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Pharmaceutical and non-pharmaceutical chemical agents have been shown to induce hepatic adenomas and carcinomas in mice and rats following chronic exposure.Evaluation of the over 586 bioassays conducted by the National Toxicology Program (NTP) since 1976 reveals that rodent liver is the most frequent target organ for carcinogenesis.The liver is usually the first pass organ for materials that are absorbed from the gastrointestinal tract from feeding or gavage studies and as such is the primary site of metabolism of many of the carcinogenic compounds in rodents.Over the past two decades, regulatory organizations have developed approaches to the utilization of rodent chronic studies for human cancer risk assessment.These approaches have followed several reviews and recommendations by the National Research Council, and in 2005 the US EPA galvanized the latest cancer risk assessment guidelines.A significant portion of this framework is the development of mode of action information that helps to understand the mechanism by which chemical agents produce cancer, and the utilization of this rodent mode of action in the consideration of possible human risk.Chemical agents induce liver tumors in rodents through either genotoxic or non-genotoxic (non DNA reactive) mechanisms.Genotoxic agents have been studied extensively and, in general, produce their effects to modulation of genomic DNA, resulting in a mutation which coupled with cell proliferation stimuli, either endogenous from the site of mutation itself or exogenous through hormonal, dietary or other chemical modification.Non-genotoxic carcinogens function through mechanisms not directly involving adducts formation or direct interaction of the chemical or its metabolite with genomic DNA.A number of potential modes of action for non-genotoxic rodent carcinogens have been identified.This includes receptor mediated processes, cytotoxicity, oxidative stress and damage, and infection.A common key event of these non-genotoxic modes of action is the induction of an increase in preneoplastic hepatocyte number through either an increase in cell proliferation and/or a decrease in cell death or apoptosis.This review will examine using case studies the potential modes of action for rodent liver tumor formation and using the human relevance framework, discuss the significance of the rodent mode of action to human cancer risk.