Environmental factors in the origin of cancer and estimation of the possible hazard to man

Summary The stages in the development of cancer are described as: (1) alteration of cellular function by the carcinogen; (2) reinforcing interaction by proximal altered cells-a microscopic control force; (3) failure of the restraining factors against tumorous proliferation within an organ-a macroscopic control; (4) failure of restraining forces against tumorous growth in the body as a whole. All four stages are important in human cancers. Urethane-induced lung cancer is a single-stage process atypical of cancer induction except as an example of the first stage. The relationship of dose to time of appearance of cancers is shown to have general validity as a law relating latent time to the inverse cube-root of the dose. The law is explained as the consequence of the second carcinogenesis stage, in which there is interaction of cells altered by carcinogens. Several examples of the estimation of cancer risk are presented as they apply to current problems of exposure of man to low levels of diethylstilboestrol, nitrosamines and radiation. If the cube-root of the dose applies to the estimation of the time of appearance of cancers, low-dosage exposure at some levels is virtually without risk because the expected lifespan of those exposed is exceeded by the time necessary for low concentrations of altered cells to develop into cancers.