Environmental modifiers in carcinogenesis

The natural history of neoplastic development can be divided into at least three distinct stages - initiation, promotion and progression. These stages can be defined by biological experimentation and by histopathological characterization of the lesions involved in the various stages. It is now possible, both in human beings and in experimental animals, to distinguish by morphological techniques all stages from very early 'precursor' lesions to the final malignant state. Although the final stage - progression - of the neoplastic process can be altered by therapeutic intervention, the principal site at which the natural history of neoplastic development can be actually and potentially regulated is that of promotion. Promoting agents that are relatively selective for carcinogenesis in several different tissue types have now been identified both in experimental systems and in human beings. In at least two experimental systems - those of epidermal carcinogenesis and hepatocarcinogenesis - the general characteristics of both initiation and promotion are virtually identical. Such studies have demonstrated that the activity of promoting agents exhibits a threshold level as well as a maximal level and that the action of promoting agents is reversible; the identification of promoting agents in our environment is therefore of considerable importance in understanding the nature of and preventing the development of human cancer. In addition, the interpretation of whole-animal bioassays for carcinogenic agents in the environment must take into account the existence of promoting agents and recognize that their action is distinct from that of complete and incomplete carcinogens, in order rationally to extrapolate to situations of human risk.