Evaluating the Human Relevance of Modes of Action in Animals and Replacing Default Uncertainty Factors with Data Derived Values

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The McLaughlin Centre for Population Health Risk Assessment in collaboration with the ILSI Research Foundation and scientists from the U.S. Environmental Protection Agency and Health Canada, will present a workshop on the application of a framework for evaluating the human relevance of modes of action in animals and implications for dose-response analysis. The framework, developed over the past several years, has already been widely adopted and used by government agencies and international organizations.

A course demonstrating the use of an MOA human relevance framework and replacing default uncertainty factors with data derived values will be offered February 18-19, 2009 at the University of  Ottawa. This 1½ day course is an expansion of highly successful previous courses presented at the University of Ottawa, at ILSI, scientific society meetings and universities in the U.S., at World Health Organization collaborating centres in the U.K. and Thailand and at the European Union Joint Research Centre in Ispra, and the Office of Chemical Safety in Canberra, Australia.  The current course builds on these previous courses and workshops through extension to dose-response analysis and consideration of mode of action as an important element in evolving, more efficient toxicity testing strategies.

In these workshops, opening tutorials introduce workshop participants to basic concepts and walk through an example case study. This leads to a series of facilitated interactive case studies in which participants analyze a diverse series of examples of varying complexity, drawn from recent peer reviewed publications involving real world chemicals. The case studies examine issues such as the incorporation of kinetic and dynamic information and its impact on cross-species extrapolation, the use of precursor data in dose-response analysis, and sufficiency of evidence for establishing an MOA and its human relevance. The cases selected illustrate the comparability between MOA analysis for cancer and non-cancer endpoints, the problem of data-poor situations that preclude a full MOA human relevance analysis, and differences in animal-human MOA analysis based on differences in developmental stage.

A tutorial on a framework of the International Programme on Chemical Safety introduces participants to the nature of data that is relevant and adequate for replacing of default uncertainty factors subdivided to address kinetics and dynamics for interspecies differences and human variability with chemical specific data. Examples are provided and one of the mode of action case studies is extended to consider adequacy of kinetic and dynamic data to replace default values for interspecies differences and human variability.