Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis: a significant sex difference in the hepatocellular carcinoma incidence

Abstract

Chlordecone (Kepone) has been extensively studied for its toxicity in male production workers who were exposed to large quantities of this organochlorine pesticide. Concern that these workers might be at an increased risk of developing liver cancer prompted us to test chlordecone in a two-stage rat model of hepatocarcinogenesis. Chlordecone acted largely as a liver tumor promoter rather than as a complete hepatic carcinogen in both male and female Sprague-Dawley rats. Dose-response experiments showed that the hepatocarcinogenic effects of long-term chlordecone administration became undetectable at concentrations in non-initiated rat liver in the same range as those measured in human biopsies taken from exposed workers who exhibited no liver effects. Although the toxicity of chlordecone in women has never been studied, we found a dramatic sex difference in the incidence of malignant liver tumors caused by chlordecone promotion in rats. Frank hepatocellular carcinomas were observed in up to 63% of female rats whose livers were previously 'initiated' with a subcarcinogenic dose of diethylnitrosamine given 24 h after partial hepatectomy, and then 'promoted' by 27 weeks of chlordecone administration. In contrast, none of comparably treated males had malignant liver tumors, even after 44 weeks of 'promotion' with chlordecone. Females in the diethylnitrosamine-initiated/chlordecone-promotion groups also contained gamma-glutamyltranspeptidase-positive 'preneoplastic' hepatocellular foci that were more abundant and larger than those observed in comparably-treated males. Moreover, because similar levels of chlordecone were measured in the livers of both sexes at the end of the experimental period, the development of hepatocellular carcinomas in the diethylnitrosamine-initiated female rats appeared to be due to their increased sensitivity to the promotion treatment.