Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT-Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

Abstract

Recently, a variety of physiologically based pharmacokinetic (PBPK) models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans) and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.

Figure 1

The PBPK model structure developed by Nong and coworkers [14] describing tissue manganese kinetics in adult rats. The overall PBPK model structure is shown in (a); an expanded view of the respiratory tract modeling is shown in (b). Inhaled manganese is absorbed through deposition of particles on the nasal and lung epithelium. Most of the manganese deposited in the nasal cavity is absorbed into the systemic blood while a small fraction undergoes direct delivery to the olfactory bulb. Every tissue has a binding capacity, B _max⁡, with affinity defined by association and dissociation rate constants (k _a, k _d). Free manganese moves in the blood throughout the body and is stored in each tissue as bound manganese. Influx and efflux diffusion rate constants (k _in, k _out) allow for differential increases in manganese levels for different tissues. Q _p, Q _c, Q _tissue refer to pulmonary ventilation, cardiac output, and tissue blood flows. Reprinted from [14] (with permission).

Figure 2

Parallelogram approach for developing Mn PBPK models for adult humans, as well as gestation and lactation.

Figure 3

Curves showing simulated end-of-exposure brain tissue manganese concentrations in monkeys (a) and people (b) as a function of inhalation exposure concentration (mg Mn/m³). Simulated exposures are for 90 days (5 days/week) for either 6 h/day (monkeys) or 8 h/day (human beings). The monkey simulation results at 1.5 mg/m³ (a) are compared with data from Dorman et al. [21] depicted with symbols showing means and standard errors (SEs) from four to six monkeys per time-point. The larger magnitude changes predicted in monkeys compared with humans at higher inhalation exposure concentrations could be due to the saturation of manganese binding sites in the monkey coming from higher manganese concentrations in the diet of the monkeys. Modified from [19].

Figure 4

Simulated olfactory bulb (L) and striatum (R) manganese concentrations in adult and aged (16 month old) male rats following 6 hr/d inhalation MnSO₄ exposure at 0.5 mg Mn/m³ for 90 days. Model simulations for aged rats had a 25% decrease in minute volume consistent with reported reduction in pulmonary function [22, 23].

Figure 5

Simulated globus pallidus manganese concentrations in humans following inhalation exposure to MnSO₄ at 0.00005 (a) or 0.2 mg (b) Mn/m³ for 8 hr/d, 5 d/wk, for one year. Simulations were performed using the human model developed by Schroeter et al. [19] with the following exceptions: model simulations for humans with hepatobiliary impairment had a 50% decrease in liver blood flow and a 50% decrease in biliary excretion (K _bileC) to simulate moderate hepatobiliary disease (see text for more details).

Figure 6

Distributions (min, 5th, med, 95th and max) of globus pallidus concentrations simulated for a human population with the input distributions described in Scenario 3 (see text for more details). Comparison of steady-state brain manganese concentration following 365 days of continuous exposure (24 hr/7 days). There is an overlap of tissue Mn levels between inhaled exposure and dietary variability. Changes in globus pallidal manganese concentrations from exposures <0.05 mg Mn/m³ are small when compared to the impact of normal dietary variation.

Figure 7

Simulated end-of-exposure nonhuman primate globus pallidus manganese concentrations following a 24 h/d, 7 d/wk inhalation for either 90 days (subchronic) or 2 yr (chronic) exposure to MnSO₄. These simulations indicate that globus pallidus manganese concentrations are expected to rapidly reach pseudosteady-state levels during high dose manganese exposure, and that duration of exposure has a minimal effect. Its contribution only occurs once exposures reach the threshold to cause tissue accumulation.