THE USE OF BIOCHEMICAL AND MOLECULAR-PARAMETERS TO ESTIMATE DOSE-RESPONSE RELATIONSHIPS AT LOW-LEVELS OF EXPOSURE

Biomarkers based on alterations in molecular and biochemical parameter s may be useful in chemical risk assessment for establishing the prese nce of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteratio n in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk ev aluation at low levels of exposure is discussed iii relation to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1A1 and CYP1A2 in liver and other tissues. CYP1A1 i nduction in liver increases monotonically with TCDD dosage; however, s everal of the dose-response curves for hepatic effects of TCDD are U-s haped. The U-shaped dose-response curve for hepatic tumor promotion ap pears to result because the integrated toxicologic response depends on multiple underlying processes-mitosuppression. toxicity, and cell pro liferation-each of which has a different dose-response relationship wi th respect to TCDD. Although dose-response relationships for the bioma rkers are not expected to duplicate the complex shapes seen with the i ntegrated responses, measurements and pharmacodynamic modeling of the changes in these molecular and biochemical parameters can still be use ful for obtaining an upper-bound risk estimate at low levels of exposu re.