Carcinogenicity of "non-dioxinlike" polychlorinated biphenyls.

Complex technical mixtures of polychlorinated biphenyls (PCBs) cause liver and thyroid neoplasms in rodents, whereas very few data are available on the carcinogenic potency of single non-dioxinlike (NDL) PCB congeners. In most genotoxicity assays technical PCB mixtures and individual congeners were inactive, suggesting that PCBs act as indirect, nongenotoxic carcinogens. Various mechanisms, including suppression of apoptosis in preneoplastic cells or inhibition of intercellular communication, have been suggested to be active in liver tumor promotion by PCBs. A decrease in thyroid hormone levels after PCB treatment has been suggested to play a role in the development of thyroid neoplasms in rats; however, other mechanisms may also be involved. Results from a chronic carcinogenicity study in rats indicate that not the dose of total PCBs but the total TCDD or toxic equivalents (TEQs) associated with "dioxinlike" (DL) constituents within a technical mixture are mainly if not exclusively responsible for the development of liver neoplasms in female rats. Quantitative comparison reveals almost identical dose-response curves for the total TEQs in various technical PCB mixtures and for TCDD as inducers of hepatic neoplasms in female rats. Tumor promotion experiments have shown, however, that, after initiation with a genotoxic carcinogen, technical PCB mixtures and individual DL-and NDL-PCBs act as liver tumor promoters in rodents. Based on these data, a weak carcinogenic potency of individual NDL-PCB congeners cannot be excluded. In epidemiological studies, increased mortality from cancers of the liver, gallbladder, biliary tract, gastrointestinal tract, and from brain cancer and malignant melanoma were observed in workers exposed to a series of technical PCB mixtures. A significant association between PCB concentrations in adipose tissue and non-Hodgkins lymphoma was found in another study. While in all human studies mixed exposure to DL-and NDL-PCBs occurred, no comprehensive data are available on the relative contribution of NDL-PCBs to the overall external and/or internal PCB exposure in those cohorts.

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

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.

2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was classified by the International Agency for Research on Cancer as a carcinogen in humans. It acts through an aryl hydrocarbon receptor-mediated mechanism, inducing the transcription of numerous genes, including various cytochrome P450s (CYPs - CYP1A1, 1A2, 1B1). Induction of CYPs may lead to genotoxicity by generating reactive oxygen species (ROS) which can damage DNA directly and/or via the generation of reactive metabolites. We determined ROS formation with the 2',7'-dihydrodichlorofluorescein diacetate fluorescence assay after incubation of HepG2 hepatoma cells or primary rat hepatocytes with TCDD. The amount of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA was measured using HPLC-MS/MS, the amount of CYP1A1 protein by Western blotting. The catalytic activity of CYP1A enzymes was determined as 7-ethoxyresorufin-O-deethylase (EROD) activity. Incubation of cells with TCDD for 48 h caused increased levels of ROS in primary rat hepatocytes as well as increased levels of 8-oxo-dG in DNA compared to untreated cells. In the HepG2 cell line no significant effects were observed for both ROS formation and 8-oxo-dG levels. Both effects were in good agreement with the extent of induction of CYP1A1 protein and EROD activity, suggesting that CYP1 induction is a major source of ROS formation in TCDD-treated hepatocytes.