been published in a series of articles. The most relevant ones have now been compiled in a single volume (Neel and Schull 1991). The most important finding of these studies is that there are no statistically demonstrable adverse genetic effects attributable to radiation exposures sustained by the survivors. Although cited and discussed in the UNSCEAR and BEIR reports over the years, these results did not constitute part of the “mainstream thinking” of genetic risk estimators and therefore were not used in risk estimation.

During the past few years, estimates of the baseline frequencies of Mendelian diseases have been revised and mathematical methods have been developed to estimate the impact of an increase in mutation rate (as a result of radiation exposures) on the frequencies of different classes of genetic diseases in the population. Additionally, there have been several advances in our understanding of the molecular basis and mechanisms of origin of human genetic diseases and of radiation-induced mutations in experimental systems. As a result of these developments, it now is possible to reexamine the conceptual basis of risk estimation, reformulate some of the critical questions in the field, and address some of the problems that could not be addressed earlier.

This chapter summarizes the general framework and the methods and assumptions used in risk estimation until the publication of BEIR V (NRC 1990). This is followed by a discussion of the advances in knowledge since that time, their impact on the concepts used in risk estimation, and how they can be employed to revise the risk estimates. Throughout this chapter, the terms “genetic diseases,” “genetic effects,” and “genetic risks” are used exclusively to mean “heritable genetic diseases,” “heritable genetic effects,” and “heritable genetic risks,” respectively.


Goal of Genetic Risk Estimation

The goal of genetic risk estimation, at least as envisioned and pursued by UNSCEAR and the BEIR committees, remains prediction of the additional risk of genetic diseases in human populations exposed to ionizing radiation, over and above that which occurs naturally as a result of spontaneous mutations. The concept of “radiation-inducible genetic diseases,” which emerged early on in the field, is based on two established facts and an inference. The facts are that (1) hereditary diseases result from mutations that occur in germ cells and (2) ionizing radiation is capable of inducing similar changes in all experimental systems adequately investigated. The inference, therefore, has been that radiation exposure of human germ cells can result in an increase in the frequency of genetic diseases in the population. Worth noting is the fact that although there is a vast amount of evidence for radiation-induced mutations in diverse biological systems, there is no evidence for radiation-induced germ cell mutations that cause genetic disease in humans.

Germ Cell Stages and Radiation Conditions of Relevance

From the standpoint of genetic risks, the effects of radiation on two germ cell stages are particularly important. In the male, these are the stem cell spermatogonia, which constitute a permanent germ cell population in the testes and continue to multiply throughout the reproductive life span of the individual. In the female, the corresponding cell stages are the oocytes, primarily the immature ones. The latter constitute the predominant germ cell population in the female. Female mammals are born with a finite number of oocytes formed during fetal development. These primordial oocytes, as they are called, grow, and a sequence of nuclear changes comprising meiosis takes place in them. The latter however are arrested at a particular stage until just before ovulation. Because oocytes are not replenished by mitosis during adult life and immature oocytes are the predominant germ cell population in the female, these are clearly the cell stages whose irradiation has great significance for genetic risks.

The radiation exposures sustained by germ cells in human populations are generally in the form of low-LET (linear energy transfer) irradiation (e.g., X-rays and γ-rays) delivered as small doses at high dose rates (e.g., in diagnostic radiology) or are greatly protracted (e.g., continuous exposures from natural and man-made sources). In estimating genetic risks to the population therefore, the relevant radiation conditions are low or chronic doses of low-LET irradiation. As discussed later, most mouse data used for estimating the rates of induced mutations have been collected at high doses and high dose rates. Consequently, assumptions have to be made to convert the rates of induced mutations at high doses and dose rates into mutation rates for radiation conditions applicable for risk estimation in humans.


Since the aim of genetic risk estimation is to predict the additional risk of genetic diseases relative to the baseline frequency of such diseases in the population, the concept of genetic diseases and their classification and attributes are considered in this section. The term genetic diseases refers to those that arise as a result of spontaneous mutations in germ cells and are transmitted to the progeny.

Mendelian Diseases

Diseases caused by mutations in single genes are known as Mendelian diseases and are further divided into autosomal dominant, autosomal recessive, and X-linked, depending on the chromosomal location (autosomes or the X chromosome) and transmission patterns of the mutant genes. In an autosomal dominant disease, a single mutant gene (i.e., in the heterozygous state) is sufficient to cause disease. Examples include achondroplasia, neurofibromatosis, Marfan syndrome, and myotonic dystrophy. Autosomal recessive

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