PERSISTENCE OF TCDD-INDUCED HEPATIC CELL-PROLIFERATION AND GROWTH OF ENZYME-ALTERED FOCI AFTER CHRONIC EXPOSURE FOLLOWED BY CESSATION OF TREATMENT IN DEN INITIATED FEMALE RATS

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent tumor promoter in two-stage models of hepatocarcinogenesis, This study focuses on the persistence or reversibility of TCDD-mediated changes in livers after 30 weeks of treatment and cessation of treatment, Diethylnitrosamine (DEN) initiated animals (175 mg/kg) were promoted bi-weekly with TCDD at a dose equivalent to 125 ng/kg/day for 30 weeks without or with a f ollowing waiting period of 32 weeks before necropsy, 2,3,7,8-Tetrachlo rodibenzo-p-dioxin liver concentration decreased 300-fold in the 32 we ek waiting period but was still five-fold above background, Induction of CYP1A1 dependent enzyme activity decreased according to TCDD tissue levels, In contrast, cell proliferation, as measured by BrdU-labeling index, was still 2.8-fold increased over controls in the TCDD group w ith waiting period compared to a 4-fold increase over controls at the end of the 30 week dosing period, Enzyme altered hepatic foci expressi ng the placental form of glutathione S-transferase decreased in number but the remaining foci were significantly increased in size and the p ercent of liver occupied by foci was higher at the end of the waiting period as compared to livers at the end of the dosing period, Liver tu mor incidence at the end of the waiting period was 71% (5 of 7 animals ) and the livers showed an increase in bile duct lesions with only mil d toxicity. There was pronounced bile duct proliferation in DEN/TCDD t reated animals after the waiting period with intense expression of TGF alpha in bile duct epithelial cells as detected by immunohistochemica l methods, In comparison, at the end of the 30 week dosing period the livers showed more severe toxicity and only mild bile duct proliferati on, Also, one small hepatocellular adenoma was observed, It is conclud ed that as opposed to CYP1A1 induction the more complex biological res ponses, cell proliferation and selective growth of certain preneoplast ic foci, are persistent after prolonged TCDD treatment within the expe rimental framework of our study.