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.
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.
Teeguarden
J G
JG
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706-1599, USA.
Dragan
Y P
YP
Singh
J
J
Vaughan
J
J
Xu
Y H
YH
Goldsworthy
T
T
Pitot
H C
HC
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D013997:Time Factors
D000477:Alkylating Agents; D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D004052:Diethylnitrosamine; D005982:Glutathione Transferase