The goal of this program project is to determine whether several newly developed molecular and cellular analytical procedures can be used to measure effects of ionizing radiation on humans. We also will test whether a combination of these measurements made on each individual can provide a set of data that can be used to estimate: (1)the radiation dose received by that individual, (2)his susceptibility to radiation-induced genotoxicity, (3)the relative risk of induced health effects (e.g., cancer) in the exposed individual and/or birth defects in his progeny. Our method for accomplishing these goals is to simultaneously obtain genotoxicity measurements using four different analytical techniques on blood samples from approximately 800 individuals including people who were exposed to ionizing radiation as a result of the accident at the nuclear power plant in Chernobyl, Ukraine in April-May 1986 and their progeny. Each project in this program project is designed to provide a detailed study of one type of genotoxicity measure: 1. cytogenetics, 2. somatic mutations in the glycophorin A locus, 3. somatic mutations in the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus, 4. germinal mutations. Cytogenetics is the classical measure of radiation exposure and provides a base line for comparison of other analyses. In addition, a newly developed fluorescence in situ DNA hybridization cytogenetic technique will be tested for applicability. The glycophorin A-based genotoxicity assay has been shown to be a monitor of persistent radiation effects on humans and the kinetics of the response as well as the sensitivity of the assay will be tested. HPRT assay has been applied to several cohorts of radiation exposed people and serves as a clonogenic analysis of somatic mutation effects. The character and persistence of genomic changes that occur in the HPRT locus with human radiation exposure also will be determined. The germinal changes that occur in the HPRT locus with human radiation exposure also will be determined. the germinal mutation study is the first DNA-based analysis to be applied in humans and can provide an insight into possible genetic consequences of human radiation exposure. Data from the four areas of research will be used in two ways. For each individual assay of somatic cells, a dose-response from ionizing radiation will be generated by comparing the analytical results with physical dosimetry and with immediate biological dosimetry that was performed by the Soviet medical scientists in 1986 shortly after the Chernobyl accident. This should provide a means for interpreting each of the bioassays for its capabilities as a monitoring biodosimeter for similar radiation exposures (both sensitivity and precision will be determined). In addition, the combination of measurements from the four different research areas will allow an overall effect of exposure of each individual to be determined. A weighted sum of these effects will be derived, and in the future this may serve as an individual dosimeter for dose, an indicator for higher susceptibility to damage, and an estimator for that individual's risk to develop cancer.
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