Toxicological Sciences, Vol 51, 211-223, Copyright © 1999 by Society of Toxicology
JG Teeguarden, YP Dragan, J Singh, J Vaughan, YH Xu, T Goldsworthy and HC Pitot
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.
ARTICLES
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
McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706-1599, USA.
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