QUANTITATIVE-ANALYSIS OF MULTIPLE PHENOTYPE ENZYME-ALTERED FOCI IN RAT HEPATOCARCINOGENESIS EXPERIMENTS - THE MULTIPATH MULTISTAGE MODEL

The promotional effect of phenobarbital and 1-hydroxymethyl-pyren on e nzyme altered lesions in the rat liver were quantified within the fram ework of two separate multipath/multistage multistage models. The expe riment analyzed followed an initiation-promotion protocol in which fem ale Wistar rats were initiated with a single dose of diethylnitrosamin e at 0.15 mu mol/g body wt followed by a 3 week treatment-free period. A promotor, 1-hydroxymethyl-pyren or phenobarbital was then administe red continuously in the diet for 120 days. All animals were sacrificed 3 weeks after treatment and their livers were examined for enzyme his tological changes. Focal lesions were classified into three phenotype categories: adenosine triphosphatase altered (ATPase), sulfotransferas e altered (ST) and jointly altered lesions (ATPase and ST). Quantitati ve methods were used to analyze the data, which consisted of the numbe r and sizes of these enzyme-altered lesions. Both multipath/multistage models fitted to the data clearly demonstrate that phenobarbital prom otion produced more observable and larger foci than promotion via 1-hy droxymethyl-pyren and that the growth kinetics of the jointly altered lesions were elevated relative to the lesions expressing a single mark er. It was not possible with these data to determine if there was a pr edominant sequence in the formation of jointly altered lesions.