cancer risk. The cellular data reviewed in this report identified uncertainties and some inconsistencies in the expression of this multifaceted phenomenon. However, telomere-associated mechanisms1 did provide a coherent explanation for some in vitro manifestations of induced genomic instability. The data did not reveal consistent evidence for the involvement of induced genomic instability in radiation tumorigenesis, although telomere-associated processes may account for some tumorigenic phenotypes.

Quantitative animal data on dose-response relationships provide a complex picture of low-LET radiation, with some tumor types showing linear or linear-quadratic relationships, while studies of other tumor types are suggestive of a low-dose threshold, particularly for thymic lymphoma and ovarian cancer. However, the induction or development of these two cancer types is believed to proceed via atypical mechanisms involving cell killing; therefore it was judged that the threshold-like responses observed should not be generalized. 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 do not affect lifetime risk.

The review of cellular, animal, and epidemiologic or clinical studies of the role of genetic factors in radiation tumorigenesis suggest 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 that underlie these genetically determined radiation effects largely mirror those that apply to spontaneous tumorigenesis and are consistent with the knowledge of somatic mechanisms of tumorigenesis. In particular, evidence has been obtained that major deficiencies in DNA damage response and tumor-suppressor-type genes can serve to elevate radiation cancer risk.

A major theme developing in the study of cancer genetics is the interaction and potential impact of more weakly expressing variant cancer genes that may be relatively common in human populations. Knowledge of such gene-gene and gene-environment interactions, although at an early stage, is developing rapidly. 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.

Given that the 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 genes of interest. A preliminary conclusion is 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.

ESTIMATION OF HERITABLE GENETIC EFFECTS OF RADIATION IN HUMAN POPULATIONS

In addition to the induction of cancers in humans by radiation, there is evidence for the heritable genetic effects of radiation from animal experiments. It is now possible to estimate risks for all classes of genetic diseases. The advances that deserve particular attention are the following: (1) introduction of a conceptual change for calculating the doubling dose (from the use of mouse data for both spontaneous and induced mutation rates in 1990 to the use of human data on spontaneous mutation rates and mouse data on induced mutation rates now; the latter was the procedure used in the 1972 BEIR report); (2) elaboration of methods to estimate mutation component (i.e., the relative increase in disease frequency per unit relative increase in mutation rate) and use of estimates obtained through these methods to assess the impact of induced mutations on the incidence of Mendelian and chronic multifactorial diseases; (3) introduction of an additional factor, the “potential recoverability correction factor,” in the risk equation to bridge the gap between the rates of radiation-induced mutations estimated from mouse data and the predicted risk of radiation-inducible heritable diseases in humans, and (4) introduction of the concept that multisystem developmental abnormalities are likely to be among the principal phenotypes of radiation-induced genetic damage in humans.

The risk estimates presented in this report incorporate all of the above advances. They show that at low or chronic doses of low-LET irradiation, the genetic risks are very small compared to the baseline frequencies of genetic diseases in the population.

The total risk for all classes of genetic diseases estimated in this report is about 3000 to 4700 cases per million first-generation progeny per gray. These figures are about 0.4 to 0.6% of the baseline risk of 738,000 cases per million (of which chronic diseases constitute the predominant component—namely, 650,000 cases per million). The BEIR V risk estimates (which did not include chronic diseases) were <2400 to 5300 cases per million first-generation progeny per gray. Those figures were about 5 to 14% of the baseline risk of 37,300 to 47,300 cases per million.

EVIDENCE FROM EPIDEMIOLOGY

Studies of Atomic Bomb Survivors

The Life Span Study (LSS) cohort of survivors of the atomic bombings in Hiroshima and Nagasaki continues to serve as a major source of information for evaluating health risks from exposure to ionizing radiation and particularly for developing quantitative estimates of risk. The advantages of

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Mechanisms associated with the structure and function of telomeres, which are the terminal regions of a chromosome that include characteristic DNA repeats and associated proteins.



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