Carcinogenicity of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin in experimental models

Abstract

The contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a prototype compound of a whole class of halogenated aromatic hydrocarbons termed 'dioxinlike' contaminants present in food, human tissue, mothers milk, and environmental samples. Among the various adverse effects caused by TCDD in animal experiments, its carcinogenic effects caused particular concern. In rodents, long-term TCDD treatment leads to the development of tumors of the liver, thyroid, lung, skin, oral cavity and other sites. The occurrence of liver tumors mainly observed in female rats has been used as a basis for quantitative cancer risk assessment for TCDD. TCDD does not behave like a 'complete carcinogen', i. e. no DNA binding of the parent compound or metabolites thereof could be detected. However, enhanced oxidative damage of hepatic DNA was observed, probably resulting from a dramatic induction of cytochrome P450 enzymes, which are under the regulatory, transcriptional control of the TCDD-activated aryl hydrocarbon receptor. The marked enhancement of TCDD-related oxidative liver DNA damage in rats by estrogens warrants further mechanistic investigation. Furthermore, TCDD acts as a tumor promoter, i. e. it facilitates the growth of putative preneoplastic hepatic lesions after initiation with a complete carcinogen. The mechanisms underlying this effect may be related to altered intracellular signaling involving pronounced changes in the phosphorylation pattern of proteins regulating growth and apoptosis. These effects are thought to result in an enhanced survival of preneoplastic cells, some of which can undergo further steps on the way to malignancy. In summary, a better understanding of the mechanisms of the carcinogenicity of TCDD is mandatory to provide a rational basis for a better inter-species extrapolation. The final aim of these efforts is a more reliable risk assessment for the carcinogenic potency of the class of dioxinlike contaminants in humans.