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ToxSci Advance Access originally published online on October 12, 2005
Toxicological Sciences 2006 89(1):51-56; doi:10.1093/toxsci/kfj001
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

FORUM

Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk

Michael P. Holsapple*,1, Henri C. Pitot{dagger}, Samuel H. Cohen{ddagger}, Alan R. Boobis§, James E. Klaunig, Timothy Pastoor||, Vicki L. Dellarco||| and Yvonne P. Dragan||||

* ILSI Health and Environmental Sciences Institute, Washington, DC 20005; {dagger} Department of Oncology, McArdle Laboratory, University of Wisconsin, Madison, Wisconsin 53706; {ddagger} Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198; § Experimental Medicine & Toxicology, Imperial College London, London, United Kingdom W12 0NN; Indiana University School of Medicine, Indianapolis, Indiana 46202; || Syngenta CropScience, Greensboro, North Carolina 27419; ||| Office of Pesticides Programs, U.S. Environmental Protection Agency, Washington, DC 20460; and |||| National Center for Toxicology Research, Jefferson, Arkansas 72079

Received June 20, 2005; accepted September 27, 2005

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.


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