and location of work, lack of funding, and political/legal conflicts. As long as work exists there will be occupational diseases that demand our attention, and a need for epidemiologic studies designed to characterize these risks and to support the development of preventive strategies. Despite the challenges and given the important past contribution in this field, we are optimistic about the importance and continued vitality of the research field of occupational epidemiology.

Smoking, occupation, and histopathology of lung cancer: a case-control study with the use of the Third National Cancer Survey.

The relationships between occupation, smoking, and the three most common histologic types of lung cancer (squamous cell carcinoma, small-cell carcinoma, and adenocarcinoma) were explored in a case-control study with the use of data collected during the Third National Cancer Survey. The largest histologic group was squamous cell carcinoma (152 cases), followed by adenocarcinoma (50 cases), and small-cell carcinoma (45 cases). The control series was comprised of cancers at all anatomic sites except those believed to be associated with either smoking or occupational exposures. Cigarette smoking was significantly associated with all three histologic types of lung cancer. Overall, the relationship with small-cell carcinoma was strongest (odds ratio = 5.1), whereas those with squamous and adenocarcinoma were approximately equivalent (odds ratio = 3.1). Dose-response relationships were evident for all three histologic types; however, the linear relationship was found to be statistically significant (P less than 0.05) only for squamous and small-cell carcinomas. Squamous cell carcinoma was the type most frequently associated with occupational categories. It was significantly associated (P less than 0.05) with "blue collar" professions (odds ratio = 2.1). No occupational categories were significantly associated with adenocarcinoma. In addition, no occupational categories were associated with all histologic types of lung cancer combined. This last observation suggested that the sensitivity of epidemiologic studies might not only be increased by use of improved occupational histories but more specifically by consideration of histology in examination of associations between occupation and respiratory cancer.

Nasopharyngeal cancer, sinonasal cancer, and occupations related to formaldehyde: a case-control study.

Formaldehyde vapor induces cancer of the nasal passages in laboratory animals. In this case-control epidemiologic study, occupational information was obtained for 198 persons with sinonasal cancer (SNC), for 173 with nasopharyngeal cancer (NPC) identified as incident cases by the Connecticut Tumor Registry over 41 years among Connecticut males dying of any cause, and for 605 controls sampled from Connecticut death certificates. City directories and death certificates provided information on job, industry, employer, and year of employment for exposure classification. Without knowledge as to case-control status, an industrial hygienist particularly experienced in epidemiologic studies of formaldehyde classified each study subject with respect to probability and degree of formaldehyde exposure. For those with probable exposure to the high level 20+ years prior to death the odds ratio for NPC was 2.3 [95% confidence limits (CL): 0.9, 6.0], and for those with this same risk factor among men dying at age 68+ (the median study age at death or older) the odds ratio was 4.0 [95% CL: 1.3, 12.0--with two-sided P = .015, unadjusted for multiple significance tests, and with two-sided P = .129 in testing for interaction between this risk factor (never any exposure vs. probable exposure to high level 20+ years prior to death) and age (age less than 68 yr vs. age 68+ yr)]. Odds ratios were close to unity for 9 of 13 industries. Formaldehyde-related occupations in printing appeared to be associated with any type of nasal cancer (either SNC or NPC).

Contribution of formaldehyde to respiratory cancer.

This article reviews the available data on the carcinogenicity of formaldehyde from experimental and epidemiologic studies and makes recommendations for further research. Two definitive chronic inhalation bioassays on rodents have demonstrated that formaldehyde produces nasal cancer in rats and mice at 14 ppm and in rats at 6 ppm, which is within the domain of present permissible human exposure (8-hr time-weighted average of 3 ppm, a 5 ppm ceiling, and a 10 ppm short-term exposure limit). Biochemical and physiologic studies in rats have shown that inhaled formaldehyde can depress respiration, inhibit mucociliary clearance, stimulate cell proliferation, and crosslink DNA and protein in the nasal mucosa. No deaths from nasal cancer have been reported in epidemiologic studies of cohorts exposed to formaldehyde, but three case-control studies suggest the possibility of increased risk. Although excesses of lung cancer deaths have been observed in some studies at industrial plants with formaldehyde exposure, uncertainties in interpretation limit the evaluation of these findings. Excess cancers of the brain and of lymphatic and hematopoietic tissues have been reported in certain studies of industrial groups and in most studies of formaldehyde-exposed professionals, but whether these excesses are related to formaldehyde exposure is not known. Several properties of formaldehyde pose unique problems for future research: the mechanisms responsible for its nonlinear response; its probable mechanism of carcinogenic action as a cross-linking agent; its formation in tissues as a normal metabolite; its possible action as a promoter and/or a cocarcinogen; and the importance of glutathione as a host defense at low exposure.

Mortality among a cohort of garment workers exposed to formaldehyde: an update.

AIMS: To evaluate the mortality experience of 11 039 workers exposed to formaldehyde for three months or more in three garment plants. The mean time weighted average formaldehyde exposure at the plants in the early 1980s was 0.15 ppm but past exposures may have been substantially higher. METHODS: Vital status was updated through 1998, and life table analyses were conducted. RESULTS: Mortality from all causes (2206 deaths, standardised mortality ratio (SMR) 0.92, 95% CI 0.88 to 0.96) and all cancers (SMR 0.89, 95% CI 0.82 to 0.97) was less than expected based on US mortality rates. A non-significant increase in mortality from myeloid leukaemia (15 deaths, SMR 1.44, 95% CI 0.80 to 2.37) was observed. Mortality from myeloid leukaemia was greatest among workers first exposed in the earliest years when exposures were presumably higher, among workers with 10 or more years of exposure, and among workers with 20 or more years since first exposure. No nasal or nasopharyngeal cancers were observed. Mortality from trachea, bronchus, and lung cancer (147 deaths, SMR 0.98, 95% CI 0.82 to 1.15) was not increased. Multiple cause mortality from leukaemia was increased almost twofold among workers with both 10 or more years of exposure and 20 years or more since first exposure (15 deaths, SMR 1.92, 95% CI 1.08 to 3.17). Multiple cause mortality from myeloid leukaemia among this group of workers was also significantly increased (8 deaths, SMR 2.55, 95% CI 1.10 to 5.03). CONCLUSIONS: Results support a possible relation between formaldehyde exposure and myeloid leukaemia mortality. Previous epidemiological studies supporting a relation between formaldehyde exposure and leukaemia mortality have been primarily of formaldehyde exposed professional groups, not formaldehyde exposed industrial workers. Limitations include limited power to detect an excess for rare cancers such as nasal and nasopharyngeal cancers and lack of individual exposure estimates.

Assessment of silicosis risk for occupational exposure to crystalline silica.

Epidemiologic studies of workers exposed to silica were reviewed to identify data on airborne concentrations of quartz that are not associated with an increased risk of silicosis, the lowest concentrations associated with silicosis, and studies that used statistical models to quantitate the risk of silicosis as a function of silica exposure. The no observed adverse effect levels varied from 7 to 100 mu g center dot m-3, and the lowest observed adverse effect levels ranged from 8 to 252 mu g center dot m-3 in five different cohorts. Studies using quantitative exposure-response models revealed a wide difference in the cumulative risk estimates for silicosis. The differences in the risk estimates and the no observed and lowest observed effect levels may have been the result of errors in exposure estimates, physicochemical characteristics of silica and quartz content of the dust, cohort differences, and reader variability. Further research is needed to define the dose-response relationship between silica exposure and silicosis.

Human cancer risk and exposure to 1,3-butadiene--a tale of mice and men.

OBJECTIVES: The purpose of this study was to evaluate empirically the relevance of animal-bioassay-based models for predicting human risks from exposure to 1,3-butadiene (BD) using epidemiologic data. METHODS: Relative-risk results obtained with a regression model in a recent epidemiologic study were used to estimate leukemia risk for occupational and environmental exposures to BD and to compare these estimates with those previously derived from an analysis of animal bioassay data. RESULTS: The estimates of risk were found to be highly dependent on the model used when low levels of exposure were evaluated that are of environmental concern, but not at the levels of occupational concern. For example, at the level (1 part per million) of the recently revised standard of the Occupational Safety and Health Administration in the United States the estimates of lifetime excess risk ranged from 1 to 8 per 1000 workers. The range of the risk estimates derived from the epidemiologic models was remarkably similar to the range of risk estimates for occupational exposures (1 to 9 per thousand) previously developed by Dankovic et al in 1993 from an analysis of a mouse bioassay study for lymphocytic lymphoma. CONCLUSIONS: Results for BD seem to provide another example of a high degree of concordance between the risk predictions from models of toxicologic and epidemiologic data, particularly at occupational levels of exposure.

Cardiovascular mortality among munitions workers exposed to nitroglycerin and dinitrotoluene.

A retrospective cohort mortality study with 5529 nitroglycerin, 4989 dinitrotoluene, and 5136 unexposed workers compared the mortality of the exposed groups with that of the United States population and that of the unexposed group with life-table analysis and Poisson regression. Mortality from ischemic heart disease was close to that expected, and mortality from cerebrovascular disease was slightly less than that expected, for the workers with both nitroglycerin and dinitrotoluene exposure and for those with dinitrotoluene exposure only. A significant interaction between age and nitroglycerin exposure was detected in the Poisson regression analyses for ischemic heart disease, particularly for workers actively exposed to nitroglycerin. The rate ratio for the workers under 45 years of age and actively exposed to nitroglycerin was 3.30 (95% confidence interval 129-8.48). This study did not show a chronic effect of nitroglycerin or dinitrotoluene exposure on cardiovascular disease risk. Potential biases related to the company's medical screening program may have limited the ability to detect chronic cardiovascular effects.

Methodological issues of using observational human data in lung dosimetry models for particulates.

INTRODUCTION: The use of human data to calibrate and validate a physiologically based pharmacokinetic (PBPK) model has the clear advantage of pertaining to the species of interest, namely humans. A challenge in using these data is their often sparse, heterogeneous nature, which may require special methods. Approaches for evaluating sources of variability and uncertainty in a human lung dosimetry model are described in this study. METHODS: A multivariate optimization procedure was used to fit a dosimetry model to data of 131 U.S. coal miners. These data include workplace exposures and end-of-life particle burdens in the lungs and hilar lymph nodes. Uncertainty in model structure was investigated by fitting various model forms for particle clearance and sequestration of particles in the lung interstitium. A sensitivity analysis was performed to determine which model parameters had the most influence on model output. Distributions of clearance parameters were estimated by fitting the model to each individual's data, and this information was used to predict inter-individual differences in lung particle burdens at given exposures. The influence of smoking history, race and pulmonary fibrosis on the individual's estimated clearance parameters was also evaluated. RESULTS: The model structure that provided the best fit to these coal miner data includes a first-order interstitialization process and no dose-dependent decline in alveolar clearance. The parameter that had the largest influence on model output is fractional deposition. Race and fibrosis severity category were statistically significant predictors of individual's estimated alveolar clearance rate coefficients (P < 0.03 and P < 0.01-0.06, respectively), but smoking history (ever, never) was not (P < 0.4). Adjustments for these group differences provided some improvement in the dosimetry model fit (up to 25% reduction in the mean squared error), although unexplained inter-individual differences made up the largest source of variability. Lung burdens were inversely associated with the miners' estimated clearance parameters, e.g. individuals with slower estimated clearance had higher observed lung burdens. CONCLUSIONS: The methods described in this study were used to examine issues of uncertainty in the model structure and variability of the miners' estimated clearance parameters. Estimated individual clearance had a large influence on predicted lung burden, which would also affect disease risk. These findings are useful for risk assessment, by providing estimates of the distribution of lung burdens expected under given exposure conditions.

A retrospective cohort mortality study of a phosphate fertilizer production facility.

A retrospective cohort mortality study of phosphate fertilizer production workers was undertaken to determine whether this group is at increased risk of dying from any cause, particularly from lung cancer. A total of 3,199 workers who had ever been employed at one facility were included in this investigation. These workers were followed for vital status ascertainment from their first date of employment up to December 1, 1977, or the date of death, whichever occurred first. Overall, no statistically significant elevations in cause-specific mortality were observed for the entire study population. However, when the analysis was stratified by duration of employment, and length of follow-up, a statistically significant (P less than .05) excess in lung cancer mortality was observed among workers with more than 10 yr of employment and follow-up (standardized mortality ratio = 411). Because of the small number of deaths involved, and because we had prior knowledge of a lung cancer cluster at this plant, we believe that these findings should be viewed as suggestive, and that other investigations in plants with similar exposures are needed to clarify whether an occupationally related lung cancer excess truly exists.

Methodologic issues in using epidemiologic studies of occupational cohorts for cancer risk assessment.

This paper focuses on presenting a review and discussion of the major methodologic issues involved in using epidemiologic studies of occupational groups for assessing human cancer risks. Although animal studies have been most often used for quantitative risk assessment, it is generally recognized that well conducted epidemiologic studies would provide the best basis for estimating human risk. However, there are several features related to the design and analysis of epidemiologic studies which frequently limit their usefulness for quantitating risks. The lack of accurate information on exposure in epidemiologic studies is perhaps the most frequently cited limitation of these studies for risk assessment. However, other features of epidemiologic study design such as statistical power, length of follow-up, selection bias, confounding and effect modification may also limit the inferences that can be drawn from these studies. Furthermore even when the aforementioned limitations are overcome, substantial uncertainty exists concerning the choice of an appropriate statistical (or biologic) model for extrapolation beyond the range of exposures observed in a particular study. An empirical example is provided in which estimates of risk varied by nearly 3 orders of magnitude depending on which functional form of the model was chosen. Modeling of epidemiologic data for QRA should be based upon internal comparisons rather than on modeling Standardized Mortality Ratios (SMRs) when possible. Because of the limitations discussed in this paper, epidemiologic data should not be viewed as a panacea for the problems inherent in using animal bioassay data for QRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparing toxicologic and epidemiologic studies: methylene chloride--a case study.

Exposure to methylene chloride induces lung and liver cancers in mice. The mouse bioassay data have been used as the basis for several cancer risk assessments. The results from epidemiologic studies of workers exposed to methylene chloride have been mixed with respect to demonstrating an increased cancer risk. The results from a negative epidemiologic study of Kodak workers have been used by two groups of investigators to test the predictions from the EPA risk assessment models. These two groups used very different approaches to this problem, which resulted in opposite conclusions regarding the consistency between the animal model predictions and the Kodak study results. The results from the Kodak study are used to test the predictions from OSHA's multistage models of liver and lung cancer risk. Confidence intervals for the standardized mortality ratios (SMRs) from the Kodak study are compared with the predicted confidence intervals derived from OSHA's risk assessment models. Adjustments for the "healthy worker effect," differences in length of follow-up, and dosimetry between animals and humans were incorporated into these comparisons. Based on these comparisons, we conclude that the negative results from the Kodak study are not inconsistent with the predictions from OSHA's risk assessment model.

Occupational exposure to chrysotile asbestos and cancer risk: a review of the amphibole hypothesis.

OBJECTIVES: This article examines the credibility and policy implications of the "amphibole hypothesis," which postulates that (1) the mesotheliomas observed among workers exposed to chrysotile asbestos may be explained by confounding exposures to amphiboles, and (2) chrysotile may have lower carcinogenic potency than amphiboles. METHODS: A critical review was conducted of the lung burden, epidemiologic, toxicologic, and mechanistic studies that provide the basis for the amphibole hypothesis. RESULTS: Mechanistic and lung burden studies do not provide convincing evidence for the amphibole hypothesis. Toxicologic and epidemiologic studies provide strong evidence that chrysotile is associated with an increased risk of lung cancer and mesothelioma. Chrysotile may be less potent than some amphiboles for inducing mesotheliomas, but there is little evidence to indicate lower lung cancer risk. CONCLUSIONS: Given the evidence of a significant lung cancer risk, the lack of conclusive evidence for the amphibole hypothesis, and the fact that workers are generally exposed to a mixture of fibers, we conclude that it is prudent to treat chrysotile with virtually the same level of concern as the amphibole forms of asbestos.

A retrospective cohort mortality study of workers exposed to formaldehyde in the garment industry.

In order to assess the possible human carcinogenicity of formaldehyde we conducted a retrospective cohort mortality study of workers exposed for at least three months to formaldehyde in three garment facilities which produced permanent press garments. A total of 11,030 workers contributing 188,025 person-years were included in the study. Vital status was successfully ascertained through 1982 for over 96% of the cohort. The average (TWA) formaldehyde exposure at the three plants monitored in 1981 and 1984 by NIOSH was 0.15 ppm but past exposures may have been substantially higher. In general, mortality from nonmalignant causes was less than expected. A statistically significant excess in mortality from cancers of the buccal cavity (SMR = 343) and connective tissue (SMR = 364) was observed. Statistically nonsignificant excesses in mortality were observed for cancers of the trachea, bronchus and lung (SMR = 114), pharynx (SMR = 112), bladder (SMR = 145), leukemia and aleukemia (SMR = 113), and other lymphopoietic neoplasms (SMR = 170). Mortality from cancers of the trachea, bronchus and lung was inversely related to duration of exposure and latency. In contrast, mortality from cancers of the buccal cavity, leukemias, and other lymphopoietic neoplasms increased with duration of formaldehyde exposure and/or latency. These neoplasms also were found to be highest among workers first exposed during a time period of high potential formaldehyde exposures in this industry (1955-1962). However, it should be recognized that these findings are based on relatively small numbers and that confounding by other factors may still exist. The results from this investigation, although far from conclusive, do provide evidence of a possible relationship between formaldehyde exposure and the development of upper respiratory cancers (buccal), leukemias, and other lymphopoietic neoplasms in humans.

A re-examination of risk estimates from the NIOSH Occupational Noise and Hearing Survey (ONHS)

This paper describes a new analysis of data from the 1968-72 National Institute for Occupational Safety & Health (NIOSH) Occupational Noise and Hearing Survey (ONHS). The population consisted of 1172 (792 noise-exposed and 380 "controls") predominately white male workers from a cross section of industries within the United States. The analysis focused on how risk estimates vary according to various model assumptions, including shape of the dose-response curve and the amount of noise exposure among low-noise exposed workers (or controls). Logistic regression models were used to describe the risk of hearing handicap in relation to age, occupational noise exposure, and duration exposed. Excess risk estimates were generated for several definitions of hearing handicap. Hearing handicap is usually denoted as an average hearing threshold level (HTL) of greater than 25 dB for both ears at selected frequencies. The frequencies included in the biaural averages were (1) the articulation-weighted average over 1-4 kHz, (2) the unweighted average over 0.5, 1, and 2 kHz, and (3) the unweighted average over 1, 2, and 3 kHz. The results show that excess risk estimates for time-weighted average sound levels below 85 dB were sensitive to statistical model form and assumptions regarding the sound level to which the "control" group was exposed. The choice of frequencies used in the hearing handicap definition affected the magnitude of excess risk estimates, which depended on age and duration of exposure. Although data were limited below 85 dB, an age-stratified analysis provided evidence of excess risks at levels ranging from 80 to 84 dB, 85-89 dB, and 90-102 dB. Due to uncertainty in quantifying risks below 85 dB, new data collection efforts should focus on better characterization of dose-response and longitudinal hearing surveys that include workers exposed to 8-hour time-weighted noise levels below 85 dB. Results are compared to excess risk estimates generated using methods given by ANSI S3.44-1996.

Excess hepatobiliary cancer mortality among munitions workers exposed to dinitrotoluene.

An analysis of the mortality experience of workers exposed to dinitrotoluene (DNT) was conducted to test the hypothesis that DNT exposure is associated with an increased risk of cancers of the liver and biliary tract. A total of 4,989 workers exposed to DNT and 7,436 unexposed workers who had worked for at least 5 months at the study facility between January 1, 1949 and January 21, 1980, were included in this investigation. Workers were considered exposed if they had worked at least 1 day on a job with probable exposure to DNT. The vital status as of December 31, 1982, was successfully ascertained for approximately 97% of these workers. Standardized mortality ratios (SMRs) were estimated based upon comparisons with the US population using a modified life-table program. In addition, standardized rate ratios (SRRs) were computed based upon direct comparisons between the DNT and the internal unexposed cohort. An excess of hepatobiliary cancer was observed among workers exposed to DNT in this study. The rate ratio for hepatobiliary cancer was 2.67 (six cases observed) based upon comparison with the US population (SMR = 2.67, 95% CI = 0.98, 5.83), and 3.88 based upon comparison using the internal unexposed referent group (SRR = 3.88, 95% CI = 1.04, 14.41). This study failed to demonstrate an exposure-response relationship between duration of DNT exposure and hepatobiliary cancer mortality. Our study was limited by the small number of workers with long duration of exposure to DNT, and by the lack of quantitative information on exposure to DNT and other chemicals.(ABSTRACT TRUNCATED AT 250 WORDS)