Confirmation of the Two-step Nature of Chemical Carcinogenesis in the Rat Colon Adenocarcinoma Model

Carcinomas were obtained in the large intestine of BD IX rats using four different dose levels of 1,2-dimethylhydrazine. Analyses of the relationship between dose, number of cells at risk, time, and tumor yield, together with previous observations on the biological behavior of the tumors, indicated that malignant transformation necessitates two distinct and essential changes in the affected cells. The first change is caused by the carcinogen, the effect of which is additive when similar doses are being repeated. This change is transmissible within the renewing mucosa for prolonged periods. The affected cells have no second change does not require carcinogen exposure (although continued presence of the carcinogen can probably contribute to it). It randomly affects cells having undergone the first change, at a rate which is essentially constant, at least within the considered tissue.