Estimation of genetic risks of exposure to ionizing radiation: status in the year 2000

This paper provides an overview of the advances in the estimation of genetic risks of exposure of human populations to ionizing radiation with particular emphasis on the advances during the last decade. Among the latter are: (a) an upward revision of the estimates of the baseline frequencies of Mendelian diseases (from 1.25 to 2.4%); (b) the conceptual change to the use of a doubling dose based on human data on spontaneous mutation rates and mouse data on induced mutation rates (from the one based entirely on mouse data on spontaneous and induced mutation rates, which was the case thus far); (c) the fuller development of the concept of mutation component (MC) and its application to predict the responsiveness of Mendelian and chronic multifactorial diseases to induced mutations; (d) the concept that the major adverse effects of radiation exposure of human germ cells are likely to be manifest as multi-system developmental abnormalities and (e) the concept of potential recoverability correction factor (PRCF) to bridge the gap between induced mutations studied in mice and the risk of genetic disease in humans. For a population exposed to low LET, chronic/low dose-rate irradiation, the current estimates of risk for the first generation progeny are the following (all estimates per million live born progeny per Gy 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 2,000 cases. The total risk per Gy 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. The main message is that at low doses of radiation of interest in risk estimation, the risk of adverse hereditary effects is small.     

Comparative lethal effects of uv and ionizing radiation in Ames tester strains of Salmonella

In the three (parent-daughter) pairs of Ames Salmonella tester strains TA1535-TA100, TA1537-TA2637, and TA1538-TA98 in which the daughter strains carry the pKM101 plasmid but the parent strains do not, the pKM101 plasmid uniformly confers resistance of the host to uv radiation which indicates that the muc genes of the plasmid are present and function correctly in all three daughter strains. This uniform protection against killing by uv contrasts with the lethality responses of the same parent-daughter pairs to ionizing radiation (ir) where pKM101 again confers lethality protection to TA100 and TA2637 but sensitizes TA98 toward the lethal effects of ir. From these results we conclude that the pathways for error-prone repair of lethal lesions induced by uv and by ionizing radiation are not the same and that the muc genes of the plasmid alone are not sufficient to carry out error-prone repair of lethal lesions induced by ionizing radiation. We infer that a segment of plasmid DNA that is present in TA100 and TA2637 and is required to repair potentially lethal damage induced by ir is deleted in TA98.     

N-methyl-N''-nitro-N-nitrosoguanidine-induced resistance to ionizing radiation

Summary N-methyl-N-nitro-N-nitrosoguanidine (MNNG) pretreatments increase the resistance of Escherichia coli to -radiation. The increased resistance is dependent on functional polA, recA, recB, recC, and lexA genes and is partly dependent on recN. The MNNG-induced resistance is additive to resistance induced by pretreatment with -radiation but not by increases induced by hydrogen peroxide. The MNNG-induced resistance occurs in adaptive response mutants and at pretreatment levels of MNNG that do not activate cells to reactivate UV-inactivated lambda phage. The MNNG-induced resistance appears to be distinct from other inductions to -radiation resistance.     

High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation

When mammalian cells are irradiated in vitro, the component cells of a normal-appearing survivor colony or clone are commonly thought to have proliferative capacity equivalent to that of the unirradiated cells. We have found, however, that cells appearing in survivor colonies may carry heritable lethal defects which come to light, perhaps only after numerous successful divisions, in the form of plating efficiencies that are reduced below those of unirradiated cells in a dose-dependent manner. We regard these heritable defects as signs of the induction of lethal mutations, which, like non-lethal mutations, may require many generations before they are expressed. This effect has been noted in two very dissimilar mammalian cell lines, one a primary culture from adult tissue, the other an immortal cell line. We suggest that induction of lethal mutations may occur also in somatic cells in vivo; this would account for the well-known observation that previously irradiated but apparently healed tissue is subsequently proved to be extraordinarily sensitive to subsequent exposure to irradiation or cytotoxic drugs. The results of our experiments in vitro suggest that current methods of estimating mutation or transformation yields may yield underestimates. If lethal mutations are induced also in vivo, interpretations of the results of fractionation experiments on normal tissues may have to be reconsidered.     

Exposure of human lymphocytes to ionizing radiation reduces mutagenesis by subsequent ionizing radiation

The effect of prior incubation with [3H]thymidine on survival and mutagenesis after X-irradiation of human lymphocytes was studied by incubating lymphocytes with 0.001-1.0 mu Ci/ml [3H]thymidine for 6 h at 37 degrees C and then irradiating with 150 or 300 rad. Survival was measured using lymphocyte cloning and mutagenesis was measured using 6-thioguanine selection to detect clones mutated at the hypoxanthine phosphoribosyltransferase locus. [3H]Thymidine alone had no effect on survival or mutagenesis and X-radiation alone produced the expected decrease in survival and increase in mutations. [3H]Thymidine prior to X-radiation had no effect on lethality of X-radiation but at concentrations of 0.1 and 1.0 mu Ci/ml produced a significant decrease in the number of mutations induced after both 150 and 300 rad. The results suggest that ionizing radiation, produced by disintegration of 3H, reduces the mutagenic effect of a subsequent exposure to ionizing radiation by induction of a system which prevents or repairs a restricted class of radiation damage.     

The effect of He-Ne laser radiation on the survival of HeLa cells subjected to ionizing radiation]

A monolayer of HeLa cells, at the stationary phase of growth, exposed to He-Ne laser radiation (632.8 nm; 100 J/m2) either 5 min or 60 min prior to gamma irradiation (0.1-10 Gy; 6.75 Gy/min), or 5 min after irradiation has been investigated. With a 5-min interval between irradiation sessions (both sequences) the survival curves are virtually the same as those for gamma-irradiated cells only. With He-Ne laser radiation delivered 60 min before gamma irradiation with doses exceeding 5 Gy, a fraction of radioresistant cells is identified whose D0 is almost twice as high as D0 of basic cell mass (3.6 and 1.7 Gy respectively. The survival curve becomes a two-component one. A hypothesis is proposed that He-Ne laser radiation activates, in some cells, the processes that promote the repair of radiation damages.     

The effect of ionizing radiation on the respiration of rat thymocytes

The oligomycin-sensitive component of the rate of oxygen consumption by rat thymocytes increased by 22% after X-irradiation. The postirradiation increase in the thymocyte respiration rate was connected with the impairment of a balance between sodium, potassium and calcium and with the protein synthesis activation, and was independent of lymphokine production by lipoxygenase. Irradiation was ineffective with respect to electron transport in the respiratory chain and electrogenic leakages through the inner membrane of thymocyte mitochondria.     

Estimation of interaction function gamma(x) with sparsely ionizing radiation

The interaction function gamma(chi), which was introduced in the theory of dual radiation action as the probability that two energy transfers separated by distance chi combine with each other to produce a lesion, was estimated with sparsely ionizing radiation (60Co gamma rays and 40 kV X rays). Gamma(chi) was deduced on the assumption that the sensitive matrix is made up of small spherical flocculi distributed over the cell nucleus. The diameter of a flocculus was estimated at (4.0-11.2) X 10(-8) m when the diameter of the cell nucleus d was assumed to be 5 microns, and (4.0-11.4) X 10(-8) m when d was assumed to be 10 microns. It seems reasonable to hypothesize that the flocculus corresponds to the linker DNA in the chromatin structure of DNA, because the size of the linker DNA as a target (about 40 nm) is consistent with the diameter of flocculi obtained in this study.