Hepatocarcinogenesis in female Sprague-Dawley rats following discontinuoustreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin

In this study, rye investigated the time course of promotion of tumors and putatively preneoplastic altered hepatic foci in the livers of diethylnitro samine (DEN)-initiated female Sprague-Dawley rats. These rats had been trea ted with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) under different dosing regimens, but we used the same administered biweekly dose of 1.75 mu g/kg o f body weight. Animals were treated continuously for up to 60 weeks, or con tinuously for 30 weeks, followed by cessation of treatment for up to 30 wee ks. In addition, TCDD treatment in these groups was begun either 2 or 18 we eks after initiation with DEN. Liver tumors were only observed in animals a fter 60 weeks on the study and were increased by continuous TCDD treatment, relative to controls. The incidence of hepatocellular adenoma and carcinom a combined, in animals treated with TCDD for 30 weeks followed by no TCDD t reatment for 30 weeks (17%), was lower than in animals receiving either TCD D (79%) or vehicle control (corn oil) alone (55%) for 60 weeks. The lower l iver-tumor incidence after cessation of TCDD treatment paralleled time-depe ndent decreases in the volume fraction occupied by placental glutathione S- transferase-positive altered hepatic foci and the number of foci per unit v olume, but not the mean focus volume that exhibited a time-dependent increa se after cessation of TCDD treatment. Cessation of TCDD treatment led to re ductions in liver TCDD levels, and these changes were reflected in a cessat ion of reduced body weight because of TCDD treatment. These data indicate t hat liver-tumor promotion by TCDD in female rats is dependent upon continuo us exposure to TCDD, and that alterations in patterns of TCDD exposure can have significant effects on tumor incidence not reflected by standard measu res of dioxin exposure.