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.