Contribution of human data to the analysis of human carcinogenesis

Human data strongly suggest that small doses or low concentrations of genotoxic agents cause only a relatively small number of human cancers. They emphasize the role of promotion, in particular that associated with cell proliferation. There is therefore a qualitative difference between high doses of genotoxic agents which provoke cell death and a compensatory increase in cell division, and low doses which do not. During the promotion phase, human data demonstrate the importance of induced genetic instability and defects in apoptosis as well as that of cell immortalization which play a main role for the accumulation in a cell genome of several specific lesions. Carcinogenesis is a complex process in which initial mutations do not appear to be a limiting or crucial step. This view is supported by the paramount influence of age on the induction by radiation of thyroid and breast cancer. It is also compatible with practical thresholds observed in subjects whose bones or liver were exposed to alpha-emitters, as well as with the curvilinearity in the leukemia incidence dose-response in the Japanese atomic bomb survivors. The linear no threshold model assumes that: 1) the probability of DNA lesion repair is constant whatever the dose and, hence, the number of lesions provoked in the same cell and the surrounding cells; 2) the probability for a damaged cell to evolve toward an invasive cancer is not influenced by the possible promotional effect of further irradiation or induced tissue proliferation, nor the control exerted by surrounding cells. These assumptions deserve a critical analysis.