Exploration of the mechanisms of retention and clearance of low-toxicity particles in the rat lung using a mathematical model

A mathematical model of the mechanisms of clearance or retention of inhaled particles in rat lungs is used to explore the extent to which a hypothesized sequence of events (including phagocytosis, macrophage-mediated clearance, transfer into the interstitium, transfer to lymph nodes, and overloading of the defense mechanisms) can account for data from a series of inhalation experiments with a low-toxicity, insoluble dust – titanium dioxide, TiO2. These data include mean lung burdens and mean lymph-node burdens in groups of rats exposed to concentrations of 1, 10, 30, 50, and 90 mg m-3, with exposure periods for as long as 2 yr (at 10 mg m-3), up to 7 mo at 50 mg m-3, and 3.5 mo at 1 and 30 mg m-3. The estimation of the parameters in the model is based mainly on information from other experimental studies or prior modeling. Values within the biologically plausible range were evaluated for the main parameters by inspection of predictions in comparison with data from the lowest concentration experiments. The suitability of the selected values was then confirmed by comparison of model predictions with data from the higher concentration experiments (at 30, 50, and 90 mg m-3). During inhalation, clearance rates are affected by translocation of dust and by overloading. The characterization of overload appears to describe these experiments well. Comparison with the effect of lung burden reported for other types of particles supports the hypothesis that overload is more dependent on the volume rather than the mass of the particles.