It is clear that overall estimates of such cannot be based simply on empirical linear fits of available epidemiological data from relatively high dose exposures - even when adjustments are made for low dose and low dose rate exposures. Such an extrapolation can either over- or underestimate the risks. It is extremely difficult to measure directly small changes in most biological end points, particularly carcinogenesis. Thus, scientifically defensible tools and approaches for determining risk must be developed that can be accepted with confidence. We hypothesize that experimentally determined molecular mechanisms operating at relatively high doses will also be applicable at low doses. Hence, we can develop theoretical models for estimating risk at low doses and low dose rates. Our strategy is to extrapolate mechanisms and not risk from high dose to low dose, taking into consideration those effects that are non-linear with dose.

Specific Aim 1: We will develop geometric models for prototypical interphase diploid mammalian cell nuclei. As data becomes available, will map genomic sequence information onto these architectural models of chromosomes.
Specific Aim 2: We will combine our Monte Carlo track structure code for different energy electron tracks with interphase nuclear models to determine the spatial and temporal (for those rate consideration) distributions of strand breaks and base damages. Time dependent repair processes will be incorporated into the model.
Specific Aim 3: The misrepair of local clusters of damage will be correlated with point mutations and small deletions. Misrepair of double strand breaks will allow us to evaluate intermediate and large scale rearrangements such as chromosome aberrations. Integration of these mechanisms will allow us to develop a comprehensive, gene specific theory of mutation induction value at al doses and dose rates.

In order to achieve these specific aims, we will develop comprehensive polymer models of whole chromosomes, incorporating information on the chromatin loops between matrix attachment regions in both heterochromatin and euchromatin. Ultimately, whole nuclei will be modeled including locations on chromosomes of specific genes and regulatory elements important in carcinogenic process. The development of a general theory of mutation induction will provide the essential foundations for a mechanistically based theory of radiation risk which will be valid at all doses and dose rates. As a starting point, we will incorporate our mutation model into existing multi-stage models of carcinogenic risk, such as, for example, the two-stage stochastic mutation model of Moolgavkar, which includes two mutations (initiation and progression) combines with clonal expansion (promotion). Development of such models will provide the only realistic hope of determining reliably whether there exist threshold effects in the radiation induction of cancer. This will allow rational decisions when evaluating when and how much radioactive waste cleanup is required.