Enhanced tumorigenesis by small, protracted doses of densely ionizing radiation

Starting with observations that were first published in 1982, a series of additional findings led to the discovery of an important property of cells in late G2/mitosis. In addition to being the most sensitive to killing, cells in this age-interval were also shown to be the most sensitive to radiation-induced neoplastic transformation. In this work, C3H mouse cells, designated 10T1/2, were irradiated with fission-spectrum neutrons and assayed in vitro via the endpoint focus formation on a monolayer of normal cells. From these observations, a biophysical model was developed to explain the anomalous finding that the frequency of transformation by low doses was enhanced when the exposure was protracted. In contrast to transformation by X- and gamma-rays where repair and kinetics during exposure play dominant roles, with radiations like reactor neutrons and alpha-particles repair has a minimal effect; only cell kinetics acts significantly to modify transformation due to protracted doses. In this report, the lack of responsiveness of mitotic cells to promotion by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate is shown further to agree with the findings with fission-neutrons and the model that, at low dose rate, enhanced transformation is due principally to the progression of cells into the window of sensitivity. Implications of this model for lung cancer due to environmental radon are also discussed.