The long term objective of this application is to define and begin to search for an understanding of the enhanced effects that exposures to neutrons at low doses and doses rates cause on such endpoints as neoplastic transformation and mutation. In particular, the study will define at the cell level the energy dependence of this phenomenon both to gain more knowledge of the biophysical limitations determining the effects and to determine if the risks to humans exposed are confined to those occupationally exposed to fission neutrons or to a wider spectrum of people who may be exposed to neutons and other high LET radiations of various energies. In order to do this, the specific aims of the project are: 1. To define more clearly the energy dependence of enhanced carcinogeneic effects at low doses with protracted exposures to neutrons. 2. To make a molecular analysis of DNA from mutant clones produced by exposing cells to neutrons of various energies. 3. To define the role of repair of strand breaks and the significance of unrepaired breaks produced by exposure of cells to neutrons to various energies. 4. To test the hypothesis that low dose rate neutrons have """"""""promoter-like"""""""" properties. 5. To test the hypothesis that a form of error-prone repair may be involved in both the production and the expression of lesions that cause the enhanced effects. Using neutrons produced at the UCLA cyclotron from protons on Beryllium at 46, 30, 20, and 12 MeV, the following major endpoints will be measured after rodent and human cells are exposed to acute and/or protracted exposures: Neoplastic transformation in C3H10T1/2 cells, mutation at the HGPRT and TK loci in V79, transformed human P3 and/or normal human IMR- 91 cells, DNA single and double strand break production, its repair and fidelity of the repair and finally restriction fragment analysis of DNA from mutant clones to determine what are the deletion types and patterns.
