Manganese Tissue Dosimetry in Rats and Monkeys: Accounting for Dietary and Inhaled Mn with Physiologically based Pharmacokinetic Modeling

Abstract

Manganese (Mn) is an essential nutrient required for normal tissue growth and function. Following exposures to high concentrations of inhaled Mn, there is preferential accumulation of Mn in certain brain regions such as the striatum and globus pallidus. The goal of this research was to complete a physiologically based pharmacokinetic (PBPK) model for Mn in rats and scale the model to describe Mn tissue accumulation in nonhuman primates exposed to Mn by inhalation and diet. The model structure includes saturable tissue binding with association and dissociation rate constants, asymmetric tissue permeation flux rate constants to specific tissues, and inducible biliary excretion. The rat PBPK model described tissue time-course studies for various dietary Mn intakes and accounted for inhalation studies of both 14-day and 90-day duration. In monkeys, model parameters were first calibrated using steady-state tissue Mn concentrations from rhesus monkeys fed a diet containing 133 ppm Mn. The model was then applied to simulate 65 exposure days of weekly (6 h/day; 5 days/week) inhalation exposures to soluble MnSO(4) at 0.03 to 1.5 mg Mn/m(3). Sensitivity analysis showed that Mn tissue concentrations in the models have dose-dependencies in (1) biliary excretion of free Mn from liver, (2) saturable tissue binding in all tissues, and (3) differential influx/efflux rates for tissues that preferentially accumulate Mn. This multispecies PBPK model is consistent with the available experimental kinetic data, indicating preferential increases in some brain regions with exposures above 0.2 mg/m(3) and fairly rapid return to steady-state levels (within several weeks rather than months) after cessation of exposure. PBPK models that account for preferential Mn tissue accumulation from both oral and inhalation exposures will be essential to support tissue dosimetry-based human risk assessments for Mn.