Development of a risk assessment model for mixtures of dioxin congeners based on their competitive binding to the Ah‐receptor∗

Abbreviations Used: Ah Receptor, Aryl hydrocarbon receptor; ED₅₀, effective dose for 50% displacement; NHATS, National human adipose tissue survey; PAH, Polycyclic aromatic hydrocarbon; PCBs, Polychlorinated biphenyls; PCDF, Polychlorinated dibenzofurans; TCDD, 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin; TEF, Toxicity equivalence factor.

Abstract

Molecular and biochemical evidence support Aryl hydrocarbon (Ah) receptor‐mediated mechanism for most of the known toxic effects of dioxins. However, this approach does not consider modification of toxic responses due to the simultaneous presence of other congeners with comparable affinities for the Ah receptor. In this paper we describe (a) the biochemical rationale for a competitive binding of TCDD and other congeners 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 relative mass balance, and binding affinities of congeners to the Ah receptors, from rat liver cytosolic preparations. Using the model, a quantitative biochemical parameter for the formation of the total receptor bound to TCDD, defined as “Competitive Binding Ratio” (f), was calculated for adipose tissue dioxin‐residue data from human populations. Using Monte Carlo methods, we calculated the cumulative probability of the distribution of Ah receptor bound to TCDD as a fraction of total bound receptors.

Notes

Abbreviations Used: Ah Receptor, Aryl hydrocarbon receptor; ED₅₀, effective dose for 50% displacement; NHATS, National human adipose tissue survey; PAH, Polycyclic aromatic hydrocarbon; PCBs, Polychlorinated biphenyls; PCDF, Polychlorinated dibenzofurans; TCDD, 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin; TEF, Toxicity equivalence factor.