tifactorial diseases” because of the multiple factors involved in their etiology. Advances in human genetics now suggest that the frequencies of Mendelian diseases (i.e., those that are due to mutations in single genes and show simple and predictable patterns of inheritance) have to be revised upwards from the 1.25% used previously (based on estimates made in the mid-1970s) to 2.40% at this time.
Mouse data on rates of radiation-induced mutations constitute the primary basis for estimating the risk of radiation-inducible genetic diseases in humans. Advances in the molecular biology of human genetic diseases and in studies of radiation-induced mutations in experimental systems show that mouse mutation rates cannot readily be converted into rates of genetic disease in human live births and that a correction factor, the potential recoverability correction factor (PRCF), is required to make the transition from induced mutations in mice to inducible genetic disease in humans. A framework and methods have been developed to estimate PRCFs for Mendelian and chronic multifactorial diseases.
The adverse hereditary effects of radiation are more likely to be manifest as multisystem developmental abnormalities than as Mendelian diseases. This concept incorporates elements of current knowledge of the mechanisms of radiation-induced genetic damage, the molecular nature of radiation-induced mutations, the phenotypic manifestations of naturally occurring multigene deletions in humans, empirical observations in mice on the phenotypic effects of radiation-induced multigene deletions, and the enormous number and distribution of genes involved in development in nearly all the human chromosomes. Appropriate mouse data that can serve as a basis for a preliminary estimate of radiation-induced adverse developmental effects have been identified and used.
Risk estimates have been made only for the first two postirradiation generations. The population genetic theory of equilibrium between mutation and selection (i.e., the equilibrium theory) underlies the DD method that is used to estimate genetic risks of radiation. This theory postulates that the stability of mutant gene frequencies (and therefore of disease frequencies) in a population is a reflection of the existence of a balance between the rates at which spontaneous mutations arise in every generation and enter the gene pool and the rates at which they are eliminated by natural selection. When such an “equilibrium population” sustains radiation exposure generation after generation, additional mutations are introduced into the gene pool, and these are also subject to the action of natural selection. The prediction is that a new equilibrium between mutation and selection will be reached. The time it takes in terms of generations to attain the new equilibrium, the rate of approach to it, and the magnitude of increase in mutant (and disease) frequencies are dependent on the induced mutation rate, the intensity of selection, and the type of disease.
Research Need 7. Heritable genetic effects of radiation
Further work is necessary to establish (1) the potential roles of DNA DSB repair processes in the origin of deletions in irradiated stem cell spermatogonia and oocytes (the germ cell stages of importance in risk estimation) in mice and humans and (2) the extent to which large, radiation-induced deletions in mice are associated with multisystem development defects. In humans, the problem can be explored using genomic databases and knowledge of mechanisms of the origin of radiation-induced deletions to predict regions that may be particularly prone to such deletions. These predictions can subsequently be tested in the mouse, these tests can also provide insights into the potential phenotypes associated with such deletions in humans.
With respect to epidemiology, studies on the genetic effects of radiotherapy for childhood cancer, of the type that have been under way in the United States and Denmark since the mid-1990s, should be encouraged, especially when they can be coupled with modern molecular techniques (such as array-based comparative genomic hybridization. These techniques enable one to screen the whole genome for copy number abnormalities (i.e., deletions and duplications of genomic segments) with a resolution beyond the level of a light microscope.
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. Its advantages include its large size, the inclusion of both sexes and all ages, a wide range of doses that have been estimated for individual subjects, and high-quality mortality and cancer incidence data. In addition, the whole-body exposure received by this cohort offers the opportunity to assess risks for cancers of a large number of specific sites and to evaluate the comparability of site-specific risks.
As an illustration, Figure 13-1 shows estimated ERRs of solid cancer versus dose (averaged over sex and standardized to represent individuals exposed at age 30 at attained