Bridging radiation epidemiology and radiation biology

Induction of somatic mutations has long been considered as the major mechanism in radiation carcinogenesis, but earlier onset hypothesis has also been proposed. The mutation induction hypothesis assumes that radiation affects a fraction of exposed individuals, but which is unable to explain the parallel shift of mouse survival curves toward younger ages following an irradiation. In the latter hypothesis, there are two alternative explanations; either a radiation exposure may cause one oncogenic mutation and thereby skips one step of the whole processes necessary for the development of a spontaneous tumor, or a radiation exposure may damage the irradiated tissue to cause an activation (inflammation) which subsequently facilitates growth of spontaneously arising malignant cells to form a tumor. The problem associated with the former explanation is that it cannot explain the parallel shift of the mouse survival curves. In contrast, the latter explanation can explain the parallel shift smoothly and hence looks essential. The inflammation is thought to be initiated by cell death or unrepaired DNA damage and maintained by various cytokines (TGF-β, NF-κB, TNF, STAT3 etc.). These considerations lead one to think that the target of radiation carcinogenesis would not be epithelial stem cells but the irradiated whole tissue. And if inflammation intermediates radiation carcinogenesis, then there may be ways to reduce cancer risks following an exposure to low doses of radiation through controlling the inflammation. (author)