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Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors
Citation:
Budinsky, R., C. CORTON, C. Elcombe, J. Klaunig, D. Schrenk, AND D. Wolf. Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors. Presented at Society of Toxicology (SOT) Annual meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
A recent workshop held at the NIEHS explored the development of dose-response approaches to nuclear receptor-mediated liver cancer, within a Mode of Action (MOA) Human Relevance Framework (HRF). Case studies discussed were: AHR, CAR, PXR, and PPARalpha.
Description:
Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC report. A recent workshop held at the NIEHS explored the development of dose-response approaches to nuclear receptor-mediated liver cancer, within a Mode of Action (MOA) Human Relevance Framework (HRF). Case studies discussed were: AHR, CAR, PXR, and PPARalpha. For each case study a diverse and multi-disciplined panel of experts from academia, industry, government and other scientific organizations evaluated the key events leading to tumors. Each panel addressed whether the biology of the nuclear receptor necessitates a minimum threshold of ligand to affect activation, gene expression, and subsequent biological and toxicological responses. The panels also briefly discussed whether linear low-dose modeling was appropriate, based on the underlying science of nuclear receptor signaling biology. The MOA/HRF provided a weight-of-evidence approach for evaluating these charge questions against the available data. The AHR expert panel, for the first time in an expert panel format, rigorously applied the MOA/HFR mode of action framework and agreed on a mode of action. Similarly, the CAR/PXR expert panel identified relevant data and applied the framework with emphasis on the qualitative and quantitative aspects of human relevance. For PPARalpha,the expert panel built upon previous applications of the framework using significant new data that allowed for refinement of the key event descriptions and updated considerations related to human relevance. Each panel identified key data needs and suggested improvements for application of the MOA/HRF framework. The public workshop had broad support and funding from industry, government, universities, scientific societies, and research organizations. This abstract does not reflect EPA policy.