Significant concern continues to be expressed by both the government and the public regarding the potential of genotoxic agents to increase the germinal mutation rate and, therefore, the incidence of genetic disease in humans. Current estimates of the potential human health risk from gene mutations caused by exposure to mutagenic agents are derived from animal data generated following exposure to high doses of suspected mutagen. Animal data are used because it has not been possible to obtain sufficient data from humans. Molecular techniques for the study of gene structure have potential for generating significant quantities of data from a mother/father/child triad. These approaches are being developed as tools for estimating the heritable mutation rate in human populations. this project will focus on determining the mutation rate for insertion, deletion and/or rearrangement mutations, the molecular lesions expected to be most the frequent class of event in offspring of radiation exposed individuals. A restriction-enzyme-site- mapping strategy will be employed to screen approximately 1000 loci in each triad. The 750 offspring to be studied will have been born to individuals exposed to significant levels of radiation during the cleanup at Chernobyl. The triads will focus on fathers receiving high doses (>0.25Sv) during short time periods, the group expected to have the highest mutation rate. Appropriate control triads will also be screened. The technology employed in this study will be transferred to our Soviet collaborators for inclusion into future studies in the continuing monitoring of this population. Thus, this study, which will generate a data base of 750,000 locus tests, should be viewed as an initial pilot study in a longer term effort. The study of germinal gene mutations in humans addresses one of the significant issues for man, namely, the component of the genetic burden and health risk transmitted to future generations that is caused by exposure to mutagenic agents. This integrated program of 4 projects will be a model for future efforts to estimate human risk, using approaches that combine measures of human exposure with the results of predictive tests in model systems to estimate potential increases in human mutation rates and subsequent genetic disease.