Biologic evidence for the existence of thesholds in chemical carcinogenesis.

In a search for evidence for the existence of threshold levels below which chemical carcinogens do not induce cancer, it is essential to consider all aspects of the carcinogenic process. We should not confine our thoughts solely to the generally accepted stages of carcinogenesis: initiation, promotion, and progression. Several factors may influence thresholds even before the proximate carcinogen reaches the target tissue. Important is the number of molecules that can react with the target tissue. Apart from the level of exposure, this number depends on several conditions. First, not all molecules with carcinogenic potential are equally well absorbed, and the degree of absorption will affect the number available. Second, not all of the molecules which enter the organism reach the target tissue. For many molecules, metabolic change may produce noncarcinogenic derivatives, while others will be activated to the proximate carcinogen. The ultimate number of molecules in this group is dependent upon the metabolic capability of the organism to perform the necessary conversions. This may be a function of the state of enzyme induction or tissue damage. Once in the active state, a large proportion of the carcinogenic molecules may be lost to the carcinogenic process by interaction with molecules other than DNA, that is, with any molecules that can be alkylated, such as a diversity of small molecules, with macromolecules, such as protein or RNA. While damage may result from these reactions, no heritable changes are produced. From the foregoing, it is evident that several processes which have no relationship to car-