Radiation-induced life shortening in mice is largely a reflection of cancer mortality, and the data reviewed generally support the concept of a linear dose-response at low doses and low dose rates. Other dose-response data for animal tumorigenesis, together with cellular data, contributed to the judgments developed and the choice of a DDREF for use in the interpretation of epidemiologic information on cancer risk.
Adaptive responses for radiation tumorigenesis have been investigated in quantitative animal studies, and recent information is suggestive of adaptive processes that increase tumor latency but not lifetime risk. However, these data are difficult to interpret, and the implications for radiological protection remain most uncertain.
Research Need 5. Tumorigenic mechanisms
Further cytogenetic and molecular genetic studies are needed to reduce current uncertainties about the specific role of radiation in multistage radiation tumorigenesis; such investigations would include studies with radiation-associated tumors of humans and experimental animals.
The review of cellular, animal, and epidemiologic or clinical studies on the role of genetic factors in radiation tumorigenesis suggests that many of the known strongly expressing cancer-prone human genetic disorders are likely to show an elevated risk of radiation-induced cancer, probably with a high degree of organ specificity. Cellular and animal studies suggest that the molecular mechanisms underlying these genetically determined radiation effects largely mirror those that apply to spontaneous tumorigenesis and are consistent with knowledge of somatic mechanisms of tumorigenesis. In particular, evidence was obtained that major deficiencies in DNA damage response and tumor-suppressor-type genes can serve to elevate radiation cancer risk.
Limited epidemiologic data from follow-up of second cancers in gene carriers receiving radiotherapy were supportive of the above conclusions, but quantitative judgments about the degree of increased cancer risk remain uncertain. However, since major germline deficiencies in the genes of interest are known to be rare, it has been possible to conclude from published analyses that they are most unlikely to create a significant distortion of population-based estimates of cancer risk. The major practical issue associated with these strongly expressing cancer genes is judged to be the risk of radiotherapy-related cancer.
A major theme developing in cancer genetics is the interaction and potential impact of more weakly expressing variant cancer genes that may be relatively common in human populations. The animal genetic data provide proof-of-principle evidence of how such variant genes with functional polymorphisms can influence cancer risk, including limited data on radiation tumorigenesis. Attention was also given to human molecular epidemiology data on associations between functional polymorphisms and cancer risk, particularly with respect to DNA damage response genes.
Given that functional gene polymorphisms associated with cancer risk may be relatively common, the potential for significant distortion of population-based risk was explored with emphasis on the organ specificity of the genes of interest. An interim conclusion was that common polymorphisms of DNA damage response genes associated with organ-wide radiation cancer risk would be the most likely source of major interindividual differences in radiation response.
Research Need 6. Genetic factors in radiation cancer risk
Further work is needed in humans and mice on gene mutations and functional polymorphisms that influence the risk of radiation-induced cancers. Where possible, human molecular genetic studies should be coupled with epidemiologic investigations.
As noted in BEIR V, heritable effects of radiation are estimated using what is referred to as the “doubling dose method” and expressed in terms of increases in the frequencies of genetic diseases in the population over and above those that occur as a result of spontaneous mutations. The doubling dose (DD) is the amount of radiation required to produce as many mutations as those that occur spontaneously in a generation and is calculated as a ratio of the average rates of spontaneous and induced mutations in defined genes. If the DD is small, the relative mutation risk per unit dose (i.e., 1/DD) is high, and if DD is large, the relative mutation risk is low. The DD, therefore, provides a convenient yardstick to express risks and a perspective of whether the predicted increases are trivial, small, or substantial relative to the baseline.
In the BEIR V report, mouse data on both spontaneous and induced mutation rates were used for DD calculations. A reassessment of the assumptions underlying this procedure revealed that the use of mouse data for spontaneous mutation rates can no longer be considered appropriate and that reverting to the use of human data on spontaneous mutation rates for DD calculations, as was first done in the 1972 BEIR report, is correct. The DD calculated is 1 Gy and is the same as the one based entirely on mouse data.
The baseline frequencies of genetic diseases constitute an important quantity in risk estimation. While there is no reason to consider revision of the baseline frequencies of congenital abnormalities (6%) and chronic diseases (65%), these two classes together constitute what are referred to as “mul-