IPCS Conceptual Framework for Evaluating a Mode of Action for Chemical Carcinogenesis

The International Programme on Chemical Safety (IPCS) is leading an activity to harmonize approaches to cancer risk assessment as a part of its larger project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. Through a series of workshops and the evaluation of case studies, a number of key components of risk assessments relating to harmonization were identified: transparency, terminology, weight of evidence, flexibility, and accessibility/communication. A major impediment to harmonization identified in the consideration of weight of evidence was the evaluation of mode of action. To address this need, a conceptual framework was developed, based on the general principles involved in considering the chemical induction of a specific tumor in animals. This is based partly on the Bradford Hill criteria for causality as modified by Faustman et al. (1997) for developmental toxicity. The framework is described in this paper followed by a worked example. It is recognized that the framework addresses only one stage in the overall characterization of hazard to humans of chemical carcinogens. Another important but separate step is the assessment of relevance to humans. This is a priority area for future work in this project.