CYTOGENETIC MODELS FOR ASSESSING LOW DOSE RADIATION RISK

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Science-based assessments of environmental or occupational cancer risks from sparsely ionizing radiation estimate effects on large populations from doses that are very small compared to typical experimental doses and small compared even to epidemiologically tractable doses. A priority is developing credible dose-response relationships, both in an intermediate-dose range (up to 2 Gy or more) where epidemiology is feasible and in the most relevant, low-dose range (<0.1 Gy). The pertinent initial damage, such as DNA double strand breaks, is almost certainly produced linearly with dose, so the main issue is cellular processing of initial damage, via molecular repair/misrepair pathways, which can result in more complex endpoints such as chromosome aberrations and, ultimately, cancer. Exchange-type chromosome aberrations, produced during the GOIGl cell cycle phase and scored at the next metaphase, are complex endpoints, characteristic of ionizing radiation damage and highly relevant to carcinogenesis risk estimation. The goal of our project is using in vitro experiments on human cells and quantitative, mechanistic modeling to find realistic dose- response relations for such aberrations in a dose range from 0.08-2 Gy, as a practical surrogate for studying carcinogenesis in vivo at low doses. Biophysical and Monte Carlo computer analysis, comparing the best currently available models of molecular aberration formation pathways to data is emphasized as a relatively inexpensive approach. We have assembled a team of modelers and experimental radiobiologists from UC Berkeley, Columbia, and Harvard for the project. Exchange-type chromosome aberrations will be measured with state-of-the-art fluorescent in situ hybridization techniques after y-irradiation of human lymphocytes. Modeling will use extensions of sophisticated CAS (chromosome aberration simulator) computer software previously written and successfully applied by members of our team. The main novelties in the proposal are: close integration of mechanistic computer modeling with low-dose experiments; using repeated low-dose fractions to enhance response above background; including inversions and complex aberrations among the aberrations measured for risk-estimation purposes; and explicit consideration of the recombination-repair aberration formation model. By studying molecular, mechanisms relevant to low doses and low dose-rates quantitatively the project will help firm-up risk estimates and make them more credible.