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The frequency of reciprocal translocations (RT) induced by single injection of tritiated water (THO) (3.3; 6.3 and 12.6 MBq/g) or by referent 137Cs gamma irradiation was studied. The absorbed doses in testis were: 1; 2 and 4 Gr. The frequency of RT per 100 cells were 0.4; 1.1 and 2.5 after THO administration, and 0,5; 0.9 and 1.2 after single exposure to gamma irradiation, respectively. The RBE of tritium increased from 1 at the dose of 1 Gr to 2, at the dose of 4 Gr.

Male C3H mice were exposed to 100 W m-2 of 2.45 GHz continuous-wave microwave radiation for 6 h per day for a total of 120 h over an 8-week period. The exposure level was chosen so that the specific energy absorption rate (SAR) would be approximately equal to the level of 4 W kg-1 which is considered by a number of organizations to be a threshold for adverse biological effects. At the end of the treatment period the mice were mated with a different group of (C3H x 101) F1 hybrid females each week for the following 8 weeks. There was no significant reduction in pregnancy rate, preimplantation survival or postimplantation survival in the exposed group compared to sham-exposed controls. At the end of the mating period a cytogenetic analysis was carried out of meiotic chromosome preparations of testicular tissue, thus sampling cells that were stem cell spermatogonia during the treatment regime. The results showed no difference in the frequency of reciprocal translocations between the sham and treated groups, or in the frequency of cells with autosome or sex chromosome univalents. Low levels of fragments and exchanges were found in both groups. It is concluded that there is no evidence in this experiment to show that chronic exposure of male mice to 2.45 GHz microwave radiation induces a mutagenic response in male germ cells. This conclusion is in agreement with the observations of Berman et al. (1980), who reported a lack of male germ cell mutagenesis after repetitive or chronic exposure of rats to 2.45 GHz.

The effect of material repair on induction of paternal mutations was tested with radiosensitive rad(2)201G1 mutant. Basc males were irradiated at doses from 0 to 60 Gy of gamma-rays and mated to the radiosensitive mutant or control females. Frequencies of sex-linked recessive lethals and dominant lethals (induced in the paternal genome) were determined. With control females, the rate of recessive lethals increased linearly from 0 to 60 Gy. With rad(2)201G1 mutant, an increase in spontaneous and induced rates of paternal dominant lethals was observed; the rate of sex-linked recessive lethals increased non-linearly from 0 to 60 Gy.

A total X-ray dose of 50 Gy was applied to the nematode Panagrellus redivivus using dose-rates ranging from 0.23 Gy/min to 10.49 Gy/min, and the frequency of lethal X-chromosomes was determined. This frequency ranged from approximately 1.6% at the lower dose-rate to 4.3% at the highest dose-rate, indicating a dose-rate dependency of mutation frequency in the spermatogonia and oogonia of this organism.

The genetic effect of incorporated radiocarbon was studied after single, long-term (33 days) and chronic (6 and 12 months) treatment of male mice (CBA X C57B1) F1 with [14C]glucose. The genetic effect in male germ cells was estimated by 3 tests: DLM frequency in post- and pre-meiotic cells, RT frequency in stem spermatogonia and frequency of abnormal sperm heads. Absorbed doses in the gonads were: 0.22, 0.50 and 1.01 Gy, after a single exposure; 0.74 and 1.47 Gy, after long-term exposures; and 0.006 and 0.031 Gy, after chronic exposure for 6 months; and 0.013 and 0.066 Gy, for 12 months. The results suggest that DLM frequency in post-meiotic cells increased linearly with increasing the dose of 14C single and long-term exposures at a dose of 1.47 Gy only. A chronic treatment with [14C]glucose induced no increase in DLM frequency. RT frequency in stem spermatogonia was statistically significantly higher than the control level after the single and long-term exposure to 14C. A comparison of the results with the results of external single and chronic gamma-irradiation allows the conclusion that the relative genetic efficiency of radiocarbon as compared with that of gamma-rays is about 1.

Adult male rats were given 1300 rad of chronic gamma-irradiation (0.08 rad/min) Dominant lethal rates were found to be high (ranging from 48 to 75%) in irradiated postmeiotic cells and clearly lower (6.8%) in spermatogonia. The chromosome aberration (reciprocal translocation) yields observed with 1300 rad chronic irradiation were comparatively low, averaging 1.6%. Spermatogonia irradiation at low dose rate resulted in a smaller effect as compared to the genetic effects of a single acute exposure.

Male mice were given mechlorethamine (2.0 mg/kg) followed immediately or 1, 2, 4, or 8 h later by procarbazine (100 mg/kg) and vincristine (0.67 mg/kg) in a protocol that stimulated the drugs and dosages used in a single cycle of clinical MOPP therapy. Seven weeks later and continuing for the next five weeks, the mice were mated to females and the dominant lethal mutant frequencies determined in their offspring by an in vitro assay. Significant (Student's t-test, p less than 0.05) mutant frequencies were detected when the interval between drug administration was between 2 and 8 h. In another series of experiments, mice were injected with these drugs using a 4-h interval between mechlorethamine and the vincristine and procarbazine (MOPP), two cycles of MOPP separated by one week, one cycle of MOPP and 2.0 Gy x-radiation separated by one week, or 2.0 Gy x-radiation alone. When each group was assayed for its dominant lethal mutant frequency, all were found to have similar, highly significant (0.001 less than p less than 0.005) induction. Together these data suggest that stable mutagenic lesions are induced in spermatagonial stem cells by both x-radiation and chemotherapeutic drugs and the frequency with which they are produced can be approximated by a single treatment. Clinical strategies to minimize genetic effects should concentrate on the sequence and timing of drug administration on those days when the drugs are administered in combination.

The induction of congenital malformations among the offspring of male mice treated with X-rays at pre-meiotic and post-meiotic stages has been studied in two experiments. Firstly, animals were exposed to varying doses (108-504 cGy) of X-rays and mated at various time intervals (1-7, 8-14, 15-21 and 64-80 days post-irradiation), so as to sample spermatozoa, spermatids and spermatogonial stem cells. In the second experiment, only treated spermatogonial stem cells were sampled. One group of males was given a single 500-cGy dose, a second group a fractionated dose (500 + 500 cGy, 24 h apart) and a third group was left unexposed. In the first experiment, induced post-implantation dominant lethality increased with dose, and was highest in week 3, in line with the known greater radiosensitivity of the early spermatid stage. Preimplantation loss also increased with dose and was highest in week 3. There was no clear induction of either pre-implantation or post-implantation loss at spermatogonial stem cell stages. There was a clear induction of congenital malformations at post-meiotic stages, the overall incidence being 2.0 +/- 0.32% in the irradiated series and 0.24 +/- 0.17% among the controls. The induction was statistically significant at each dose. At the two highest doses the early spermatids (15-21 days) appeared more sensitive than spermatozoa, and at this stage the incidence of malformations increased with dose. The data from Expt. 1 on the induction of malformations by irradiation of spermatogonial stages were equivocal. In contrast, Expt. 2 showed a statistically significant induction of malformations at both dose levels (2.2 +/- 0.46% after 500 cGy and 3.1 +/- 0.57% after 500 + 500 cGy). The relative sensitivities of male stem cells, post-meiotic stages and mature oocytes to the induction of congenital malformations were reasonably similar to their sensitivities for specific-locus mutations, except that the expected enhancing effect of the fractionation regime used was not seen. Dwarfism and exencephaly were the two most commonly observed malformations in all series.

Frequency of dominant lethal mutation, occurrence of spermatozoa with abnormal heads, and changes in the testis mass were studied after the administration to mice of 238Pu in doses from 7 to 1850 Bq/g. The frequency of genetic lesions in the testis was not a function of alpha-radiation dose. The rate of the testis mass decrease was a linear function of the dose absorbed. RBE of 238Pu-alpha-radiation, as determined by the incidence of abnormal spermatozoa heads and by the changes in the testis mass, was from 14 to 35 with regard to the chronic effect of gamma-radiation.

The sensitivities of 8 R-factor plasmid pKM101-mediated E. coli strains with different DNA-repairing capacities to UV, AF-2 and MMS were investigated. The clear protective effect of pKM101 to lethal damage induced by these agents was only seen in the recA+ lexA+ and the uvr- lex- strains. The results support the hypothesis that the protective effect of pKM101 depends on the recA+ genotype. It is also possible to suggest that the product of pKM101 works not only on SOS repair which requires the recA and lexA gene functions but also on some unknown repair mechanisms.

The frequencies of spontaneous and UV-induced recessive lethal mutations were compared for UV-sensitive and wild-type heterokaryons of Neurospora crassa. These heterokaryons were homokaryotic either for one of two alleles of uvs-3, or for uvs-6 or uvs+. For uvs-3, which is known to have mutator effects, spontaneous recessive lethals were found to be 4-6 times more frequent than observed in uvs+. After correction for clonal distribution of spontaneous mutants, an observed 2-fold increase for uvs-6 was not statistically significant and may have been due to chance occurrence of a few large clones of mutants. Treatment with low doses of UV (50-200 J/m2) produced very similar overall rates of increase for recessive lethals in uvs and uvs+ heterokaryons. This means, that in contrast to results obtained when mutation to ad-3 was measured, both uvs-3 alleles showed highly significant increases for recessive lethals when treated with UV. It is proposed that certain types of UV damage may be processed into recessive lethal mutations by an alternate mechanism from that responsible for viable mutations.

Lethal and mutagenic effects of UV light were studied in two synchronized UV-sensitive Chinese hamster cell clones differing in the degree of sensitivity (CHS1, CHS2). It is shown that the phase of mitosis is most resistant to the lethal effect of UV. The sensitivity of both cell clones increases in the pre-synthetic phase and reaches its maximum during the phase of DNA synthesis. Positive correlation of cell sensitivity to mutagenic and lethal action of UV was observed when studying induced mutability in both cell clones during the phase of DNA synthesis. However, the study of the mutagenic effect of UV on different phases of the synthesis. However, the study of the mutagenic effect of UV on different phases of the cell cycle (M, G1, S) in the less UV-sensitive cell clone has revealed that the maximal mutation yield takes place when cells are irradiated at G1 (CHS1). The discrepancy observed may be due to different probability of the phenotypic detection of pre-mutational lesions, arising at different phases of the cell cycle. It is shown that only one cell generation is necessary for the expression of pre-mutational changes. These data allow to conclude that the increased mutation rate observed at G1 (as compared with S) reveals rather a probability of the expression but not of the occurrence of pre-mutational lesions. It is suggested that the fixation of mutations in the cells studied proceeds during the post-replication repair synthesis.

The stem germ cells of the prenatal pig are highly vulnerable to the cytotoxic effects of ionizing irradiation. This study was conducted to determine whether sensitivity to killing was also marked by a sensitivity to mutation and how prenatal depletion of the germ-cell population affects reproductive performance. Germ-cell populations were reduced by continuously irradiating sows at dose rates of either 0.25 or 1.0 rad/day for the first 108 days of gestation. The prenatally irradiated boars were tested for sperm-producing ability, sperm abnormalities, dominant lethality, reciprocal translocations, and fertility. Prenatally irradiated females were allowed to bear and nurture one litter, then tested for dominant lethality in a second litter; germ cell survival and follicular development were assessed in their serially sectioned ovaries. Sperm production was not significantly affected in the 0.25-rad boars, but boars irradiated with 1.0 rad per day produced sperm at only 17% of the control level. Incidence of defective sperm was 4.9% and 11.1% in the 0.25 and 1.0 groups, respectively. Four of the 1.0-rad boars were infertile, but prenatal irradiation apparently caused neither dominant lethality nor reciprocal translocations in fertile males. Number of oocytes was reduced to 66 +/- 7% of control in the 0.25-rad gilts, but reproductive performance was unaffected and no dominant lethality was observed. Only 7 +/- 1% of the oocytes survived in the 1.0-rad group. Reproductive performance was normal for the first litter, but four of the 23 sows tested were infertile at the second litter and a significant incidence of dominant lethality was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

When laying females or males of the small fish Oryzias latipes were irradiated with gamma-rays and then mated with a non-irradiated partner, the fertility and hatchability of the embryos were reduced as the doses increased. In respect to hatchability (the induction of dominant lethality), the male was more sensitive than the female, and mature sperm were most sensitive among the various stages of spermatogenetic cells. The dose-rate effects on the production of the dominant lethality were observed in spermatogonia and spermatocytes. The inbred strain of the fish, HB-1, was sensitive to gamma-rays. Since the relationship between dose and the decrease in hatchability was almost linear, at least within a limited range, we think that this system would be useful for monitoring mutagenic factors in an aquatic environment.

Adult male South African clawed frogs, Xenopus laevis, were mutagenized by 3-day immersion in aqueous solutions of ethyl methanesulfonate (EMS), diethyl nitrosamine (DEN), or ethyl nitrosourea (ENU), or by acute exposure to gamma radiation. They were then spawned repeatedly at 2-week intervals with untreated females, and embryonic survival of the progeny was used to assess genetic damage. Recessive lethal effects were assessed from reduced survival of androgenetic haploid progeny. Neither recessive nor dominant lethal effects were obtained after exposure to 100 mg/liter EMS or 2 g/liter DEN. At 250 mg/liter EMS, peak dominant lethality occurred 3-5 wk after treatment. Most embryos hatched, but many were abnormal and died shortly after hatching. Haploid survival was significantly reduced over a broader period, from 1 to 13 wk after mutagenesis. Treatment with 75 mg/liter ENU produced effects similar to the 250-mg/liter EMS mutagenesis. At 400 mg/liter EMS, the frequency and severity of the effects on both diploid and haploid embryos were increased over the lower dose. Gamma irradiation at 1,500 R produced effects similar to the 400-mg/liter mutagenesis, except that peak dominant lethality extended from 1 to 7 wk.

The radiobiological experiences over 4 years research with the biomedical pion channel of the 590 MeV proton-accelerator of the Swiss Institute for Nuclear Research (SIN) have been summarized. Mainly sensitive biological systems have been chosen (limiting factor: dose-rate not more than 10 rad/min, exceptionally till 30 rad/min). The RBE values in the peak region vary between 0.7-3.3 and in the plateau region between 0.4-1. The gain factors for pion radiotherapy of cancer are, beside the excellent physical dose distribution, irradiation in the same treatment with two types of radiation: sparsely ionizing (low LET) radiation in plateau (healthy tissue) region and densely ionizing (high LET) radiation in peak (tumor) region. The biological effectiveness ratio in peak and plateau as the clinically most important relation vary between 1.4-4.2. This is valid also for clinically limiting factors such as reaction of skin, of small intestine, vascular damage, dominant lethals in hypoxic cells, tumor induction. For peak pions the RBE in hypoxic cells (tumor cells) can be much higher than in euoxic cells (healthy tissue). This preclinical work supports the hope in a highly effective cancer therapy with negative pions.

The problem of the dependence of the biological efficiency of ionizing radiation on the Linear Energy Transfer (LET) is still unsolved. Unexpected reactions of heavy ion irradiated cellular systems such as an increasing Relative Biological Effectiveness (RBE) up to a LET of about 100 keV/micron and then a decrease below 1 oblige to dismiss some conventional interpretations. Several years ago we suggested that, especially by higher ionization density in addition to the DNA, repair systems and (or) membraneous systems could also be injured (dual target theory). Our experiments with heavy ions at the Lawrence Berkeley Laboratory with LET's between 102-970 keV/micron on different types of mutations show a strict distinction between events connected with fusion modalities (repair or misrepair) and those associated with nonfusion. With very high LET misrepair reactions such as translocations disappear, suggesting the direct damage of the repair systems and confirming our previous experiments with peak pions and ions of LET's between 1100-4800 keV/micron.

The combined effect of X-irradiation and transposon mobility on the frequencies of X-linked recessive lethals and dominant lethals was investigated in female hybrids in the P-M system of hybrid dysgenesis. X-linked lethals were measured in G2 hybrid dysgenic females whose X chromosome was derived from the M X P cross. To test for additivity or synergism, the mutation rate in irradiated dysgenic females was compared to that of unirradiated females as well as to irradiated nondysgenic hybrid females derived from M X M crosses. Eggs collected for 2 days after irradiation, were represented by the more radiation-sensitive A and B oocytes (about 75%) and the least sensitive C oocytes (about 25%). The production of X-linked lethal events in X-irradiated dysgenic females was 8.1%, as compared to 4.5% in dysgenic controls and 3.4% in irradiated, nondysgenic controls, demonstrating an additive effect of radiation and dysgenesis-induced genetic damage. The effect of irradiation on sterility of dysgenic hybrid females was a negative one, resulting in 20% less sterility than expected from an additive effect. The combined effect of radiation and dysgenesis on dominant lethality tested in A, B and C oocytes of the same hybrid females was synergistic. Egg broods collected for 3.5 days after irradiation showed that significantly more damage was induced in the presence of ionizing radiation in dysgenic females than in their nondysgenic counterparts. This effect was most obvious in B and C oocytes. The synergism observed may be related to the inability of cells to repair the increased number of chromosome breaks induced both by radiation and transposon mobility.

The sensitivity to gamma-rays of a hyperkinetic mutant (HK1), characterized by high metabolic activity, has been studied and compared with gamma-ray sensitivity of the wild-type Oregon-K. Radiation damage, as measured by the frequency of induced dominant lethals (DL) and sex-linked recessive lethals (SLRL), was more in HK1 as compared with Or-K. The maximal sensitivity differences for these parameters were observed in the first brood. Translocations, on the contrary, were in general fewer in the HK1 compared with Or-K. These results have been interpreted in terms of reduced repair of mutational lesions in the energy-stressed cells of KH1.

A study was made of the genetic effects of iodine radioactive isotopes in male germ cells of (CBA X C57Bl)F1 hybrid mice. After a single intraperitoneal administration of Na131I (1.48 to 740 kBq/g) or Na125I (148 to 7400 kBq/g) to males the occurrence of dominant lethal mutations (DLM), reciprocal translocations (RT), and abnormal sperm heads (ASH) was studied. The radioactive iodine isotopes induced DLM at the postmeiotic spermatogenesis stages only. After the effect of the isotopes, the frequency of RT increased insignificantly with dose. The frequency of ASH was only increased with the highest 131I dose. Relative biological effectiveness of 131I and 125I was less than 1 with a reference to the indices under study.

The mutagenic effect of SHF microwave radiation was studied in male mice using three test: frequency of dominant lethal mutations; frequency of abnormal sperm heads and frequency of chromosome aberrations in cells of bone marrow. The results of acute (60 and 800 mW/cm2 for 12 min, and 21 s., respectively) and fractionated (800 mW/cm2 for 21 s. X 10 days exposures of male mice did not induce any mutagenic effect.

A study was made of the effect of 14C glucose after long-term (33 days) and chronic (6 and 12 months) per os administration to male mice (CBA X C57B1)F1. The average absorbed doses in gonads were 1.47 and 0.74 Gy after long-term administration and 0.066 and 0.013 Gy after chronic administration of 14C glucose. The tests used were: the frequencies of dominant lethal mutations (DLM), reciprocal translocations (RT), and abnormal sperm heads (ASH). The frequencies of DLM and RT were only shown to increase, with radiation dose, after long-term administration of 14C glucose. After chronic administration, of 14C glucose in the doses applied the effect was absent.