Chronic exposure to Mn inhalation may have lasting effects: A physiologically-based toxicokinetic model in rats

Abstract

In humans, inhaled manganese (Mn) initiates neurodegeneration in the striatum and produces manganism, a disorder phenotypically mimetic of Parkinson's disease (PD), and it is unclear how Mn has this effect. The main route of inhaled Mn passage to striatum – via direct transneuronal transport via the olfactory system or indirectly via lungs to blood, and the relative contributions of each of these pathways – also remain unclear. The primary goal of this investigation was to explore these questions – and others – quantitatively in a rat model. An 11-compartment whole-body physiologically-based toxicokinetic (PBTK) model of Mn distribution, optimally and simultaneously fitted to a single set of multiorgan rat data was used. The fully quantified model provided numerous kinetic parameters, including the relative distribution of whole-body Mn for each compartment in response to a constant simulated input of inhaled Mn, and the relative contributions of olfactory and pulmonary pathways. The liver, which actively concentrates Mn, was found to contain the greatest percentage (∼6.7%). Both the striatum and cerebellum had (∼0.1%) of total Mn, which is notable given that striatum volume is approximately 100-fold less than cerebellum. The relative percentages of olfactory (∼52%) and pulmonary (∼48%) contributions to Mn in striatum were approximately constant computed for up to 200 days after aerosolized exposure. Following simulated acute exposure (>1 mg Mn/m3), clearance from striatum was nearly complete after ∼100 days. In a separate simulation of low-level chronic exposure (∼0.01 mg Mn/m3), striatal Mn was saturated and reached an approximately steady value at 100 days.