Pharmacokinetic modeling of manganese in the rat IV: Assessing factors that contribute to brain accumulation during inhalation exposure

A recently published physiologically based pharmacokinetic (PBPK) model successfully accounted for steady-state tissue manganese (Mn) concentration seen with normal dietary intakes and for biphasic, whole-body time-course profiles observed with tracer (54Mn) dosing. In this present study, PBPK modeling was used to evaluate Mn kinetics and brain concentrations in rats exposed to Mn both in their diet and by inhalation. Three published studies were used: (1) rats fed on diets ranging from 2 to 100 ppm, (2) rats on 125 ppm in diet and exposed via inhalation at 0.0 to 3.00 mg Mn/m(3) each day for 14 d, and (3) rats to 0.1 or 0.5 mg Mn/m(3) for 6 h/d, 5 d/wk over a 90-d period. The original model structure with well-mixed and deep compartments for each tissue could not describe rapid increases in tissue concentrations and rapid declines seen in high concentration inhalation studies. A second structure was developed that included (1) saturable, high-affinity binding of Mn in all tissues and (2) asymmetric diffusion from blood into brain (i.e., transport into and out of specific brain regions such as the striatum was described with different diffusion constants). This second model was consistent with liver and striatum experimental data. Preferential increases in some brain regions were predicted for exposures above 0.2 mg/m(3) and had a rapid (i.e., 1 or 2 wk) return to steady-state levels. Multi-dose-route PBPK models for Mn based on this alternative model structure can be readily scaled to evaluate tissue Mn kinetics in other species and for human populations. Once validated across test animals, these PBPK models will be useful in tissue-dose based risk assessment with manganese.