BIOLOGICALLY BOUNDED RISK ASSESSMENT FOR RECEPTOR-MEDIATED NONGENOTOXIC CARCINOGENS

We have developed a biologically bounded marginal effect model for use in risk assessment of human exposure to receptor-mediated nongenotoxi c carcinogens. Schematically this model can be reduced to four compone nts: CI, the absence of an observable biological response; CII, observ able biochemical responses but no observable pathology; CIII, observab le pathology; and CIV both observable pathology and lethality. The inf lection point in the marginal response curve between CI and CII is def ined as the biologically evaluated scientifically tested no observable effect level (BESTNOEL). We demonstrate the utility of this approach by applying it to the well-studied nongenotoxic carcinogen 2,3,7,8-tet rachlorodibenzo-p-dioxin (TCDD). Using a well-developed mechanistic un derstanding of the initial interactions of TCDD with the cell, we just ify the selection of the minimal effective dose for CYP1A1 mRNA induct ion as the BESTNOEL. With allowance for variation in human sensitivity to TCDD, the BESTNOEL is assigned a human liver tissue burden of appr oximately 0.25-25 ppt and an allowable daily intake level in the range of 15-1500 fg/kg/day. In the future, the BESTNOEL can help establish a lower boundary for acceptable extrapolation when using either statis tical or biologically based attributable risk models. (C) 1995 Academi c Press,Inc.