The long-term goals of the research proposed in this application are to elucidate some of the mechanisms involved in the production of chromosomal aberrations following exposure to ionizing radiation as they pertain to both the assessment of low-level radiation hazards, and processes associated with cell killing that are more pertinent to cancer treatment by radiotherapy. More specifically, the proposed experiments are designed to test the plausibility of repair-saturation models in explaining various curvilinear biological dose-responses to sparsely ionizing radiation, as well as provide information on the nature of RBE/LET relationships. The approaches to be used in achieving these goals are outlined as follows: 1. Utilizing the technique of premature chromosome condensation (PCC), the rate of chromosome break rejoining will be measured as a function of dose delivered to quiescent normal human fibroblasts. A decrease in this rate, over the dose range associated with the """"""""shoulder"""""""" region of survival response, will be interpreted as evidence of repair-saturation at the cytogenetic level. 2. By immediately fusing irradiated and unirradiated mitotic CHO cells together, it should be possible to determine whether exchange aberrations occur between damaged and undamaged chromatin, when the syncytia reach the next mitosis. Such exchanges would be predicted to occur under the assumptions of certain repair-saturation models. 3. The dose response of human interphase chromosomes (PCC) to initially produced breaks caused by alpha-particles will be studied, as well as the rate at which these lesions are rejoined by cells. Comparing the results of these studies to those obtained using gamma-rays will indicate whether damage from densely ionizing radiation is inherently less repairable, as repair-saturation models generally maintain. 4. Further improvements in PCC methodology are proposed, specifically the ability to unequivocally identify the centromeric regions of G0/G1 PCC. This would allow the accurate measurement of radiation-induced chromosome breaks caused by doses well below 10 rad.
