Quantitative analysis of dose- and time-dependent promotion of four phenotypes of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p- dioxin in female Sprague-Dawley rats

Abstract

Determining both the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) acts as a tumor promoter and the shape of the dose-response curve at low doses remains an important goal of risk-assessment-directed research. In this report, we extend previous mechanistic and descriptive work done on the effect of TCDD on promotion in the two-stage model of hepatocarcinogenesis, to include lower, more clinically relevant doses. After initiation [PH + 10 mg diethylnitrosamine (DEN)/kg], groups of female Sprague-Dawley rats were administered TCDD in one of four doses: 0.01, 0.1, 1.0, or 10 ng/kg/day for 1, 3, or 6 months. Early increases in liver weight (19-69%) due to hepatocyte hypertrophy were resolved after 3- or 6-months exposures to TCDD, and were not associated with the effects of TCDD on promotion. Non-focal cell proliferation in DEN-treated groups was significantly reduced after 1 or 3 months of exposure to 0.1 ng/kg/day TCDD, leading to U-shaped dose-response curves. TCDD effects on non-focal cell proliferation were not associated with effects on promotion. GSTP-positive AHF represented approximately 97% of the total AHF. Significant increases in both the volume fraction and the number of altered hepatic foci (AHF) were observed at the highest dose (10 ng/kg/day) for GSTP-positive AHF in DEN-treated groups. Increases in the number of G6Pase- and ATPase-deficient AHF/cm3 were observed at TCDD doses as low as 0.01 ng/kg/day. This is the lowest tumor-promoting dose of TCDD reported to date. This study represents an unusually complete data set for further dose-response analysis and simulation or mathematical modeling of TCDD-mediated promotion in the rat liver.