Carcinogenic risks of dioxin: mechanistic considerations

Dioxins and dioxin-like chemicals demonstrate high affinity binding to the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, which mediates most, if not all, of the toxic responses of these agents. Since dioxins are not directly genotoxic their carcinogenic effect is likely the result of their tumor promoting activity produced by activation of the AhR. For the purpose of risk assessment extrapolation from effects in the observable high dose range to background dietary exposure is necessary. In the present review, we discuss various aspects of low-dose-response of receptor-mediated processes in general, including threshold phenomena with regard to tumor promotion during multi-stage carcinogenesis. In this connection the reversibility of tumor promotion plays an important role but this may not be valid for dioxins due to their long half life. The relevance of cytochrome P 4501 A-induction as biomarker for prediction of carcinogenic effects of dioxins at low doses is considered. Dioxins may act in concert with endogenous ligands of the AhR, an effect which becomes particularly relevant at low toxicant concentrations. At present, however, the nature and role of these postulated ligands are unknown. Furthermore, it is unclear whether dioxins produce synergistic tumor promotional effects with non-dioxin-like chemicals to which humans are also exposed. Dioxins and, e.g., non-dioxin-like PCBs act through different receptors and there is, albeit yet limited, experimental evidence from experimental studies to suggest that they may act on different target cell populations within the same target organ. From the available data the existence of a (physiological) threshold of effects cannot be proven and may not even exist. For regulatory purposes the application of a so called "practical threshold" for the carcinogenic effect of dioxins is proposed. Further mechanistic studies should be conducted to get insight into the dose-response characteristics of relevant events of dioxin-like and non-dioxin-like agents and into the consequences of potential interactions between both group of compounds during carcinogenesis.