Developments in Modeling Alveolar Retention of Inhaled Insoluble Particles in Rats

Abstract

The development of a non-linear, physiology-oriented compartmental kinetics model of clearance and retention of insoluble particles in the alveolar region of rat lungs is described. The model recognizes the dominant role of the alveolar macrophages in alveolar clearance and retention and assumes that, eventually, increasing burdens of phagocytized particles impair the mobility of alveolar macrophages. Thus, the macrophage-mediated particle removal process will be retarded. In continuous inhalation exposures, this may cause the sequestration of heavily loaded macrophages arid a general overloading of the alveolar region of the lung with retained particles. A basic model design accounting for macrophage life time, phagocytosis rate, mobility decline and limited load capacity was applied for the simulation of experimental data of several chronic and subchronic inhalation studies. The results were very good, but some of the model parameters did not comply with the self-imposed quality criteria. Apparently, the average load of the macrophage pool was an insufficient parameter to account consistently for sequestration. The model was then revised and features now particle load distributions in the macrophage pool. Preliminary efforts to simulate the same experimental inhalation data as before gave again very good results and the model parameters utilized did no longer show the previous inconsistencies.