| Receptor Mechanisms and Dose-Response Models for the Effects of Dioxins George W. Lucier,1 Christopher J. Portier,1
and Michael A. Gallo2 1National Institute of Environmental Health Sciences, Research
Triangle Park, NC 27709 USA; 2University of Medicine and Dentistry
of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08855
USA Abstract
There is increasing evidence that receptor-mediated events impact one or more stages responsible for tumor development in experimental animals and humans. Although many chemicals and endogenous hormones require receptor interactions as a necessary event in their carcinogenic activity, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and its structural analogs are the most visible examples of receptor-mediated carcinogens. TCDD, or dioxin as it is frequently called, interacts with the Ah receptor (AhR) , which functions in a manner analogous to receptors for steroids. TCDD produces a wide spectrum of biochemical and toxic responses in in vitro and in vivo systems, and the Ah receptor is generally considered necessary for most if not all of these responses. Risk assessments for dioxin made by the United States and other countries throughout the world have been based on its carcinogenecity in experimental animals. Recently, epidemiology studies have indicated that TCDD is a human carcinogen at high doses. Because TCDD appears to be acting like a potent and persistent hormone agonist, it appears reasonable to incorporate mechanistic information on receptor-mediated events in risk assessments for TCDD. This information may be obtained from steroid receptor action and from molecular data on the Ah receptor. In this paper, we evaluate the scientific foundation on which mechanistic models for estimating dioxin's risks should be based. These models need to recognize the mechanisms possible for the diversity of biological responses that are initiated by a single receptor interacting with a single ligand. The U.S. EPA is currently reevaluating dioxin's risks by examining the possibility of developing biologically based models. This paper details the considerations that must be made in developing such models, including information on mechanisms of steroid hormone action, characteristics of the Ah receptor, diversity of receptor actions, and design issues that are crucial for the translation of biological phenomenon into valid dose- response models. Environ Health Perspect 101(1) :36-44
Address reprint requests to G. W. Lucier, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709 USA
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