The overall objectives of this project are to examine the mutagenic effects of ionizing radiation in two different human cell systems: human diploid lymphoblasts grown in suspention, and diploid skin fibroblasts (HDF) grown in monolayer. Our general approach will be to focus on linear dose effects, their possible dependence on dose-rate and radiation quality and how they are influenced by cellular recovery processes, as well as to develop cell systems that may permit the study of the role of specific molecular processes in mutagenesis and to relate these to carcinogenesis in vivo.
The specific aims are: 1) to determine the dose-response relationships for the induction of mutations in human lymphoblasts at two genetic loci by low doses of X-rays; 2) To compare the shape of these dose-response curves with those obtained for mutations induced by X-rays at the HGPRT locus in a human diploid bibroblast strain; 3) to examine the effects of dose-rate on the induction of mutations in lymphoblasts by two techniques: first, by comparing the effects of single and multiple daily exposures to X-rays; and second, by varying the specific activity and duration of incubation with 3H2O; 4) to examine the effect of different qualities of radiation on mutagenesis by use of radionuclides incorporated into cellular DNA: 3H will be used as a model for sparcely ionizing radiation, and 125I as a model for densely ionizing radiation; and 5) to study the mutagenicity of X-rays in cells derived from patients with genetic disorders associated with an enhanced susecptibility to spontaneous and/or radiation-induced cancer. These studies will include dose response determinations and measurements of the kinetics of the change in induced mutants during """"""""liquid holding.""""""""
