Workshop on Mode of Action for Nuclear Receptor Mediated Liver Cancer
Four manuscripts from the September 2010 Nuclear Receptor Workshop organized by TERA have been published in Critical Reviews in Toxicology (January 2014). The workshop explored the development of dose‐response approaches to nuclear receptor‐mediated liver cancer, within a Mode of Action (MOA) Human Relevance Framework (HRF). Workshop case study teams prepared papers on the AHR, CAR, and PPARalpha receptors, and TERA and the workshop co‐chairs authored an additional overview paper describing the workshop and overarching issues. For each case study a diverse and multi-disciplinary panel of experts from academia, industry, government, and other organizations evaluated the key events leading to liver tumors, and discussed whether the biology of the nuclear receptor necessitates a minimum threshold of ligand to affect activation, gene expression, and subsequent biological and toxicological responses.
Downloads of the papers published in Critical Reviews in Toxicology are being made available for a limited time free of charge. Please view the published ePrint here.
Workshop held September 27-29, 2010 at NIEHS, Research Triangle Park, North Carolina, USA
Sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm in human health risk assessment, but the application of dose-response modeling approaches with a threshold has been recently questioned (White, et al., 2009; NAS, 2008). The growing body of molecular toxicology information is allowing us to explore the presence or absence of sub-threshold doses for a number of receptor-mediated modes of action.
A recent workshop 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 addressed activation of AHR, CAR, and PPARalpha receptors. For each case study a diverse and multi-disciplinary panel of experts from academia, industry, government and other organizations evaluated the key events leading to liver tumors. Each panel discussed 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 discussion questions against the available data for each case study. The AHR expert panel, for the first time in an expert panel format, rigorously applied the MOA/HRF mode of action framework and agreed on a mode of action. Similarly, the CAR 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.
Workshop Handouts
WebCast of Monday Morning Plenary Session
Workshop Co-Chairs
Melvin Andersen, The Hamner Institutes for Health Sciences
Julian Preston, U.S. EPA
Steering Committee
Richard Becker, American Chemistry Council
Robert Budinsky, Dow Chemical Co.
Michael Cunningham, NIEHS
Vicki Dellarco, U.S. EPA
Michael Dourson, Toxicology Excellence for Risk Assessment
Cliff Elcombe, CXR Biosciences, University of Dundee Medical School
James Klaunig, Indiana University
Michael Honeycutt, Texas Commission on Environmental Quality
Sponsors
Alliance for Risk Assessment
American Chemistry Council's Center for Advancing Risk Assessment Science and Policy
Chlorine Chemistry
CropLife America
CXR Biosciences
DuPont
The Hamner Institutes for Health
Indiana University, Dept. of Environmental Health
Society of Toxicology
Society for Risk Analysis
3M Company
Toxicology Excellence for Risk Assessment
U.S. EPA, National Health and Environmental Effects Research Laboratory
U.S. EPA, Office of Chemical Safety and Pollution Prevention
U.S.EPA, Office of Water
Presentations on Results of the Nuclear Receptor Workshop:
For more information, contact Jacqueline Patterson (patterson@tera.org or 513-542-7475)