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The radioprotective effect of a stable prostaglandin E 1 analogue, misoprostol, was studied in cells from mice with severe combined immunodeficiency (SCID) and in normal cells using X-ray-induced chromosomal aberrations and/or cell killing as the end points. The results clearly show misoprostol-induced radioprotective effects in spermatocytes of the first meiotic division when analyzed for X-ray-induced chromosomal aberrations. The protective effect was independent of Trp53 (formerly known as p53) status. Since spermatocytes are relatively easy to isolate, this appears to be a suitable in vivo model that will allow biochemical studies of the mechanisms involved in radioprotection mediated by misoprostol. Using transfected CHO-K1 cells that stably express a PGE 2 receptor (CPE cells), significant radioprotection mediated by misoprostol from both chromosome breakage and cell death could be demonstrated under in vitro conditions. In addition, evidence was obtained indicating that the degree of radioprotection was dependent on the cell cycle and that S-phase cells were less responsive to misoprostol-mediated radioprotection. These results suggest that CPE cells may be a suitable in vitro model for further studies on the cellular pathways involved in radioprotection by misoprostol in particular and prostaglandins in general.

Individuals genetically predisposed to cancer may be more sensitive to cancers induced by ionizing radiation than those who are not so predisposed. Should this be true, under conditions of radiatio...

This paper presents an overview of current knowledge on genetic predisposition to cancer and on enhanced sensitivity of cancer-predisposed genotypes to cancers induced by ionizing radiation. It is intended to provide a background and set the stage for the next papers in this series in which we will assess how such heterogeneity (with respect to predisposition to cancer and presence of radiosensitive genotypes) in a population may affect estimates of the risk of radiation-induced cancers. The main findings and/or conclusions of the present paper are the following: (1) "Cancer-predisposing genes" (i.e. those at which germinal mutations predispose to cancer) are present in the human genome; these genes are responsible not only for the rare familial cancer syndromes but also for a proportion of the common cancers. At least 21 such genes have now been cloned (including 9 tumor suppressor genes, 11 DNA repair genes and 1 proto-oncogene); further, at least 8 putative tumor suppressor genes and a gene involved in...

A detailed presentation is made of the experimental data from the various systems used by Abrahamson et al. [2] to conclude that the per locus per rad (low LET) radiation-induced forward mutation rates in organisms, whose DNA content varies by a factor of about 1000, is proportional to genome size. Additional information pertinent in this context is also reviewed. It is emphasized that the mutation rates cited by Abrahamson et al. [2], although considered as pertaining to mutations at specific loci, actually derive from a broad variety of genetic end-points. It is argued that an initial (if not sufficient) condition for sound inter-specific mutation rate comparisions, covering a wide range of organisms and detecting systems of various sensitivities, requires a reasonalbly consistent biological definition of a specific locus mutation, namely, a transmissible intra-locus change. Granting the differences between systems in their resolving power to detect intragenic change, the data cited in this paper do not support the existence of a simple proportionality between radiotion-induced intra-locus mutation rate and genome size for the different species reviewed here. Furthermore, in Drosophila melanogaster, where individual salivary gland chromosome bands (that can differ greatly in DNA content) are usually associated with individual loci or at least distinct complementation groups, radiation-induced intra-locus mutation rates are not correlated with apparent differences in the DNA content of bands. This result is incompatible with the notion that most of the DNA in a band represents a radiation-mutable target capable of eliciting the kind of mutation observed in mutation rate experiments. All these considerations argue against the validity of the hypothesis of Abrahamson et al. [2] and their generalization that, for the evaluation of genetic radiation hazards in man, we can now "extrapolate from mutation rates obtained in lower organisms to man with greater confidence" on the basis of DNA content (italics are ours).

Non-disjunction plays a major role in generating aneuploidy in man. About 50% of spontaneous abortions are chromosomally abnormal and among these, trisomies constitute the major group (∼50%), followed by monosomy X (18%), triploidy (17%), tetraploidy (6%) and others. Over 30% of all trisomies are due to trisomy for chromosome 16. There seems to be an association between maternal radiation history and spontaneous abortions in the sence that the work reported, mothers of chromosomally abnormal foetuses have received higher mean gonadal doses relative to comparable controls. About 6% of babies who die perinatally are chromosomally abnormal and the majority are trisomics especially for group E chromosomes. The results of six major surveys of consecutive newborns show that 6 out of 1000 (0.6%) carry one or another kind of chromosome anomally. The breakdown is as follows: 0.22%, sex-chromosomal abnormalities; 0.14%, autosomal trisomies (+D, +E and +G); 0.19%, balanced structural rearrangements and 0.06%, unbalanced structural rearrangements and others. The frequency of “clinically significant” anomalies has been estimated to be about one-half of the total of all chromosomal abnormalities detected in newborns. The spontaneous “mutation rate” for numerical anomalies of chromosomes which result in liveborn children is about 15 × 10 −4 per gamete per generation (9.3 × 10 −4 for sex-chromosomal aneuploidies and 5.7 × 10 −4 for autosomal trisomies). Autosomal aneuploidies are associated with more severe phenotypic effects than sex-chromosomal aneuploidies. The majority of the sex-chromosomal aneuploidies are constituted by XXY, XYY, XXX and XO genotypes (and mosaics). Of these, while the XYY genotype can arise only through second division paternal non-disjunction, the others can arise as a result of either first or second division non-disjunction in either the father or the mother. There is evidence showing that in about 80% of XO (Turner's syndrome) individuals, the single remaining X is of maternal origin suggesting loss of the paternal-X. The frequency of sex-chromosomal aneuploidies in children born to survivors of the Hiroshima and Nagasaki bombings is higher than in controls, but the difference is not significant. Down's syndrome, which is one of the relatively better known autosomal aneuploidies in man, is due to trisomy for chromosome 21, translocation of chromosome 21 with another autosome (usually chromosome 14) or mosaicism for an extra chromosome 21. Trisomy 21 which accounts for 95% of the cases, is due to non-disjunction during gametogenesis in one of the parents, more often in the mother. With quinacrine fluorescent techniques, evidence has been obtained which shows that non-disjunction can occur either in the father or in the mother at first or second meiotic division. The incidence of primary trisomies for chromosome 21 shows a strong correlation with increasing maternal age and this is very extensively documented (gradual increase in risk from maternal age about 20 to 30–31 and a steeper increase thereafter). The data on the association between an increase in paternal age and Down's syndrome are conflicting although some data suggest that the risk may be high for fathers above 55 years of age. Satellite associations between acrocentric chromosomes have been observed in metaphase preparations of chromosomes of lymphocytes, but the questions of whether there are preferential associations between certain chromosomes, and if so, what their relevance is for trisomy, are not yet settled. Consequently it may be premature to extrapolate the findings in somatic cells to germ cells and to the possible origin of trisomies, including that of trisomy 21. The results of 9 retrospective and 3 prospective studies designed to examine whether parental irradiation may increase the risk of producing Down's syndrome have been published. The available evidence does suggest that there is no correlation between paternal radiation and Down's syndrome in the progeny, but is conflicting on the question of correlation between maternal irradiation and Down's syndrome. Thus, after nearly two decades of work on this aspect, no unequivocal answers are available. Both trisomy 18 (Edward's syndrome) and trisomy 13 (Patau's syndrome) are associated with severe phenotypic effects; the incidence rates are about one on 10 000 and one in 15 000 births, respectively. These trisomies are not compatible with survival to adulthood. Other, relatively rare trisomies include those for chromosomes 8 and 22. In Fig. 1 is presented a broad summary of the frequencies of different chromosomal anomalies and thier effects, relating these to one million conceptions (under the assumption that 15% of all conceptions are spontaneously aborted and 2% of the children die perinatally and making use of the different frequencies cited in the text with respect to the kinds of anomalies). The technique of fusion of human spermatozoa with golden hamster eggs, the details of which were published recently, appears to be a promising one since, this permits a direct analysis of the chromosome constitution of human spermatozoa and hopefully, studies on the effects of physical and chemical agents at a level that has hitherto been impossible.

This paper reports the results of a study on the effects of the phenolic antioxidant butylated hydroxytoluene (BHT) on the sensitivity of Drosophila germ cells to the X-ray and chemical induction of genetic damage. Prior to irradiation or chemical treatment, the flies were raised in normal, BHT-containing or dimethyl sulphoxide (DMSO)-containing media. In one series of X-ray experiments, male pupae raised in these different media were irradiated. The concentration of BHT in the medium was 0.05% (in 0.5% DMSO) and that of DMSO, 0.5%. In the X-ray experiments, the frequencies of sex-linked recessive lethals and of autosomal translocations in spermatids of males raised in the BHT-containing medium were significantly lower than in those of males raised in the other two media. If however, the spermatids in pupae were irradiated, the amounts of genetic damage in the three groups of males were nearly the same. Likewise, no significant protective effects attributable to BHT treatment could be demonstrated with respect to the induction of dominant lethals in mature spermatozoa, stage-7 and stage-14 oocytes or of autosomal recessive lethals and sex-chromosome losses in stage-7 oocytes. In the dominant lethal experiments with mature spermatozoa and stage-7 oocytes, the yields were generally higher in males of the DMSO group than in the other two, pointing to a radiosensitizing effect of DMSO. In the ‘maternal effect’ experiments (males raised in a normal medium irradiated and mated to females raised in normal, DMSO-containing or BHT-containing media), the frequencies of dominant lethals in spermatozoa were similar in all the three groups, suggesting no DMSO- or BHT-mediated maternal effects. With both chemicals tested (diepoxybutane and diethylnitrosamine), significantly lower yields of sex-linked recessive lethals were recovered in spermatids of males raised in the BHT-containing medium than in those of males raised in the other two media. In some of these experiments, this protective effect of BHT was measurable in more advanced stages of spermatogenesis as well. These results have been interpreted taking into account the radical-scavenging, enzyme-inducing and enzyme-inhibiting properties of BHT.

The sensitivity of male germ cells of ebony (UV and X-ray sensitive) and Canton-S (wild-type) flies to the induction of sex-linked recessive lethals by 3 direct-acting mutagens (methyl methanesulphonate (MMS), N-ethyl-N-nitrosourea (ENU) and 1,2:3,4-diepoxybutane (DEB) and 2 chemicals that require metabolic activation (N-nitrosodiethylamine (DEN) and 1-(2,4,6-trichlorophenyl)-3-3-dimethyltriazene (2,4,6-CI3-PDMT) was investigated. In addition, experiments were carried out to examine whether mutational lesions induced by MMS, ENU and DEN in mature spermatozoa of males were processed differently by the oocytes of ebony and Canton-S flies (maternal effect studies). With all 3 direct-acting mutagens, the mutational responses of the post-meiotic male germ cells of the ebony and Canton-S flies were similar. After DEN treatment however, the ebony males responded with significantly lower frequencies of sex-linked recessive lethals in their pre- and post-meiotic germ cells. Measurements of microsomal P-450 enzymes revealed no detectable differences between the 2 strains with respect to either total cytochrome P-450 content or benzo[a]pyrene hydroxylation activity; the p-nitroanisole demethylation activity however, was lower in the ebony than in Canton-S flies. With 2,4,6-C13-PDMT, the spermatids of ebony males responded with higher frequencies of recessive lethals than those of Canton-S males. The maternal effect studies provided no evidence for any differential processing of mutational lesions in the Canton-S and ebony females. The contrasting responses observed with DEN and 2,4,6-C13-PDMT have been explained on the basis of the assumption that in the ebony flies, there is an increased bioactivation of the triazene and a less efficient activation of DEN to their respective mutagenic metabolites, relative to the situation obtained in the Canton-S flies.

The effect of treatment of thyrotoxicosis with drugs, radioactive iodine, or surgery in different age groups is reviewed. In Graves' disease and toxic multinodular goitre the remission rate is about 40-50% after antithyroid drugs, but these drugs have little effect in toxic adenoma. Hypothyroidism developed in 35-49% of patients who had had thyroidectomy, and the risks of operation are high. The risk of malignant disease and genetic abnormalities was not significantly greater after treatment with radioactive iodine in any age group. In general, treatment with radioactive iodine should have priority over thyroidectomy at all ages.

The arm number hypothesis proposed by Brewen and colleagues in 1973 has been examined in the light of information thus far available from mammalian studies. In experiments with peripheral blood lymphocytes (radiation in vitro), a linear relationship between dicentric yield and the effective chromosome arm number of the species was obtained in the mouse, Chinese hamster, goat, sheep, pig, wallaby and man. However, the data are not consistent with such a relationship in several primate species (marmoset, rhesus monkey, cynomolgus monkey, squirrel monkey and the slow loris), the cat and the dog. In the rabbit, the data are conflicting. In the mouse and Chinese hamster the frequencies of reciprocal translocations recorded in spermatocytes descended from irradiated spermatogonia are in line with the expectation based on the arm number hupothesis, whereas in the golden hamster, rabbit and the rhesus monkey they are not. In man and the marmoset, the limited data are not inconsistent with a 2-fold higher sensitivity of these species relative to the mouse although they do not rule out a difference as high as 4-fold. In the guinea-pig, the situation is unclear. New data on the transmission of reciprocal translocations in mice suggest that the frequency in the F 1 progeny may be close to one-quarter of that recorded in the spermatocytes of the irradiated fathers (spermatogonial irradiation) at an exposure level of 150 R, whereas at higher exposures, the reduction factor is about one-eighth, the latter being in line with the earlier finding. All these results taken together suggest that inter-specific extrapolation from the radiosensitivity of somatic cells (to dicentric induction) to that of germ cells (to translocation induction) is fraught with uncertainty at present. Certain aspects that need to be studied in more detail in the context of induced chromosome aberrations are discussed.

The principal aspects of the 'doubling-dose method' currently used by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) and the Committee on the Biological Effects of Ionizing Radiation (BEIR) of the U.S. National Academy of Sciences, for the evaluation of genetic radiation hazards in man are briefly reviewed. With this method, which is primarily applicable to autosomal dominant and X-linked disorders, the expected increase in risk from radiation is expressed as a fraction of the current prevalence of these disorders, and thus in relation to an understandable frame of reference. Since the doubling dose is estimated as a ratio of spontaneous to induction rates of mutations, its magnitude is susceptible to changes in either the numerator (spontaneous rate) or the denominator (induction rate). Studies during the past 20 years or so with a number of experimental systems have demonstrated the existence of mobile DNA sequences in the genome and their causal role in the origin of spontaneous mutations, although the proportion of the latter among all spontaneous mutations is not known for any species. If a major proportion of spontaneous mutations in man is mediated by these mobile DNA sequences, and if their mobility is unaltered by radiation exposures, the calculation of the doubling dose in the manner mentioned above, and its use in risk evaluations becomes questionable. However, considerations based on the organization of the human genome would suggest that it is unlikely that a major fraction of spontaneous mutations that lead to disease states in man is due to mobile genetic elements. Consequently, the use of the doubling-dose method for the evaluation of genetic radiation hazards in man would appear to be valid at the present time.

The effects of sodium butyrate-mediated alterations in chromatin structure on the yields of X-ray-induced chromosomal aberrations were studied in human peripheral blood lymphocytes. Unstimulated (G 0 ) lymphocytes were pre-treated with sodium butyrate (5 mM) for 24 h, X-irradiated and then stimulated to pass through the cell cycle. Cells in their first post-radiation metaphase were scored for chromosomal aberrations. In parallel biochemical experiments nucleoid sedimentation technique was used to examine the induction and repair of DNA-strand breaks. The results show that sodium butyrate pre-treatment leads to a significant increase in the frequencies of dicentrics and rings, but not of fragments. The data from biochemical studies suggest that the numbers and rates of repair of X-ray-induced DNA-strand breaks are the same in butyrate-treated and untreated cells. We therefore suggest that the observed effect is probably a consequence of butyrate-induced conformational changes in the chromatin of G 0 lymphocytes.

Wild-type (Oregon-K) Drosophila melanogaster males were X-irradiated and mated to Oster females (y scs1 In49sc8; bw; st pp) that had received a 20 R X-ray exposure (Group MF) or no irradiation (group M). Mature spermatozoa of the irradiated males were sampled and the frequencies of dominant lethals, sex-linked recessive lethals and 2–3 translocations were measured. In the group in which the irradiated males were mated to irradiated females, the survival of eggs was significantly higher than in the group in which only the males were irradiated. However, there was no consistent and detectable difference between the two groups with respect to the frequencies of recessive lethals and translocations. The relatively higher egg survival in the MF group is amenable to an interpretation based on an inducible repair process in females that acts on radiation damage induced in spermatozoa but, such an explanation is inadequate to explain the other results. It is concluded that the observations considered together preclude a general and unifying interpretation based on a low-dose-X-ray-inducible genetic repair process in females (acting on damage in spermatozoa). Possible reasons for the discrepancy between the expectation of differences in response between the MF and M groups (in sex-linked lethal and translocation frequencies) and the observation of no consistent differences between them are discussed.

Young (0—4-h-old) Drosophila melanogaster females were X-irradiated with single or fractioned exposured over a range up to 6000 R and the induction of dominant lethals in immatuer (stage-7) oocytes was studied. The results show that (i) the frequencies of dominant lethals are higher after single than after fractionated exposures; (ii) at any given exposure level, the higher the number of fractions, the lower is the frequency of dominant lethals; (iii) conserquently, the reduction in dominant lethality relative to single exposures increases with increasing number of fractions; and (iv) this relative reduction in dominant lethality approaches a maximum value when the magnitude of the single X-ray exposure approaches zero (i.e., when tha egg survival after single X-ray exposure approaches 100%); the maximum, however, are different for the different fractionation regimes, being higher with increasing number of fractions. These findings are consistent with the assumed kinetics of X-ray induction of dominant lethality in stage-7 oocytes. It is shown that it is possible to predict the expected relative reduction in dominant lethality after fractionation, from appropriate dominant lethal data from single unfractioned exposures.

Yegorova and colleagues (1978) showed that a mutant strain of Drosophila melanogaster (ebony) was more sensitive to UV-induced killing of embryos and also less proficient in photoreactivating (PR) ability than a wild-type (Canton-S) strain and that the genes governing UV sensitivity and PR ability were different and presumably located on the autosomes. The experiments reported in the present paper were designed to compare the patterns of sensitivity of these 2 strains and their hybrids to X-irradiation. The sensitivity of the larvae to the killing effects of X-irradiation, and of male and female germ-cell stages to the X-ray induction of genetic damage was studied. It was found that the larvae of the ebony strain are more sensitive to X-ray-induced killing than those of the Canton-S strain. The frequencies of radiation-induced dominant lethals and sex-linked recessive lethals are higher in spermatozoa sampled from ebony males than in those of Canton-S males. In spermatozoa sampled from hybrid males, the yields of dominant lethals are no higher than in those sampled from Canton-S males and do not seem to depend on the origin of the X-chromosome. There are no statistically significant differences between the ebony and Canton-S strains in the sensitivity of their spermatozoa to the induction of autosomal translocations. Stage-7 oocytes sampled from ebony females are more sensitive to the X-ray induction of dominant lethality than are those from Canton-S females; oocytes sampled from hybrid females manifest a level of sensitivity that is significantly lower than that in either parental strain. The frequencies of X-chromosome losses induced in in this germ-cell stage are significantly lower in ebony than in Canton-S females at least at the exposure level of 3000 R at which 3 experiments were carried out. There are no measurable differences in the amount of dominant lethality induced in stage-14 oocytes of ebony, Canton-S and hybrid females. When X-irradiated Berlin-K males are mated to ebony or Canton-S females, the yields of dominant lethals are higher when ebony females are used, showing that there is a “maternal effect” for this kind of damage. Such a maternal effect is also found for sex-linked recessive lethals (irradiated Muller-5 males mated to ebony or Canton-S females). However, when irradiated ring-X-chromosome-carrying males are mated to ebony or Canton-S females, the frequencies of paternal sex-chromosome losses (scored as XO males) are lower when ebony females are used. These results have been interpreted on the assumption that the ebony strain is homozygous for recessive, autosomal genes that confer increased radiosensitivity and that the Canton-S strain carries the normal, wild-type alleles for these genes. The higher yields of dominant and recessive lethals in mature spermatozoa and of dominant lethals in stage-7 oocytes are a consequence of an enhanced sensitivity to the mutagenic (in particular, to the chromosome-breaking) effects of X-irradiation and/or of defective repair of radiation-induced genetic damage. The lower yield of XO males from irradiated stage-7 oocytes of ebony females is probably a consequence of a defect in the repair of chromosome-breakage effects, resulting in the conversion of potential X losses in females into dominant lethals. The “maternal effects” for dominant lethals, sex-linked recessive lethals and for the loss of ring-X chromosomes are assumed to have a common causal basis, namely, a defective repair of chromosome-breakage events in the females of the ebony strain.

The evaluation of genetic radiation hazards in man is an ongoing scientific enterprise from about the mid-1950s. Since estimates of genetic risks are essential for providing a basis for protecting our genetical endowment and since strictly relevant human data are limited, there is no alternative at present but to use the data from mouse and certain non-human primates. This paper reviews the general principles and methods that have thus far been used, appraises the evolution of the conceptual framework, the data base and the assumptions involved, presents current estimates of genetic risks and provides some perspective of the advances that are likely to be made in the near future.

This paper presents epidemiological data on the prevalence of 26 common (i.e., having a lifetime prevalence of more than 1 per 10(4) individuals in the population) multifactorial diseases in Hungary and estimates of detriment associated with them. The detriment is expressed using 3 indicators, namely years of lost life (LL), potentially impaired life (PIL) and actually impaired life (AIL). The total prevalence of these diseases in Hungary has been estimated to be about 6500 per 10(4) individuals in the population. This estimate is in agreement with published data for other parts of the world. On the basis of clinical severity, these diseases have been split into 3 groups, namely (1) very severe (schizophrenia, multiple sclerosis, epilepsy, acute myocardial infarction and related conditions, and systemic lupus erythematosus); (2) moderately severe and/or episodal or seasonal (15 entities including Graves' disease, diabetes mellitus, gout, affective psychoses, essential hypertension, peptic ulcers, asthma, etc.); and (3) less severe than those in the first 2 groups (varicose veins, allergic rhinitis, atopic dermatitis, Scheuermann disease and adolescent idiopathic scoliosis). The essential clinical and genetic aspects of these diseases are briefly discussed. With the exception of epilepsy, none of the diseases included in our list causes mortality between ages 0 and 19. However, they are among the leading causes of death between ages 20 and 69 and thereafter. A sizeable proportion of those with essential hypertension, diabetes mellitus, rheumatoid arthritis, etc. survive to 70 years and beyond, as do those with gout, glaucoma, allergic rhinitis, psoriasis, etc. Overall, about 16% of all deaths that occur in Hungary every year (all age groups) can be attributed to these diseases. The mean number of years of PIL covers a wide range (about 20-40, 12-70 and 40-60 for groups 1, 2 and 3, respectively), the overall mean being about 24 years. However, the nature and degree of impairment and the impact on the life quality of those afflicted differ for the different diseases. Likewise, the mean number of years of AIL (for which the interval between the mean age at premature retirement and mean age at death was used as a rough index) also spans a wide range from 16 to 45, and the overall mean is about 20 years. At the population level, the diseases considered in this paper cause about 2700 years of LL, 96,000 years of PIL and about 5800 years of AIL per 10(4) individuals in the population. Relative to Mendelian diseases as a whole, these multifactorial diseases are associated with much greater detriment (LL: 1.4 X; PIL: 30 X and AIL: 3.9 X).

The effects of administering X-irradiation at high versus low exposure-rates and as single versus fractionated exposures (total exposure split into two equal fractions separated by various time intervals) on genetic damage induced in immature oocytes of Drosophila were investigated. The results show that in stage 7 oocytes, the frequencies of recessive lethals are the same irrespective of the mode of irradiation; in stages immediately preceding stage 7, there is some suggestive evidence for a lowering of the frequencies at low exposure rates. The frequencies of dominant lethals induced in stage 7 oocytes are markedly reduced after low intensity radiation as well as after fractionation of the exposure; while with the former regime the frequencies continue to decrease up to 60 min (the longest duration employed), with the latter regime the maximal reduction in frequency is obtained when the interval between the exposure fractions is 10–20 min. Increasing the interval to more than 20 min does not lead to any further measurable reduction in the frequency.

A series of X-irradiation experiments was carried out using Drosophila melanogaster females homozygous for a third chromosome mutator gene and females which had a similar genetic background except that the mutator-bearing third chromosomes were substituted by normal wild-type chromosomes. The mutator females had been previously shown by Gold and Green to manifest a higher level of radiation-induced mutability (as measured by the X-ray-induction of sex-linked recessive lethals) in their pre-meiotic germ cells compared to normal females at an exposure of 100 R. In the present work, the sensitivity of the pre-meiotic germ cells of mutator and normal females to the X-ray induction (2000 R) of sex-linked recessive lethals was studied. In addition, experiments were conducted to examine the sensitivity of the immature (stage 7; prophase I of meiosis) oocytes of both kinds of females to the induction of dominant lethals, X-linked recessive lethals and X-chromosome losses. The results show that in pre-meiotic germ cells, the frequencies of radiation-induced recessive lethals are similar in both kinds of females. However, the proportion of these mutations that occur in clusters of size 3 and higher, is higher in mutator than in normal females. In stage-7 oocytes, the frequencies of radiation-induced dominant lethals and sex-linked recessive lethals were similar in both kinds of females. The X-loss frequencies however, were consistently higher in mutator females although statistical significance was obtained only at higher exposures (3000 and 3750 R) and not at lower ones (750–2250 R). Possible reasons for the discrepancy between the present results and those of Gold and Green with respect to pre-meiotic germ cells are discussed.

The response of mature spermatozoa to the X-ray induction (500 R and 3000 R) of sex-linked recessive lethals was studied in Drosophila melanogaster males known to be deficient in excision- or post-replication repair of UV damage in somatic cells. The results show that the induced frequencies of recessive lethals in the excision-repair-deficient males (mei-9a and mei-9L1) are similar to those in the appropriate repair-proficient males (mei+ and Berlin-K). However, in the post-replication-repair-deficient males (w mus(1)101D1), these frequencies are significantly lower than in the comparable repair-proficient males (w) after 500 R, but not after 3000 R.

The X-ray induction of recessive visible specific locus mutations at 14 X-chromosome loci was studied in Drosophila melanogaster using the “Maxy” technique. The X-ray exposure was 3000 R to 5-day-old males and the sampling of germ cells was restricted to mature spermatozoa. Presumptive mutant females recovered in the F1 generation were tested for transmission, allelism, fertility and viability in males. A total of 128 mutations (115 completes and 13 mosaics including those that were male-viable as well as male-lethal) recovered among 38 898 female progeny were found to be transmitted. On the basis of the above frequency, the average mutation rate can be estimated as 7.8 × 10−8/locus/R; for mutations that were viable and fertile in males, the rate is 3.0 × 10−8/locus/R (49 mutations among 38 898 progeny). The frequency of mutations at the different loci encompassed a wide range: while no mutations were recovered at the raspberry and carnation loci, at others, the numbers ranged from 1 at echinus to 31 at garnet; in addition, the proportion of mutations that was male-viable was also different, depending on the locus. Schalet's extensive data on spontaneous mutations at 13 (of the 14 loci employed in the present study) loci permit an estimate of the spontaneous rate which is 6.1 × 10−6/locus (a total of 39 mutations among 490 000 progeny); for mutations that were viable and fertile in males, the rate is 3.0 × 10−6/locus (19 mutations among 490 000 progeny). The mutability of the different loci varied over a 9-fold range. When the different loci are ranked depending on their relative mutability (for spontaneous and induced mutations) it is found that in general, loci that mutate spontaneously relatively more frequently are also those at which more mutations have been recovered in the radiation experiments and likewise, those that are less mutable spontaneously are also those that mutate less after irradiation. Since the data are limited, it is concluded that the above finding is not inconsistent with the assumption of proportionality between spontaneous and induction rates of mutations. On the basis of the above results, a doubling dose of 100 R can be calculated for the X-ray induction of specific-locus mutations in Drosophila spermatozoa.

Drosophila females were injected with Actinomycin-D. After a day they were mated (for 24 h only) to males that had been exposed to 2000 or 2500 R X-irradiation, so that only mature spermatozoa were sampled. The radiation-induced frequencies of dominant lethals, II–III translocations and recessive sex-linked lethals in the paternal genome were determined. When compared to the appropriate controls, it is found that such treatment of the females with Actinomycin leads to an inrease of the frequency of dominant lethals and to a decrease of those of translocations and recessive lethals. Characteristic is the delayed expression of the Actinomycin effect, in that the modification of translocation and recessive lethal frequencies is most pronounced in oocyte stages utilized 4–6 days after injection. The present findings are interpreted to mean that Actinomycin acts by partially inhibiting the restitution of chromosome breaks, thereby increasing the frequency of dominant lethals, and decreasing that translocations and recessive lethals. This implies that maternal repair processes acting at the stage of pronucleus formation are required for the repair (restitution) or misrepair (reunion giving rise to translocations) of chromosome breaks induce mature spermatozoa.

Current estimates of the genetic hazards arising from the exposure of human populations to radiation are to a large extent, based on the results obtained with experimental organisms, especially laboratory mammals. During the past few years there has been substantial progress in the field of mammalian radiation genetics; some of the findings have confirmed and extended earlier ones while others have exposed new and interesting facets of the radiation response of the mammals. The present review is devoted to an examination of some of the recent results from the standpoint of their applicability to the problem of genetic risk estimates in man.

Tumor growth inhibition and a decreased mitotic index was evident following treatment with 5-FU or its ribosides, FUR and FUDR; as well as hydrocortisone treatment. Little or no changes were observed histochemically for DNA, histone or total protein after treatment with hydrocortisone. 5-FU treatment, in contrast to this, produced unbalanced growth with changes in the ratio of DNA to histone and protein per cell, since histone and protein were found increased in relation to DNA. Autoradiographic studies support these histochemical findings. The relative amounts of protein-bound sulf-hydryl groups in 5-fluorouracil treated tumor cells was decreased, while the disulfide groups were increased.

The induction of dominant lethals in Drosophila melanogaster males with a ring-X chromosome was studied following irradiation with 4000 R under anoxia with nitrogen and oxygen post-treatments. The post-radiation treatment with these gases varied from 25 min to 120 min. The frequencies of induced dominant lethals were found to be in the range of 67% to 73% in the different experiments with no significant differences resulting from the contrasting post-treatments. These frequencies increased linearly in the successive egg-collecting periods, the trend being independent of the different post-treatments. Following prolonged nitrogen treatments, a sharp increase in the proportion of unhatched eggs was noticed. Examination of the ventral receptacles and spermathecae of females inseminated by nitrogen-treated males revealed that with nitrogen treatment (1) there occurred a drastic reduction in the number of spermatozoa stored, the magnitude of reduction being dependent on the length of nitrogen treatment and (2) there was a decrease with time in the number of spermatozoa remaining in the storage organs, with the effect being pronounced with 96 and 120 h of storage following insemination. These findings are discussed in relation to physiological damage to the treated sperm and sperm exhaustion.

Mature (stage-14) oocytes of Drosophila melanogaster were exposed to different levels of X-irradiation in nitrogen, oxygen or air. Exposures in the first two gases were followed by post-treatments with either nitrogen or oxygen while those in air were followed by nitrogen or air post-treatments. Egg-survival was used as a criterion to study the effects of such treatment combinations. It was found that ( 1 ) the dose-effect relationship observed was consistent with a one-hit survival kinetics, ( 2 ) with post-irradiation anoxia, there was a significant reduction in survival, and ( 3 ) this effect of anoxia could be reproduced even if the flies were post-treated with oxygen for the first 45 min following irradiation, and then with nitrogen for the next 45 min. The available data also support the conclusion that the stage-14 oocytes have more oxygen available than stage-7 cells under normal conditions in air. It is suggested that this differential oxygenation in air between the two germ-cell stages may constitute one of the several factors which contributes to the higher radiosensitivity of the stage-14 cells relative to the stage-7 cells. The Oxygen-Enhancement-Ratio for the stage-14 oocytes has been estimated to be between 3.52 and 3.85, which is much higher than 2.53–2.65 for the stage-7 oocytes.

Mutagenicity test systems play a dual role in public health: (1) to identify chemicals in our environment that are capable of causing genetic alterations and thus pose a threat of genetic damage to generations yet unborn and (2) as a faster screen (than many of the conventional carcinogenicity tests) to identify chemicals with carcinogenic potentials. In this paper the different mutagenicity test systems currently available are reviewed together with a discussion of their advantages and disadvantages. It is argued that our current data base does not permit a realistic quantitative assessment of genetic hazards ensuing from exposure to environmental chemicals and that only qualitative conclusions are possible. A framework which may be useful in the context of the latter is briefly outlined.

Publisher Summary This chapter discusses the sources and magnitude of radiation exposures sustained by the human populations; the assumptions, methods, and data actually used in estimating the amount of transmissible genetic damage likely to result from radiation exposures; their effects in term of increased load of genetic and partially genetic disorders; and their impact on health and well-being in man. It discusses the problems that one faces in attempting to make such estimates for mutagenic chemicals and how these are likely to be handled in the years to come. Ionizing radiation is a proven mutagen: It is known to produce mutations and chromosomal aberrations, the principal genetic changes that underlie cancer and genetic disease in man. The patterns and levels of radiation exposure experienced by human populations are reasonably well known, and there are established methods to assess absorbed doses in the target organ or the tissues of interest. The physical properties of radiation provide a firm basis for comparing the biological effects of different kinds of radiation, for predicting the effects expected of one kind of radiation from another, and for reliably combining the effects of different types of radiation.

The influence of the maternal genotype ( Canton-S , proficient in the repair of X-ray-induced chromosome breaks and ebony , less proficient in this regard) on the recovery of X-ray-induced autosomal (II–III) translocations and ring-X chromosome losses in mature spermatozoa was studied. In the first series of experiments, males carrying appropriate markers on their second and third chromosomes were irradiated and mated to Canton-S or ebony females and the frequencies of II–III translocations were determined. In the second series of experiments, males carrying ring-X chromosomes were irradiated in N 2 or in O 2 , mated to Canton-S or ebony females and the frequencies of XO males were determined; additionally, under similar gas-treatment and radiation conditions, the pattern of egg-mortality was also assessed. The data on translocations show that the yields are higher with ebony than with Canton-S females; these and earlier results on dominant lethals and sex-linked recessive lethals support the interpretation that the maternal repair system in the ebony strain is less proficient and more error-prone than that of the Canton-S strain. Those on the losses of ring-X chromosomes demonstrate that (i) the absolute yields of XO males are lower with ebony than with Canton-S females irrespective of whether the parental males are irradiated in N 2 or in O 2 ; (ii) the exposure-frequency relationships are all linear, but the slopes are higher when the males are irradiated in O 2 and are consistent with an oxygen-enhancement-ratio of about 1.5 and (iii) the relationships between the logarithm of egg-survival and XO male frequency are also linear, but the slopes for the O 2 groups are lower than those for the N 2 groups (slope ratios of 0.86–0.87). The finding that at given survival levels, the XO frequencies are lower in the O 2 than in the N 2 groups of both the Canton-S and ebony series viewed in the context of the mechanisms that have been postulated to explain the loss of ring-X chromosomes in irradiated mature spermatozoa permits the following interpretation for the observed results: (i) a higher proportion of potential XO zygotes is lost through dominant lethality in the O 2 groups than in the N 2 ones presumably because the chromosome breaks induced in O 2 are qualitatively different in the sense that they have higher probability to undergo reunions relative to restitution, compared with breaks induced under anoxia and (ii) this leads to lower than expected oxygen-enhancement ratios (i.e., expected on the basis of published data on sex-linked recessive lethals, another kind of genetic damage which shows a linear exposure-frequency relationship).

This paper represents an attempt to estimate quantitatively, the detriment associated with spontaneously arising congenital anomalies in man. The system used in the International Classification of Diseases (Chapter XIV, entries 740–759) has been followed to classify the congenital anomalies. Detriment was assessed using estimates of the years of life lost, years of life potentially impaired and years of life actually impaired, as indicators. The data on birth prevalences for the various conditions were derived from several epidemiological surveys carried out in Hungary and from the Hungarian Congenital Malformation Registry. Most of the information on mortality profiles was obtained from the records of the Hungarian Central Statistical Office, Budapest. An overall comparison of the prevalence figures in Hungary with those for the U.S. (this study aimed at complete ascertainment) and for the Canadian province of British Columbia (in this study, ascertainment is believed to be incomplete) showed that, in Hungary, at least certain classes of congenital anomalies, particularly some of the less severe ones, have been under-ascertained. Since detriment estimates are heavily dependent on accurate estimates of birth prevalences, we believe that the estimates of detriment arrived at using the Hungarian data may also be underestimates. In Hungary, the total birth prevalence of all isolated major congenital anomalies is of the order of about 600/104. Our calculations show that these congenital anomalies may cause, per 104 livebirths, about 4800 years of life loss, about 37 000 years of potentially impaired life and about 4500 years of actually impaired life. In these calculations, it has been assumed that the average life-expectancy at live birth for the general population is 70 years. These estimates are considerably higher than those made by Carter for detriment associated with spontaneously arising monogenic disorders.

Ionizing radiation from natural sources has always been part of the human environment, and that from artifical (man-made) sources, since the beginning of the twentieth century. The fact that exposure to ionizing radiation—irrespective of whether it is from external sources or from internally deposited radionuclides— increases the risk of incurring adverse health effects was dramatically brought to the attention of the public by the atomic bombing of Hiroshima and Nagasaki in 1945. Since then, considerable attention has been paid over the years to the levels and effects of radiation.