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Journal of Toxicology
Volume 2012 (2012), Article ID 946742, 10 pages
Review Article

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

1College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
2Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA
3Health, Safety, Environment, and Security, Afton Chemical Corp., Richmond, VA 23219, USA

Received 30 September 2011; Accepted 18 January 2012

Academic Editor: Kannan Krishnan

Copyright © 2012 David C. Dorman 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.


Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments.