COMPARISON OF HUMAN AND RODENT LUNG DOSIMETRY MODELS FOR PARTICLE CLEARANCE AND RETENTION

Abstract

Interspecies differences in the kinetics and/or mechanisms of particle retention can influence the amount and location of particle retention in the lungs, which can also influence the tissue response to a given particle burden. Dosimetric models may be used to adjust for differences in the exposure-dose relationships in different species, thus allowing for comparison of lung responses at equivalent doses. Although the rat is one of the most frequently used animal models for assessing the risk of exposures to hazardous substances in humans, few data are available for comparison of human and animal responses to inhaled particles. A biologically-based human dosimetric lung model was developed to describe the fate of respirable particles in the lungs of humans, using data from U.S. coal miners and assumptions about the overloading of alveolar clearance from studies in rats. This model includes alveolar, interstitial, and hilar lymph node compartments. The form of the model that provides the best fit to the lung dust burden data in these coal miners includes a first-order interstitialization process and either no dose-dependent decline in alveolar clearance or much less decline than expected from rodent studies. These findings are consistent with the particle retention patterns observed previously in the lungs of primates. This human lung dosimetry model is useful for investigating the factors that may influence the relationships between the airborne particle exposure, lung dust burden, and fibrotic lung disease.