DEVELOPMENT OF A RISK ASSESSMENT MODEL FOR MIXTURES OF DIOXIN CONGENERS BASED ON THEIR COMPETITIVE-BINDING TO THE AH-RECEPTOR

Molecular and biochemical evidence support Aryl hydrocarbon (Ah) recep tor-mediated mechanism for most of the known toxic effects of dioxins. However, this approach does not consider modification of toxic respon ses due to the simultaneous presence of other congeners with comparabl e affinities for the Ah receptor. In this paper we describe (a) the bi ochemical rationale for a competitive binding of TCDD and other congen ers for the Ah receptor, and (b) the elements of a competitive binding model to estimate the formation of an Ah receptor-TCDD complex in the presence of other competing ligands. The model is based on the relati ve mass balance, and binding affinities of congeners to the Ah recepto rs, from rat liver cytosolic preparations. Using the model, a quantita tive biochemical parameter for the formation of the total receptor bou nd to TCDD, defined as ''Competitive Binding Ratio'' (f), was calculat ed for adipose tissue dioxin-residue data from human populations. Usin g Monte Carlo methods, we calculated the cumulative probability of the distribution of Ah receptor bound to TCDD as a fraction of total boun d receptors.