DOE Low Dose Radiation Research Program Workshop I Abstracts November 10-12, 1999, Washington, D.C.

39. Cytogenetic Tests of Radiobiological Models Relating Epidemiologically Measurable Risks to Low-Dose Risks

R.K. Sachs, D.J. Brenner, C. Geard, and L. Hlatky
Department of Mathematics, Evans Hall, UCB, Berkeley, CA 94720
sachs@math.berkeley.edu

Summary: The project will use experiments and mechanistic modeling for chromosome aberrations, which are closely related to cancer but are more amenable to laboratory investigations, to find credible dose-response relations for sparsely ionizing radiation in the range from the low doses mainly relevant to risk estimation to somewhat higher, epidemiologically tractable doses.

Abstract: A priority for risk analysis is understanding dose-response relationships, both in the low-dose range and in an intermediate-dose range where quantitative epidemiology is feasible. The relevant initial damage, such as DNA double-strand breaks (DSBs), is almost surely produced linearly with dose. So the main issues relate to cellular processing of initial damage, which can result in more complex endpoints such as chromosome aberrations and, ultimately, cancer.

Exchange-type chromosome aberrations, produced during the G0/G1 phase of the cell cycle and usually scored at the next metaphase, result from the interplay between DNA repair and misrepair and are highly relevant to carcinogenesis risk estimation. The general goal of our project is using experiments and quantitative modeling to find credible dose-response relations for such aberrations in the low-LET dose range from <0.1 to 2 Gy, i.e. from the low doses mainly relevant to risk estimation to somewhat higher, epidemiologically tractable doses. We will gather experimental information at the higher doses, use computer models to extrapolate to the lower doses, and check the extrapolation with low-dose experiments. We have assembled a team of modelers and radiation cytogeneticists to carry out the following specific aims:

1. Measuring exchange-type chromosome aberrations with several fluorescent in situ hybridization (FISH) techniques after gamma-ray irradiation of human lymphocytes in vitro. Doses used will range from 0.08 Gy up to 2 Gy. Repeated fractions of 0.08 Gy each will also be used, to improve the signal to background ratio. Aberrations measured at 2 Gy will include translocations (closely associated with leukemias), inversions (which have been somewhat neglected in radiation risk estimation but are very probably relevant to carcinogenesis), rings, dicentrics, and complex aberrations (informative about damage mechanisms).

2. Analyzing low-LET aberration frequencies quantitatively and mechanistically, using standard current chromosome aberration models, implemented by extensions of sophisticated CAS (chromosome aberration simulator) Monte Carlo computer software previously written and applied by members of our team. The computational algorithms closely interrelate various kinds of aberrations, simple or complex, and interrelate different doses. In addition to our data, we will model related data from the literature; low-dose results obtained on dicentrics by a large-scale, multi-year, multi-laboratory effort; various recent FISH experiments, usually at higher doses but related to low-dose results by the mechanistic biological modeling; and molecular-level data on mutations at specific loci, also involving higher doses.

3. Determining low-LET dose-response relations for exchange-type aberrations at low doses. In particular, checking if the recombinational-repair ("one hit") chromosome aberration formation pathway, a linear no-threshold molecular mechanism, makes a quantitatively significant contribution to aberration formation at low doses.

The project will result in state-of-the-art computational techniques and mechanistic models for determining risk, which can relate information from cellular and molecular studies at low doses to available data from epidemiological studies. A secondary result will be additional aberration data at low doses. Biophysical and mathematical analysis of aberrations is emphasized as a practical, relatively inexpensive way to help firm-up risk estimates and make them more credible.