Hindawi Publishing Corporation Journal of Toxicology Volume 2012, Article ID 946742, 10 pages doi:10.1155/2012/946742 Review Article Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned David C. Dorman,1 Melvin E. Andersen,2 Jerry M. Roper,3 and Michael D. Taylor3 1 College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA 2 Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA 3 Health, Safety, Environment, and Security, Afton Chemical Corp., Richmond, VA 23219, USA Correspondence should be addressed to Michael D. Taylor, mike.taylor@aftonchemical.com 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. 1. Introduction Methylcyclopentadienyl manganese tricarbonyl (MMT , a registered trademark of Afton Chemical Corporation) is an organometallic fuel additive that was developed by the Ethyl Corporation in the 1950s. MMT is currently marketed globally by Afton Chemical Corporation among others. MMT has been used in a variety of fuels, including leaded and unleaded gasoline, diesel and turbine fuel, and fuel oil to raise octane and improve combustion [1]. Manganese concentrations in unleaded gasoline typically range from 5 to 20 ppm when MMT is used. In the United States, MMT is approved for use up to 8.3 ppm in conventional unleaded gasoline. As a fuel additive, MMT falls under the regula- tory domain of the United States Environmental Protec- tion Agency (USEPA), and MMT manufacturers and/or importers are subject to relevant provisions of the USA Clean Air Act (CAA). This paper provides an overview of the novel CAA Alternative Tier 2 test program for MMT designed to collect critical manganese pharmacokinetic data in animals (all test reports and correspondence related to the Alternative Tier 2 Testing for MMT can be found in the Federal Docket Management System (FDMS) at http://www.regulations.gov identiﬁed by docket number EPA-HQ-OAR-2004-0074.). Follow-up eﬀorts led to the development of a series of physiologically based pharmacokinetic (PBPK) models for manganese. This paper will brieﬂy examine the toxicology of manganese, the regulatory history of MMT, the design and conduct of the Alternative Tier 2 program for MMT, key research ﬁndings derived from the health eﬀects research program, and critical lessons learned that can be applied to other chemicals. The second paper in this two-part series [2] describes the PBPK models in greater detail and provides a framework for their application to the risk assessment of manganese.