On the Application of Data on Mode of Action to Carcinogenic Risk Assessment

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Abstract
In the Forum article in this issue of Toxicological Sciences, Cohen et al. (2004) discuss a framework for systematic analysis of data on modes of carcinogenic action of chemicals in experimental animals, and its application to cancer risk assessment. This summarizes an exercise recently completed by the ILSI Risk Science Institute (Cohen et al., 2003), which builds on a harmonization initiative of the International Programme on Chemical Safety (Sonich-Mullin et al., 2001). The framework approach is based fundamentally on advances that have been achieved in recent decades in understanding the pathogenesis of neoplasia. It is now recognized that cancers originating from at least some cell types may arise by a variety of independent pathways. It is also established that different carcinogens may have different modes of action (MOAs), and that some carcinogens can act by more than one MOA in different tissues. Some MOAs lead to cancers in both experimental rodents and humans, but others that lead to cancers in rodents do not do so in humans, at least under realistic circumstances of human exposure. To refine and improve the process of carcinogenic hazard identification, and to avoid misidentification of harmless substances as possible human carcinogens, it has therefore become imperative that MOA analysis be undertaken for regulatory purposes, and that data to support such analysis be collected in a thorough and scientifically rigorous manner.

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