2016 SOT FDA Colloquium: Role of Mode of Action in Dose-Response Assessment for Carcinogens

The Society of Toxicology in conjunction with the US FDA Center for Food Safety and Applied Nutrition (CFSAN) have partnered to provide this colloquia series. The series presents scientific information that is high-quality, cutting-edge, future-oriented toxicological science to provide a well-grounded foundation to inform the work of US FDA employees.

On January 25, 2016, SOT and US FDA co-hosted a colloquium that included an overview talk about dose-response, including recommendations from the NRC Silver Book; a discussion of mode of action including definition, differences from mechanism of action, and some framework key events; a case study of the choices in dose-response analysis for a mutagenic mode of action; and recommendations from the Risk21 project on the role of key events in deciding on the dose-response analysis.

Among the primary goals of a risk assessment are 1) determination of the presence or absence of a cause-effect relationship and 2) quantifying the risk through dose-response analysis. Dose-response data may be derived from in vivo studies in animals or humans, which usually provide the basis for risk characterization, and in vitro studies, which are often related to investigations of mode of action (MOA). MOA information describes key events and processes that would explain the overall process of development of a toxic effect. MOA can also be relevant in considering susceptibility factors within populations and in considering the cumulative effects of exposure to more than a single agent. Over the last several years, advances in our understanding of the ways that chemicals interact with biological systems have yielded several frameworks for evaluating toxicity datasets to determine biologically plausible modes of action and relevance to humans. These frameworks can be used to consider the weight of evidence of hypothesized modes of action in animals and their potential human relevance for both cancer and non-cancer effects. This could result in a move away from defaults to adopt modern knowledge on MOA to improve risk assessments, including the choices for dose-response assessment.