QUANTITATIVE-ANALYSIS OF ENZYME-ALTERED LIVER FOCI IN RATS INITIATED WITH DIETHYLNITROSAMINE AND PROMOTED WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN OR 1,2,3,4,6,7,8-HEPTACHLORODIBENZO-P-DIOXIN

A quantitative method based upon a stochastic model was used to estima te rates of initiation (alteration to express the ATPase-deficient phe notype) and of clonal growth of altered cells in an initiation promoti on experiment in the livers of female Wistar rats. Diethylnitrosamine (DEN) was used as the initiating agent followed by 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin ( HCDD) as promoters, Two distinct versions of the stochastic model, cal led Model I and Model II, were fitted to the data. Model I made the as sumption that, after the initial phase of acute initiation with DEN, b ackground rates of initiation were equal in animals treated with DEN a nd controls that were not so treated. Model II, which fit the data sub stantially better than Model I, assumed that background rates of initi ation were different in DEN-treated animals and animals not so treated , even after the acute phase of initiation was over, Both models indic ate that the rates of cell division and apoptosis of altered cells are increased during TCDD treatment, In contrast, the rate of division re mains more or less constant during treatment with HCDD, but the rate o f apoptosis is decreased. The background rate of initiation during tre atment with HCDD is equal to that in controls not administered promote rs, With TCDD treatment, however, the rate of initiation estimated fro m the model is substantially increased over controls. The analysis als o suggests that there is heterogeneity within foci of the rates of cel l division, with cells on the surface of foci dividing faster than cel ls in the interior. (C) 1996 Academic Press, Inc.