Biologically Bounded Risk Assessment for Receptor-Mediated Endocrine-Active Chemicals. T. R. Sutter and J. A. Gastel, Department of Environmental Health Sciences, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205
We have developed a biologically bounded marginal effect model for use in risk assessment of human exposure to receptor-mediated nongenotoxic carcinogens. Schematically this model can be reduced to four components: CI, the absence of an observable biological response; CII, observable biochemical responses but no observable pathology; CIII, observable pathology; and CIV, both observable pathology and lethality. The inflection point in the marginal response curve between CI and CII is defined as the biologically evaluated scientifically tested no observable effect level (BESTNOEL). Previously, we demonstrated the utility of this approach by applying it to the well-studied nongenotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin. Here we consider the application of this model for risk assessment of receptor-mediated endocrine-active chemicals. In order to calculate a human BESTNOEL based on dose-response data acquired in a test species, a limited set of criteria must be fulfilled. These criteria include: (i) a partial understanding of the toxicological mechanism that includes identification of a critical cellular target with which the toxicant interacts; (ii) qualitative and quantitative evaluation of this mechanism in rodents in vivo and in vitro and in humans in vitro to ensure conservation of targets between species; (iii) sufficient information about the biological system to distinguish early and therefore sensitive responses from later and less sensitive responses; (iv) knowledge of the potential range in sensitivities in this response among human populations; and (v) a basis for quantitative comparisons of rodent and human pharmacokinetics. As functions of the well-developed mechanistic understanding of the estrogen-response pathway and of the available data concerning the activity of estrogenic chemicals, we have limited this exercise to the estrogenic component of endocrine-active chemicals. We describe the extent to which the available data fulfill the identified criteria. The issues regarding biological half-life and mixtures are identified as significant sources of uncertainty in the application of the BESTNOEL approach to endocrine-active chemicals.