Development of a biomathematical lung model to describe respirable particle retention and to investigate exposure, dose, and disease in United States coal miners

Biomathematical and statistical models were used in this study to describe exposure, dose, and disease relationships in coal miners. A three-compartment lung model was developed to investigate the long-term retention of insoluble, respirable particles in human lungs. The purposes of this model were to (1) predict the lung and lymph node dust burdens in U.S. coal miners from their working lifetime exposure histories, and (2) evaluate in humans the relevance of certain findings in rat studies, including the overloading of alveolar clearance. The 131 miners in this study had worked in the Beckley, West Virginia, area and were included in an autopsy study during the 1960's. Initial parameter estimates for this model were based on information on the biological and physical factors influencing particle deposition and clearance in the lungs of humans and animals. The model fit to the data was evaluated using both qualitative and quantitative (least squares) approaches. The lung dust burdens in these coal miners exceed those expected from first-order clearance kinetics. Yet, in the biomathematical exposure-dose models, the assumption of overloading of alveolar macrophage-mediated clearance was neither sufficient nor necessary to explain the lung dust burdens in these miners. The models that provided the best fit to the data were those that included first-order interstitialization/sequestration and either no dose-dependent decline in alveolar clearance or much less decline than expected from the rat studies. These finding are consistent with the particle retention patterns observed in the lungs of larger, nonrodent mammals. In logistic regression models, both the measured and the model-predicted lung dust burdens indicate similar probabilities of developing fibrotic lung disease in these miners. This biomathematical exposure-dose model may be useful in the development of risk assessment methods for particle-induced lung diseases.