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 (41 mg Mn/m 3 ), clearance from striatum was nearly complete after $100 days. In a separate simulation of low-level chronic exposure ($0.01 mg Mn/m 3 ), striatal Mn was saturated and reached an approximately steady value at 100 days.

Identifiability Results for Several Classes of Linear Compartment Models

“…Toxicokinetic Model of Manganese in Rats. We consider a variation of the 11-compartment physiologically based pharmacokinetic model of manganese (Mn) absorption, distribution, and clearance in rats by Douglas et al [11,12], which was used to address questions regarding clearance of manganese and the potential links between manganism and Parkinson's disease. The network structure of the original model presented in [11,12] is not strongly connected, and the strongly connected component has too many edges for application of the theorems here.…”

“…We consider a variation of the 11-compartment physiologically based pharmacokinetic model of manganese (Mn) absorption, distribution, and clearance in rats by Douglas et al [11,12], which was used to address questions regarding clearance of manganese and the potential links between manganism and Parkinson's disease. The network structure of the original model presented in [11,12] is not strongly connected, and the strongly connected component has too many edges for application of the theorems here. Thus, we modify the model slightly to include: bidirectional edges for the olfactory epithelium component (noting that diffusion would allow for at least very small reverse direction arrows), a blood-brain barrier/overall brain tissue compartment, and a simplified intestinal absorption pathway, as shown in Figure 6.…”

“…However, we note that as Mn can only be cleared via the gut (i.e. the model has only one leak, at x 5 ), manganese input and measurement from any compartment Figure 6: Compartmental model of manganese pharmacokinetics in rats, based on [11,12].…”

“…6). The outputs y vary depending on the experiment, for example blood Mn levels considered here (y = x 1 ), or the more extensive imaging study data shown in [11,12] (in which case nearly all compartments are measured) both being possibilities. However, we note that as Mn can only be cleared via the gut (i.e.…”