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

Abstract

A quantitative method based upon a stochastic model was used to estimate rates of initiation (alteration to express the ATPase-deficient phenotype) and of clonal growth of altered cells in an initiation promotion experiment in the livers of female Wistar rats. Diethylnitrosamine (DEN) was used as the initiating agent followed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HCDD) as promoters. Two distinct versions of the stochastic model, called Model I and Model II, were fitted to the data. Model I made the assumption that, after the initial phase of acute initiation with DEN, background rates of initiation were equal in animals treated with DEN and controls that were not so treated. Model II, which fit the data substantially better than Model I, assumed that background rates of initiation were different in DEN-treated animals and animals not so treated, even after the acute phase of initiation was over. Both models indicate that the rates of cell division and apoptosis of altered cells are increased during TCDD treatment. In contrast, the rate of division remains more or less constant during treatment with HCDD, but the rate of apoptosis is decreased. The background rate of initiation during treatment with HCDD is equal to that in controls not administered promoters. With TCDD treatment, however, the rate of initiation estimated from the model is substantially increased over controls. The analysis also suggests that there is heterogeneity within foci of the rates of cell division, with cells on the surface of foci dividing faster than cells in the interior.