This full-day workshop presents a systematic approach to characterizing the
mode(s) of action (MOA) of toxicants and will give participants “hands-on” experience in the application of a framework for evaluating the relevance of an animal mode of action in assessing human risk and subsequent implications for dose-response. Frameworks for characterizing MOA data for carcinogens and analyzing its human relevance have been developed over the past decade and cited in various national and international risk assessment guidelines. More recently, these concepts have been extended to non-cancer endpoints including reproductive, developmental, neurologic and other toxic effects.

The workshop will demonstrate the use of an MOA human relevance framework, through a combination of lecture and interactive case studies with group participation. An opening tutorial will introduce workshop participants to basic concepts and walk them through a model case study. This leads into 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. Case studies will 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 will also introduce participants to the nature of data that is relevant and adequate for replacing   default uncertainty factors subdivided to address kinetics and dynamics for interspecies differences and human variability with chemical specific data.  Examples will be provided and one of the mode of action case studies extended to consider adequacy of kinetic and dynamic data to replace default values for interspecies differences and human variability.

Participants are provided with background materials, copies of the presentations, and other materials specially developed for the case studies.  Case studies are worked through in small breakout groups, each guided by a speaker/facilitator.  The five speaker/facilitators for this workshop – Bette Meek, Vicki Dellarco, Kevin Crofton, Penny Fenner-Crisp, and Doug Wolf - have been leaders in the development of MOA human relevance analysis and have extensive experience in its practical use.