Goal
The goals of this project included: i) Development of a conceptual framework for evaluating the human relevance of mode of action (MOA) data gathered from animal studies, and ii) Testing the framework for its applicability to analysis of both carcinogenic and non-carcinogenic chemicals.
Project Rationale
Over the past decade, there has been increasing recognition of the importance of understanding mode of action when conducting chemical risk assessments. Various organizations, including the International Programme on Chemical Safety (IPCS) and the US Environmental Protection Agency (USEPA), have developed generic criteria for evaluating mode of action (MOA) information from a test species. Building on the IPCS and USEPA approaches, the ILSI RF/RSI project developed a framework for analyzing the human relevance of the animal MOA. This human relevance framework (HRF) features a “concordance” analysis of “key events” in the MOA based on information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. The HRF provides a structured method for systematic and transparent analysis of MOA data and information, and contributes to harmonizing principles/practices for assessing risk of carcinogenic and non- carcinogenic endpoints.
Approach
To complete the work, ILSI RF/RSI convened two types of working groups; one type focused on developing generic criteria and a framework for evaluating the human relevance of a mode of action in the test species, and the other type focused on testing/illustrating the framework via application to specific case studies. Initial case studies focused on peroxisome proliferation-activated receptor (PPAR) activation in the MOA for some animal carcinogens (see Crit Rev Toxicol. 2003 Nov-Dec; 33(6)). A follow-up effort expanded application of the HRF to case studies of DNA-reactive carcinogens as well as several non-cancer endpoints (see Crit Rev Toxicol. 2005 Oct-Nov; 35(8-9)).
Current Status
A course demonstrating the use of an MOA human relevance framework will be offered December 9, 2008 in Boston, MA in conjunction with the 2008 Annual Meeting of the Society for Risk Analysis. This 1 day workshop is an expansion of the highly successful workshops presented at Society for Risk Analysis Meetings in Baltimore and San Antonio; at ILSI in Washington, DC; at the University of North Carolina – Chapel Hill; at the 2008 Toxicology and Risk Assessment conference; and in Ottawa, Canada in collaboration with the University of Ottawa McLaughlin Centre for Population Health Risk Assessment. 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. ILSI RF/RSI is seeking further opportunities to provide training in the use of the MOA human relevance framework.
Click here for more information on the workshop to be held December 7, 2008 in Boston.
This project has been supported financially through cooperative agreements with the US Environmental Protection Agency, Office of Pollution Prevention and Toxics and Office of Pesticide Programs, and through an agreement with Health Canada. The RTP workshop is supported in part by a grant from the Regulatory Safety Evaluation Specialty Section of the Society of Toxicology.