title: Hexachlorobenzene as a promoter of diethylnitrosamine-initiated hepatocarcinogenesis in rats and comparison with induction of porphyria.
abstract: 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.
authors.affiliation: MRC Toxicology Unit, Medical Research Council Laboratories, Carshalton, Surrey, UK.
authors.forename: F P
authors.initials: FP
authors.lastname: Stewart
authors.forename: M M
authors.initials: MM
authors.lastname: Manson
authors.forename: J R
authors.initials: JR
authors.lastname: Cabral
authors.forename: A G
authors.initials: AG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D002722:Chlorobenzenes / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity*; D005260:Female; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011164:Porphyrias / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D012737:Sex Factors
chemical_list: D002273:Carcinogens; D002722:Chlorobenzenes; D004052:Diethylnitrosamine; D006581:Hexachlorobenzene