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Journal of Toxicology
Volume 2012 (2012), Article ID 791431, 17 pages
http://dx.doi.org/10.1155/2012/791431
Research Article

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

1Health, Safety, Environment, and Security, Afton Chemical Corp., Richmond, VA 23219, USA
2Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA
3College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA

Received 22 October 2011; Accepted 25 January 2012

Academic Editor: Kannan Krishnan

Copyright © 2012 Michael D. Taylor et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.