Induction of altered hepatic foci by a mixture of dioxin-like compounds with and without 2,2 ',4,4 ',5,5 '-hexachlorobiphenyl in female Sprague-Dawley rats

The hepatic tumor-promoting activity of a mixture of polyhalogenated aromat ic hydrocarbons (PHAHs) was studied in a medium term two-stage initiation/p romotion bioassay in female Sprague-Dawley rats. The PHAH mixture contained 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p -dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pen tachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 2,3, 3',4,4',5-hexachlorobiphenyl (PCB 156), 2,2',4,4',5,5'-hexachlorobiphenyl ( PCB 153) and covered >90% of the total toxic equivalents (TEQ) present in B altic herring. To determine possible interactive effects of di-ortho-substi tuted PCBs, the PHAH mixture was tested with (PHAH+) and without (PHAH-) PC B 153. Rats were initiated by a diethylnitrosamine injection (30 mg/kg body wt i.p.) 24 h after a partial 2/3 hepatectomy. Six weeks after initiation, the PHAH mixtures were administered once a week by subcutaneous injections for 20-weeks. Treatment with the PHAH mixtures caused liver enlargement an d an increased activity of the hepatic cytochrome P4501A1/2 and P4502B1/2. All PHAH exposure groups exhibited an increased occurrence of hepatic foci positive for the placental form of glutathione-S-transferase. In the PHAH-g roup dosed 1 mu g TEQ/kg body wt/week, the volume fraction of the liver occ upied by foci was significantly lower compared to the. TEQ equivalent dosed TCDD group (3.8 vs 8.7%). The volume fraction was significantly increased in the groups treated with 0.5, 1, or 2 mu g TEQ/kg body wt/week of the PHA H+ mixture (4.5, 5.2, and 6.6%, respectively) compared to the corn oil grou p (2.0%), but to a lower extent than expected on basis of the TEQ doses. Ov erall, the TEQ-based administered dose overestimated the observed tumor-pro moting effects of this PHAH mixture. The applicability of the toxic equival ency factor concept, the role of differences in toxicokinetic properties an d interactive effects of PCB 153 on hepatic deposition of the dioxin-like c ongeners are discussed. (C) 1999 Academic Press.