Integrated approach for evaluating species and interindividual differences in responsiveness to dioxins and structural analogs

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that is produced inadvertently during the synthesis of some organochlorine compounds, such as the chlorinated phenoxy pesticides. It is biologically and ecologically persistent, with an estimated half-life of 7 years in humans. It possesses high acute toxicity in rodents and is a carcinogen, teratogen, and immunotoxin. In chronic bioassays for carcinogenicity, TCDD at a dose of 10 ng/kg/day increases the incidence of liver tumors in female rats, making it one of the most potent animal carcinogens ever tested. A recent study in humans has shown an increase in the incidence of respiratory tract tumors in workers in chlorinated phenoxy herbicide plants. Considerable controversy and uncertainty remain, however concerning its carcinogenic potency in humans and the reliability of using animal data to predict human risks. It is generally accepted that most, if not all, of the effects of TCDD require its binding to the Ah receptor. In addition to its toxic effects, TCDD produces a number of biochemical effects, such as induction of CYP1A1, downregulation of binding activity of the estrogen and epidermal growth factor (EGF) receptors, and changes in cytokine pathways. These effects suggest that the Ah receptor plays an important role in regulating the cell cycle. A number of structural analogs of TCDD, such as the polychlorinated dibenzofurans, also interact with the Ah receptor and these produce the same spectrum of responses as TCDD in animal and cell models. The potency of these compounds is strongly correlated with their binding affinity to the Ah receptor Perhaps the most sensitive marker of exposure to TCDD in both rodents and humans is induction of a specific isozyme of cytochrome P450 (CYP1A1). Our data suggest that humans are at least as sensitive as rats to CYP1A1 enzyme induction (produced by transcriptional activation of the CYP1A1 gene) and to down-regulation of the EGF receptor This conclusion is based on data obtained ill vitro (accidentally exposed humans and rats subjected to a two-stage model of hepatocarcinogenesis) and in vitro (incubation of human and rodent lymphocytes with TCDD). There is considerable interindividual variation in human responses to TCDD. Our work on 'markers of susceptibility' suggests that both variation in the amount of Ah receptor and a mutation in the CYP1A1 gene may be responsible for this variation. Since TCDD gives negative results in short-term tests for genotoxicity and does not bind covalently to DNA, it can be considered a prototypical chemical for the study of receptor mediated carcinogenesis