Hexachlorobenzene as a promoter of diethylnitrosamine-initiated hepatocarcinogenesis in rats and comparison with induction of porphyria.

In rats, hexachlorobenzene (HCB) causes uroporphyria and liver tumours predominantly in females. To investigate the promotional properties of HCB, male and female rats received diethylnitrosamine (DEN) in the drinking water (0.015%) for 3 weeks. After a 2-week recovery period rats were fed control diet or one containing HCB (0.02%) for 30 weeks. HCB was an efficient promoter of DEN-initiated hepatocarcinogenesis in both sexes as judged by the size and numbers of visible tumours and by the percentage of liver sections that stained strongly positive for gamma-glutamyltranspeptidase (GGT) activity. Tumours were larger in males whereas regions of GGT-positive tumour and non-tumour tissue were greater in females. Inhibition of the haem biosynthesis enzyme uroporphyrinogen decarboxylase (UD) only occurred in the liver of females treated with HCB or DEN/HCB. In the latter group, UD was inhibited both in and outside tumours whereas uroporphyrin only accumulated in non-cancerous tissue. No significant inhibition of UD was observed in the liver of males. In another study, rats received one i.p. dose of DEN (20 mg/kg) and after 3 weeks were fed HCB for 30 weeks. Numbers of GGT-positive foci were greatly increased by HCB in both sexes, but especially in males (1.4-fold greater than females). Thus HCB was shown to be a promoter of hepatocarcinogenesis. However, the lack of a consistent marked sex difference suggests that this is only a partial explanation for the induction of tumours which mainly occur in females when this chemical is administered alone for prolonged periods.