Compartmental modeling of the long-term retention of insoluble particles deposited in the alveolar region of the lung

Abstract

The state of the art for modeling the retention of inhaled insoluble particles deposited in the alveolar region of the lung is briefly reviewed, and a new compartmental model of long-term retention is proposed. Wherever possible, this new model favors the replacement of simple first-order kinetics of particle transport processes in the lung by quantified mechanisms derived from or suggested by experimental data of published studies in lung physiology and histopathology. In particular, all macrophage-mediated transport processes, including classical alveolar clearance onto the mucociliary escalator, are modeled as dependent on actual macrophage mobility and are assumed to be influenced by the finite macrophage life time. The mobility is predicted to decrease with increasing particle burden of the macrophage, and there is a limit to the macrophage capacity for accumulating burdens of insoluble particles by phagocytosis. Furthermore, at high particle burdens, macrophages will be progressivity sequestered by irreversible aggregation and immobilization. Using published data on Fischer 344 rats for a quantitative demonstration of the patterns of the new model under chronic exposures, a basic set of model parameters predicts that, at moderate particle deposition rates, retention is limiting itself by establishing a steady state, and the alveolar burden is almost completely eliminated during the postexposure period. However, at high particle deposition rates, the alveolar particle burden increases continuously during the exposure period, and only a small fraction of the deposit is subject to clearance after termination of exposure. In qualitative terms, these are typical features of the “overload” effect which has been observed in a number of recent chronic aerosol inhalation exposure studies with animals.