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Rationale: Previous studies have shown associations between dust exposure or lung burden and emphysema in coal miners, although the separate contributions of various predictors have not been clearly demonstrated., Objectives: To quantitatively evaluate the relationship between cumulative exposure to respirable coal mine dust, cigarette smoking, and other factors on emphysema severity., Methods: The study group included 722 autopsied coal miners and nonminers in the United States. Data on work history, smoking, race, and age at death were obtained from medical records and questionnaire completed by next-of-kin. Emphysema was classified and graded using a standardized schema. Job-specific mean concentrations of respirable coal mine dust were matched with work histories to estimate cumulative exposure. Relationships between various metrics of dust exposure (including cumulative exposure and lung dust burden) and emphysema severity were investigated in weighted least squares regression models., Measurements and Main Results: Emphysema severity was significantly elevated in coal miners compared with nonminers among ever- and never-smokers (P < 0.0001). Cumulative exposure to respirable coal mine dust or coal dust retained in the lungs were significant predictors of emphysema severity (P < 0.0001) after accounting for cigarette smoking, age at death, and race. The contributions of coal mine dust exposure and cigarette smoking were similar in predicting emphysema severity averaged over this cohort., Conclusions: Coal dust exposure, cigarette smoking, age, and race are significant and additive predictors of emphysema severity in this study.

Background: The mortality experience over 22-24 years of 8,899 working coal miners initially medically examined in 1969-1971 at 31 U.S. coal mines was evaluated., Methods: A cohort life-table analysis was undertaken on underlying causes of death, and proportional hazards models were fitted to both underlying, and underlying and contributing causes of death., Results: Elevated mortality from nonviolent causes, nonmalignant respiratory disease (NMRD), and accidents was observed, but lung cancer and stomach cancer mortality were not elevated. Smoking, pneumoconiosis, coal rank region, and cumulative coal mine dust exposure were all predictors of mortality from nonviolent causes and NMRD. Mortality from nonviolent causes and NMRD was related to dust exposure within the complete cohort and also for the never smoker subgroup. Dust exposure relative risks for mortality were similar for pneumoconiosis, NMRD, and chronic airways obstruction., Conclusions: The findings confirm and enlarge upon previous results showing that exposure to coal mine dust leads to increased mortality, even in the absence of smoking., ((c) 2008 Wiley-Liss, Inc.)

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.

The quantitative relationship between exposure to respirable coal mine dust and mortality from nonmalignant respiratory diseases was investigated in a study of 8,878 working male coal miners who were medically examined from 1969 to 1971 and followed to 1979. Exposure-related mortality was evaluated using Cox proportional hazards modeling for underlying or contributing causes of death and modified lifetable methods for underlying causes. For pneumoconiosis mortality, the lifetable analyses showed increasing standardized mortality ratios (SMRs) with increasing cumulative exposure category. Significant exposure-response relationships for mortality from pneumoconiosis (p < 0.001) and from chronic bronchitis or emphysema (p < 0.05) were observed in the proportional hazards models after controlling for age and smoking. No exposure-related increases in lung cancer or stomach cancer were observed. Pneumoconiosis mortality was found to vary significantly by the rank of coal dust to which miners were exposed. Miners exposed at or below the current U.S. coal dust standard of 2 mg/m3 over a working lifetime, based on these analyses, have an elevated risk of dying from pneumoconiosis or from chronic bronchitis or emphysema.