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Liver Tumor-promoting Activity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in TCDD-sensitive and TCDD-resistant Rat Strains¹

Laboratory of Toxicology, National Public Health Institute, FIN-70701 Kuopio, Finland [M. V., J. T. T., M. U., R. P., J. M-P., J. T.]; Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden [Y. B., G. S., S. F., L. W.]; AstraZeneca, R&D Södertälje, Safety Assessment, S-15185 Södertälje, Sweden [Y. B., L. W.]; Department of Pharmacology and Toxicology, University of Kuopio, FIN-70701 Kuopio, Finland [M. U.]; National Food and Veterinary Research Institute, Regional Laboratory of Kuopio, FIN-70701 Kuopio, Finland [R. P.]; Department of Food and Environmental Hygiene, Faculty of Veterinary Medicine, University of Helsinki, FIN-00014 Helsinki, Finland [R. P.]; Department of Pathology and Forensic Medicine, University of Kuopio and Kuopio University Hospital, FIN-70211 Kuopio, Finland [V-M. K.]; Laboratory of Chemistry, National Public Health Institute, FIN-70701 Kuopio, Finland [T. V.]; and Institute of Ecological Chemistry, GSF-National Research Center, D-85758 Neuherberg, Germany [C. K., K-W. S.]

Risk assessment of dioxins is currently based on induction of liver tumors in rats. The toxicity of dioxins is characterized by large sensitivity differences among animal species and even strains of the same species, which complicates the risk assessment. The significance of these differences in dioxin-induced carcinogenicity is not known. We therefore studied the liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats differing >1000-fold in their sensitivity to the acute lethality of TCDD. Female rats were partially hepatectomized, initiated with nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered hepatic foci (AHF) were stereologically quantitated using glutathione S-transferase P as a marker. AHF were significantly (P < 0.001) and dose dependently increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at 1000 ng/kg/day and above, indicating a remarkable (100-fold) sensitivity difference between L-E and H/W rats. The same sensitivity difference but 10-fold less foci were observed between nonhepatectomized/noninitiated L-E and H/W rats. Induction of AHF was related to hepatotoxicity but not to cytochrome P4501A1 activity in the liver. Liver TCDD concentrations were similar in both strains. H/W rats are exceptionally resistant to induction of AHF by TCDD, and the resistance is associated with an altered transactivation domain of the aryl hydrocarbon receptor. Genetic differences may account for significant interindividual/intraspecies sensitivity differences in dioxin-induced carcinogenesis. Understanding the role of transactivation domain of the aryl hydrocarbon receptor in carcinogenesis is therefore likely to improve dioxin risk assessment.

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