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Spring Issue 2008

SOT Regulatory and Safety Evaluation SS Sponsors Workshop: Evaluating the Human Relevance of Modes of Action in Animals

Submitted by Stephen S. Olin, Ph.D., Deputy Director, ILSI Research Foundation

There has been a steadily increasing expectation for the use of mode of action (MOA) information to improve the scientific basis of human health risk assessment. On February 12, 2008, the ILSI Research Foundation, in collaboration with scientists from the U.S. Environmental Protection Agency, Health Canada, and the University of North Carolina, held a workshop in Chapel Hill, North Carolina entitled, “Evaluating the Human Relevance of Modes of Action in Animals.” This full-day workshop was sponsored by the Regulatory and Safety Evaluation Specialty Section of SOT and focused on the application of a framework that uses a weight of evidence approach to evaluate the human relevance of modes of action in animals. The framework, developed over the past several years, has already been widely adopted and used by government agencies and international organizations.

This framework starts with a plausible hypothesis that describes the series of key events that lead to an adverse response (including lifestage-specific responses) produced by a given compound in experimental animals. The involvement of the key events in the MOA is established based on weight of evidence using modified Bradford Hill criteria, taking into account factors such as dose-response and temporal concordance, specificity of association, biological plausibility, coherence, consistency, and alternative MOAs. If an MOA is established, qualitative and quantitative comparisons of each key event between the experimental animal and humans enables a conclusion as to likely relevance of the MOA for human risk. These comparisons are made transparent by use of concordance tables that help identify the kinetic and dynamic differences of the key events between species. Although application of the framework is not a complete risk assessment, the conclusions regarding MOA have implications for dose-response extrapolation, cross-species scaling, and risk characterization. This framework approach provides structure and transparency to the MOA analysis and clarifies the weight of evidence assessment as a basis for decision making. It also promotes use of all relevant data (including non chemical-specific) and aids in the identification of critical data needs, thus promoting an iterative dialogue between risk assessors and researchers.

The full-day workshop in North Carolina featured opening remarks by Dr. George Gray, U.S. EPA Assistant Administrator for Research and Development, speaking on “Advancing Risk Assessment at U.S. EPA.” Dr. Gray highlighted the need for risk assessment to be based on solid scientific information, provided in a timely manner, within a rigorous and transparent process. He noted that the MOA framework is invaluable as part of this process.

Following Dr. Gray’s presentation, Dr. Penny Fenner-Crisp (ILSI Research Foundation Consultant), provided an overview of the human relevance framework. Drs. Vicki Dellarco (U.S. EPA, Office of Pesticide Programs), and Kevin Crofton (U.S. EPA, Office of Research and Development) presented a case study on disruption of thyroid homeostasis to illustrate how to apply the framework approach to evaluate the human relevance of thyroid tumors and neurodevelopmental outcomes. The workshop continued with interactive case studies in which participants were divided into small groups that included a facilitator. These facilitators were Kevin Crofton, Vicki Dellarco, Penny Fenner-Crisp, Bette Meek (University of Ottawa), Jennifer Seed (U.S. EPA, Office of Pollution Prevention and Toxic Substances) and Douglas Wolf (U.S. EPA, Office of Research and Development). Participants were given toxicological information and data on hypothetical chemicals and asked to work through the framework and come to conclusions concerning: whether there was enough information to establish a MOA in animals, whether there were qualitative or quantitative species differences between the animal mode of action and humans, and lastly whether there were any susceptible population issues that might impact the use of the MOA in humans.

Attendance at the workshop exceeded the expectations of the organizers. There were a total of 43 participants, including government agencies (U.S. EPA, and NIEHS), industry (Bayer CropSciences, BASF Corporation, GlaxoSmithKline, ILS, Inc., Merial Limited, and Syngenta), and other organizations (The Hamner Institute for Health Sciences). Also in attendance were a number of students from the Curriculum in Toxicology at the University of North Carolina.

The workshop concluded with a plenary lecture given by Dr. James Swenberg, UNC Chapel Hill, entitled “Key Events for a Mutagenic MOA: Implications for Risk Assessment.” In this lecture Dr. Swenberg guided the audience through a framework risk assessment with analysis of the key events for selected mutagenic chemicals. He emphasized the need to incorporate background rates of mutagenesis in quantitative assessments of the MOA.

This workshop is the fourth in a series of training workshops on this topic organized by Health Canada, the U.S. EPA, and the ILSI Research Foundation. Previous training workshops have been held at Society for Risk Analysis Meetings (2006 and 2007) and the ILSI offices, Washington, D.C. (2007). Interest is growing to organize training workshops in Europe, Asia, Australia, and other regions. Potential target audiences include groups or organizations that are involved in hazard classification and risk assessment. The next workshop was held this past April in Cincinnati, Ohio at the Toxicology and Risk Assessment Conference.