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ToxSci Advance Access published online on October 12, 2005
Toxicological Sciences, 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
Received June 20, 2005
Revised September 27, 2005

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Mode of Action in Relevance of Rodent Liver Tumors to Human Cancer Risk - 2005 SOT Workshop Session Report

Michael P. Holsapple 1*, Henri C. Pitot 2, Samuel H. Cohen 3, Alan R. Boobis 4, James E. Klaunig 5, Timothy Pastoor 6, Vicki L. Dellarco 7, and Yvonne P. Dragan 8

1 ILSI Health and Environmental Sciences Institute, Washington, DC
2 Department of Oncology, McArdle Laboratory, University of Wisconsin, Madison, WI
3 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
4 Experimental Medicine & Toxicology, Imperial College London, London, UK
5 Indiana University School of Medicine, Indianapolis, IN
6 Syngenta CropScience, Greensboro, NC
7 Office of Pesticides Programs, U.S. Environmental Protection Agency, Washington, DC
8 National Center for Toxicology Research, Jefferson, AR

* To whom correspondence should be addressed.
Michael P. Holsapple, E-mail: mholsapple{at}ilsi.org


  Abstract

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 impact on the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the IPCS and ILSI RSI with the central tenet being the identification of a mode of action (MOA). In order 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 determined. The key events can be used to bridge across 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 considering kinetic and dynamic factors. In contrast, after considering these factors, the conclusion was 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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