Estimation of the hereditary risks of exposure to ionizing radiation: history, current status, and emerging perspectives.

摘要

This paper provides a brief overview of the advances in the field of the estimation of the genetic risks of exposure of human populations to ionizing radiation from the early 1950's to the present and of the developments that are anticipated in the coming years. The latter are based on the view that the insights gained from human genetics, especially human molecular genetics, will be increasingly applied to address problems in risk estimation. Owing to the paucity of human data on radiation-induced mutations, mouse data on radiation-induced mutations are used to predict the risk of genetic diseases in humans using the doubling dose method. With this method, the risk per unit dose is expressed as a product of three quantities, i.e., P x 1/DD x MC where P is the baseline frequency of genetic diseases, 1/DD (the relative mutation risk per unit dose; DD refers to the doubling dose, i.e., the radiation dose required to produce as many mutations as those that occur spontaneously in a generation) and MC is the disease class-specific mutation component (a measure of the relative increase in disease frequency per unit relative increase in mutation rate). The five important changes that are now introduced in genetic risk estimation include (1) an upward revision of the baseline frequency of Mendelian diseases to 2.4% (from 1.25% used until the early 1990's); (2) a reversion to the conceptual basis for DD calculations used in the 1972 BEIR report of the U.S. National Academy of Sciences, namely, the use of human data on spontaneous mutation rates and mouse data on induced mutation rates (instead of the use of mouse data for both these rates as has been the case from mid-1970's until the early 1990's); (3) the fuller development and use of the MC concept for predicting the responsiveness of Mendelian and multifactorial diseases to increases in mutation rate; (4) the introduction of a new disease-class-specific quantity called the "potential recoverability correction factor" or PRCF in the risk equation to bridge the gap between the rates of induced mutations in mice and the risk of inducible genetic diseases in humans; and (5) the introduction of the concept that multisystem developmental abnormalities are likely to be among the principal phenotypes of radiation induced genetic damage in humans. All these advances now permit, for the first time in 40 y, the estimation of risks for all classes of genetic diseases. For a population exposed to low-LET, chronic or low-dose irradiation, the risks predicted for the first generation progeny are the following (all estimates are per million live born progeny per gray of parental irradiation): autosomal dominant and x-linked diseases, approximately 750 to 1,500 cases; autosomal recessive, nearly zero; chronic multifactorial diseases, approximately 250 to 1,200 cases; and congenital abnormalities, approximately 2000 cases. The total risk per gray is of the order of approximately 3,000 to 4,700 cases, which represent approximately 0.4 to 0.6% of the baseline frequency of these diseases (738,000 per million) in the population. The advances anticipated in the coming years are likely to permit the estimation of genetic risks of radiation with greater precision than is now possible.