In this study, we investigated the time course of promotion of
tumors and putatively preneoplastic altered hepatic foci in the livers of
diethylnitrosamine (DEN)-initiated female Sprague-Dawley rats. These rats had been treated with
2,3,7,8-tetrachlorodibenzo-p-dioxin (
TCDD) under different dosing regimens, but we used the same administered biweekly dose of 1.75 microg/kg of
body weight. Animals were treated continuously for up to 60 weeks, or continuously for 30 weeks, followed by
cessation of treatment for up to 30 weeks. In addition,
TCDD treatment in these groups was begun either 2 or 18 weeks after initiation with DEN. Liver
tumors were only observed in animals after 60 weeks on the study and were increased by continuous
TCDD treatment, relative to controls. The incidence of
hepatocellular adenoma and
carcinoma combined, in animals treated with
TCDD for 30 weeks followed by no
TCDD treatment for 30 weeks (17%), was lower than in animals receiving either
TCDD (79%) or vehicle control (
corn oil) alone (55%) for 60 weeks. The lower liver-
tumor incidence after cessation of
TCDD treatment paralleled time-dependent decreases in the volume fraction occupied by placental
glutathione S-transferase-positive altered hepatic foci and the number of foci per unit volume, but not the mean focus volume that exhibited a time-dependent increase after cessation of
TCDD treatment. Cessation of
TCDD treatment led to reductions in liver
TCDD levels, and these changes were reflected in a cessation of reduced
body weight because of
TCDD treatment. These data indicate that liver-
tumor promotion by
TCDD in female rats is dependent upon continuous exposure to
TCDD, and that alterations in patterns of
TCDD exposure can have significant effects on
tumor incidence not reflected by standard measures of
dioxin exposure.