Presence of a no-observed effect level for enhancing effects of development of the alpha-isomer of benzene hexachloride (alpha-BHC) on diethylnitrosamine-initiated hepatic foci in rats

The dose dependence of the promoting effects of the alpha -isomer of benzen e hexachloride (alpha -BHC) on hepatocarcinogenesis was investigated in a m edium-term rat liver bioassay (Ito test). A total of 195 F344 male rats, 6 weeks old, were given a single intraperitoneal injection of diethylnitrosam ine (DEN) at the start of the experiment and subjected to two-thirds partia l hepatectomy at week 3. Two weeks after the administration of DEN, alpha - BHC were fed to rats at doses of 0, 0.01, 0.1, 0.5, 1, 2, 4, 7.5, 15, 30, 6 0, 125 and 500 ppm in diet for 6 weeks. All surviving animals were killed a t week 8, and their livers were examined immunohistochemically for detectio n of glutathione S-transferase placental form (GST-P)-positive foci, surrog ate preneoplastic lesions. Quantitative values for numbers and areas were d ose-dependently increased in rats given alpha -BHC at 0.5-500 ppm. However, those for groups treated with 0.01 and 0.1 ppm were decreased, albeit not significantly in comparison to the controls. Cytochrome P450 3A2 (CYP3A2) p rotein levels and activities showed a good correlation to the number and ar ea of GST-P-positive foci. These results support evidence of hormesis and i ndicate a no-observed effect level for alpha -BHC promoting potentials may exist regarding rat liver carcinogenesis, which correlates with expression of CYP3A2 in the liver. (C) 2001 Elsevier Science Ireland Ltd. All rights r eserved.