Dependence of the damage and recovery of nucleic acid metabolism on the dose rate in tritium oxide exposure

Disturbance and normalization of nucleic acid metabolism in rat thymus was studied after the effect of tritium oxide delivered in similar cumulative doses but at different dose rates. Both the disturbance and normalization were shown to be a function of dose rate, the slightest damage and the complete recovery being registered at the lowest dose rate (the amount of tritium oxide administered being 0.37 MBq/g/day). The rate of restoration was also a function of dose rate; with tritium oxide dose of 1.85 MBq/g/day (the dose rate at the stage of the equilibrium tritium content in the aqueous phase being 0.38 Gy/day) it was 9 times as high as that after a dose of 0.37 MBq/g/day (0.11 Gy/day dose rate).     

Radiation-induced carcinogenesis: mechanistically based differences between gamma-rays and neutrons, and interactions with DMBA

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis.     

Quantitative analysis of biological responses to ionizing radiation, including dose, irradiation time, and dose rate

Because biological responses to radiation are complex processes that depend on both irradiation time and total dose, consideration of both dose and dose rate is necessary to predict the risk from long-term irradiations at low dose rates. Here we mathematically and statistically analyzed the quantitative relationships between dose, dose rate and irradiation time using micronucleus formation and inhibition of proliferation of human osteosarcoma cells as indicators of biological response. While the dose-response curves did not change with exposure times of less than 20 h, at a given dose, both biological responses clearly were reduced as exposure time increased to more than 8 days. These responses became dependent on dose rate rather than on total dose when cells were irradiated for 20 to 27 days. Mathematical analysis demonstrates that the relationship between effective dose and dose rate is well described by an exponential function when the logarithm of effective dose is plotted as a function of the logarithm of dose rate. These results suggest that our model, the modified exponential (ME) model, can be applied to predict the risk from exposure to low-dose/low-dose-rate radiation.     

Mutation induction by very low dose rate gamma rays in cultured mouse leukemia cells L5178Y

Induction of cell killing and mutation to 6-thioguanine resistance was studied in growing mouse leukemia cells in culture following gamma rays at dose rates of 30 Gy/h, 20 cGy/h, and 6.3 mGy/h, i.e., acute, low dose rate, and very low dose rate irradiation. A marked increase was observed in the cell survival with decreasing dose rate; no reduction in the surviving fraction was detected after irradiation at 6.3 mGy/h until a total dose of 4 Gy. Similarly, the induced mutation frequency decreased after low dose rate irradiation compared to acute irradiation. However, the frequency after irradiation at 6.3 mGy/h was unexpectedly high and remained at a level which was intermediate between acute and low dose rate irradiation. No appreciable changes were observed in the responses to acute gamma rays (in terms of cell killing and mutation induction) in the cells which had experienced very low dose rate irradiation.     

Genetic effect of chronic gamma radiation exposure in male mice

The frequency of reciprocal translocations (RT) in mouse spermatogonia induced by gamma-rays at doses of 1.5 to 4.5 Gy and dose rates of 2.7 X 10(-6), 5.8 X 10(-6), 9.4 X 10(-5) and 4.5 Gy/min was studied. A linear increase was observed in the RT frequency with increasing the dose, at all dose rates. At 9.4 X 10(-5) Gy/min the RT frequency was, on average, 10 times lower, as compared to that for a single acute dose rate of 4.5 Gy/min. Further reduction of the dose rate did not result in a decrease of the RT yield, and at the lowest dose rate of 2.7 X 10(-6) Gy/min (the dose being 3.0 Gy) the RT frequency was higher than using the same dose at dose rates of 5.8 X 10(-6) and 9.4 X 10(-5) Gy/min. Possible reasons for an increase in the RT frequency at low dose rates are considered. A study of the frequency of abnormal sperm heads (ASH) has shown that at the dose rate of 9.4 X 10(-5) Gy/min it is independent of an accumulated dose and is equal to the value obtained when exposing to an acute dose of 3.0 Gy. At dose rates of 2.7 X 10(-6) and 5.8 X 10(-6) Gy/min ASH frequencies were only slightly increased at all doses, as compared to the control level.     

Effect of insemination dose on pregnancy rate in mares

Different insemination doses have been used for artificial insemination(AI) in horses. Since the insemination dose can affect the pregnancy rate, it is important to ensure that an adequate dose be used regardless of the type of inseminationprotocol used. The aim of this study was to find out if it is possible to decrease the insemination dose from 500 x 10(6) progressively motile spermatozoa to 300 x 10(6) progressively motile spermatozoa and still maintain an acceptable pregnancy rate when using extended fresh semen. Thirteen stallions of known fertility and a well-defined group of 64 mares were used in the study. The mares were randomly assigned to 1 of 2 insemination groups. Examination for pregnancy was performed by ultrasonography per rectum approximately 16 d after the last insemination. When using an insemination dose of 300 x 10(6) progressively motile spermatozoa the pregnancy rate per cycle was 75%. With an insemination dose of 500 x 10(6) progressively motile spermatozoa the pregnancy rate per cycle was 64%. There was no significant difference in the pregnancy rate between the 2 insemination doses (P = 0.341). We conclude that when using fresh extended semen it is unlikely that an insemination dose of 300 x 10(6) progressively motile spermatozoa would yield a lower pregnancy rate than a dose of 500 x 10(6) progressively motile spermatozoa if stallions with good quality semen are selected.     

Pulsed-dose-rate and low-dose-rate brachytherapy: comparison of sparing effects in cells of a radiosensitive and a radioresistant cell line

Pulsed-dose-rate regimens are an attractive alternative to continuous low-dose-rate brachytherapy. However, apart from data obtained from modeling, only a few in vitro results are available for comparing the biological effectiveness of both modalities. Cells of two human cell lines with survival fractions of 80% (RT112) and 10% (HX142) after a single dose of 2 Gy and with different halftimes for split-dose recovery and low-dose recovery were used. The cells were irradiated with a continuous low dose rate (80 cGy per hour) or with pulsed dose rate. Two different pulsed dose rates were tested: 4.25 Gy/h and 63 Gy/h. The effects of dose per pulse and the length of the interval between the pulses were investigated while keeping the overall treatment time constant. Survival after low-dose-rate irradiation was indistinguishable from that after pulses of 4.25 Gy/h in cells of both cell lines. Survival decreased with increasing dose per pulse. When the dose rate during the pulses was increased, survival decreased even further. This effect was most pronounced for the radiosensitive HX142 cells. In clinical pulsed-dose-rate brachytherapy, iridium sources move stepwise through the implant and deliver pulses at a high dose rate locally. These high-dose-rate pulses produce greater biological effectiveness compared to continuous low dose rate; this should be taken into account.     

Status of hemapoiesis in residents of the Techa riverside villages in the period of maximum radiation exposure. Report 1. Evaluation of the cellular composition of peripheral blood and the role of comorbidities in the oppression of hemapoiesis

Residents of the Techa riverside villages chronically exposed to ionizing radiation (the average dose rate in 1951-1956 was 0.047 Gy/year, the maximum reached 2.44 Gy/year) developed marked changes in the cellular composition of peripheral blood. The maximum reduction of peripheral blood counts occurred in the years 1951-1953, after which the beginning of the restoration of cellularity to the control level was observed. The dose rate at this point (1956) was about 0.02 Gy/year. The factors of radiation and non-radiation nature (gender, the age at the onset of exposure, health related disorders) in different combinations affect the number of peripheral blood cells. The influence of dose rate of a chronic radiation exposure on a platelet count takes precedence over other factors. The factors of gender and dose rate determine the number of erythrocytes in exposed persons. The changes accompanying the health status and dose rate significantly affect the number of neutrophils. The influence of comorbidity, age and dose rate on the number of monocytes was noted. A lymphocyte count was mainly determined by the age at the onset of exposure and concomitant diseases. A joint influence of chronic radiation exposure and concomitant diseases increases a mutual action on erythro- and thrombocytopoiesis. The decrease of the dose rate was followed by a gradual predominance of the somatic disease influence on leukocyte (neutrophils, lymphocytes and monocytes) counts.     

The effect of hypoxic cell sensitizers at different irradiation dose rates

The effect of 0.1-5 mM misonidazole and SR 2508 on hypoxic V79 cellular survival at acute (498 cGy/min) and low (890 and 933 cGy/h) irradiation dose rates was measured and compared. The experiments were designed to delineate the oxygen mimetic phenomenon and the preincubation effect of these chemicals at these dose rates. Linear regression analysis of the survival data in terms of the linear quadratic model yielded values of alpha and beta. In the absence of drug, the linear coefficient was independent of dose rate, whereas the quadratic term was greatly reduced at low dose rate. At all dose rates, the preincubation effect affected primarily the alpha term, with little influence on beta. In contrast, the oxygen mimetic phenomenon predominantly affected the beta term. Overall, the radiosensitizing ability of these drugs was higher at low dose rate than at acute dose rate.     

Changes in the activity of 5'-nucleotidase and protein kinase of the hepatic plasma membrane depending on the dose rate in x-ray irradiation of rats]

In studying the effect of X-irradiation of rats with a dose of 4 Gy at different dose rates (96 and 4.6 cGy/min) the authors have revealed an increase in 5'-nucleotidase activity at a high dose rate (the first 24 h following irradiation) and a decrease in protein-kinase activity at a low dose rate (on days 3 and 7). The preinjection of alpha-tocopherol prevents the changes observed.     

Dose-rate effect on the induction of HPRT mutants in human G0 lymphocytes exposed in vitro to gamma radiation

The influence of dose rate on expression time, cell survival and mutant frequency at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus was evaluated in human G(0) peripheral blood lymphocytes exposed in vitro to gamma rays at low (0.0014 Gy/min) and high (0.85 Gy/min) dose rates. A cloning assay performed on different days of postirradiation incubation indicated an 8-day maximum expression period for the induction of HPRT mutants at both high and low dose rates. Cell survival increased markedly with decreasing dose rate, yielding D(0) values of 3.04 Gy and 1.3 Gy at low and high dose rates, respectively. The D(0) of 3.04 Gy obtained at low dose rate could be attributed to the repair of sublethal DNA damage taking place during prolonged exposure to low-LET radiation. Regression analysis of the mutant frequency yielded slopes of 12.35 x 10(-6) and 3.66 x 10(-6) mutants per gray at high and low dose rate, respectively. A dose and dose-rate effectiveness factor of 3.4 indicated a marked dose-rate effect on the induced HPRT mutant frequency. The results indicate that information obtained from in vitro measurements of dose-rate effects in human G(0) lymphocytes may be a useful parameter for risk estimation in radiation protection.     

The low dose and low dose rate cytogenetic effects induced by gamma-radiation in human blood lymphocytes in vitro. II. the results of cytogenetic study

The yield of chromosome aberrations induced by gamma-radiation of 60Co in human blood lymphocytes in vitro at low doses (30 divided by 600 mGy) and low dose rates (0.70, 5.05, 59.2 mGy/min) was investigated. It was found that the observed level of chromosomal aberrations induced by gamma-irradiation was unaffected by the value of the dose rate when using constant dose rate and obtaining different doses by altering the exposure time. However, a relatively enhanced level of chromatid aberrations was found at 5.05 and 59.2 mGy/min dose rates in the dose range less than 250 mGy. We have found that the observed level of the sum of chromosomal aberrations induced by gamma-irradiation at doses less than 250 mGy and a dose rate of 59.2 mGy/min was essentially larger compared with the level extrapolated from high doses (above 300 mGy) using a linear-quadratic dose curve. This complied with our previous finding in 1976, 1977 when the enhanced level of dicentrics was only found at a high dose rate approximately 500 mGy/min. Such a non-linear cytogenetic effect does not manifest itself statistically significantly at dose rates of 0.70 and 5.05 mGy/min for the sum of chromosomal aberrations and does not manifest itself at all for dicentrics at all the examined dose rates.     

Mutation induction by different dose rates of gamma rays in radiation-sensitive mutants of mouse leukemia cells

Induction of cell killing and mutation to 6-thioguanine resistance was examined in a radiation-sensitive mutant strain LX830 of mouse leukemia cells following gamma irradiation at dose rates of 30 Gy/h (acute), 20 cGy/h (low dose rate), and 6.2 mGy/h (very low dose rate). LX830 cells were hypersensitive to killing by acute gamma rays. A slight but significant increase was observed in cell survival with decreasing dose rate down to 6.2 mGy/h, where the survival leveled off above certain total doses. The cells were also hypersensitive to mutation induction compared to the wild type. The mutation frequency increased linearly with increasing dose for all dose rates. No significant difference was observed in the frequency of induced mutations versus total dose at the three different dose rates so that the mutation frequency in LX830 cells at 6.2 mGy/h was not significantly different from that for moderate or acute irradiation.     

Radiation stimulated increase of plating efficiency of free plant cells

Summary Radiation induced stimulation of plating efficiency of free plant cells was observed following irradiation with X-rays (1.25 Gy, dose rate 3.1 Gy.nin^–1) and fission neutrons (1.5 Gy, dose rate 0.05 Gy.nin^–1). The dose range where the radiation stimulation effect is manifest is inversely correlated with the applied dose rate.The results are discussed in view of the radiation induced stimulation as it is applied in agricultural practice.     

Radiobiological effects of total body irradiation on the spinal cord

Total body Irradiation (TBI) is often used for conditioning, prior to bone marrow transplantation. Doses of 8–14 Gy in 1–8 fractions over 1–4 days are administered using low dose rate external beam radiotherapy (EBRT). When necessary, consolidation EBRT using conventional doses, fractionation and dose rate is given. The irradiated volume usually contains critical organs such as spinal cord. The purpose of this study was to assess the biologic effect of TBI on the spinal cord in terms of EQD₂ (equivalent dose given in fractions of 2 Gy). EQD₂ values were calculated using the linear-quadratic generalized incomplete repair (IR) model that incorporates IR between fractions and low dose rate irradiation corrections and accounts for mono and bi-exponential repair. Three fractionation schemes were studied as function of dose rate: 8 Gy in 1 and 2 fractions and 12 Gy in 8 fractions. For the 12 Gy in 8 fractions scheme, the influence of dose rate on EQD₂ was limited because the effect of IR between fractions dominates. For the 8 Gy in 1 fraction scheme, significant sparing of the spinal cord may be achieved for low dose rate (5–20 cGy/min). The extent of effects depends on the parameters used. The IR model provides a useful mathematical framework for examination of the effects of fractionated treatments of varying dose rate. Reliable experimental data are needed for accurate assessment of radiation damage to the spinal cord following fractionated low dose rate TBI.     

Effects of irradiation dose rate on quality and sterility of Queensland fruit flies, Bactrocera tryoni (Froggatt)

Queensland fruit fly (Bactrocera tryoni; Q‐fly) pupae are routinely irradiated to induce reproductive sterility in adults released in a sterile insect technique programme. Although there have been some studies of how total dose influences fly quality, dose rate has not been considered. In the present study, pupae were irradiated at a target dose range of 70–75 Gy at dose rates of approximately 5, 7, 26, 57 and 80 Gy/min and were then subjected to routine IAEA/FAO/USDA quality control tests including emergence, flight ability, mortality under stress and sterility induction. No significant effects of dose rate were found on emergence or flight ability. Sterility induction was also found to be independent of dose rate, a result conforming to a ‘one‐hit’ ionizing event hypothesis. Flies irradiated at higher dose rates suffered increased mortality under stress. This appears to stem from an increased tendency to over‐shoot the target dose when irradiating at high dose rates. We recommend that, to reduce potential error in total target dose, the lowest practical dose rate be used when irradiating Q‐fly pupae for use in the sterile insect technique.     

Effect of external irradiation with different intensity at 1 Gy dose on the DNA, RNA and total protein content in the testis and liver of rats

The content of DNA, RNA and total protein in the rat testes and liver was studied 1 and 30 days after external chronic gamma-irradiation (dose rate 1.8 and 5.76 cGy/day) and acute gamma-irradiation with relatively low dose rate (5.4 cGy/min) up to a total dose of 1 Gy. The results obtained pointed to the specific metabolic reaction of radiosensitive (testes) and radioresistant (liver) tissues of organism at external irradiation at relatively low dose of different intensity due to unequal cell capacity for proliferation.     

The effect of neutron dose rate on jejunal crypt survival

The effect of dose rate of fast neutrons over a range from 0.02 Gy/min to 22.5 Gy/min on the survival of mouse jejunal crypts was investigated. A small but significant decrease in sensitivity with decrease in dose rate was observed. A 10-fold decrease in dose rate gave a decrease in effectiveness equivalent to 0.39 Gy. The sensitivity to changes in neutron dose rate is much smaller than the sensitivity to changes in dose rate of photons.     

Organ and effective dose rate coefficients for submersion exposure in occupational settings

External dose coefficients for environmental exposure scenarios are often computed using assumption on infinite or semi-infinite radiation sources. For example, in the case of a person standing on contaminated ground, the source is assumed to be distributed at a given depth (or between various depths) and extending outwards to an essentially infinite distance. In the case of exposure to contaminated air, the person is modeled as standing within a cloud of infinite, or semi-infinite, source distribution. However, these scenarios do not mimic common workplace environments where scatter off walls and ceilings may significantly alter the energy spectrum and dose coefficients. In this paper, dose rate coefficients were calculated using the International Commission on Radiological Protection (ICRP) reference voxel phantoms positioned in rooms of three sizes representing an office, laboratory, and warehouse. For each room size calculations using the reference phantoms were performed for photons, electrons, and positrons as the source particles to derive mono-energetic dose rate coefficients. Since the voxel phantoms lack the resolution to perform dose calculations at the sensitive depth for the skin, a mathematical phantom was developed and calculations were performed in each room size with the three source particle types. Coefficients for the noble gas radionuclides of ICRP Publication 107 (e.g., Ne, Ar, Kr, Xe, and Rn) were generated by folding the corresponding photon, electron, and positron emissions over the mono-energetic dose rate coefficients. Results indicate that the smaller room sizes have a significant impact on the dose rate per unit air concentration compared to the semi-infinite cloud case. For example, for Kr-85 the warehouse dose rate coefficient is 7% higher than the office dose rate coefficient while it is 71% higher for Xe-133.     

The effect of the dose rate on the development of rat pups under chronic gamma irradiation]

Chronic exposure of rat pups to gamma radiation, during their intensive growth, at a dose rate of 0.01, 0.11 and 0.5 cGy/day did not affect their development throughout a two-month period of observation. At a dose rate of 12.9 cGy/day rat growth was inhibited during the first 15 days. With further exposure at the same dose rate (over a period of up to five months) the rate of rat pup growth was restored, which indicated the presence of adaptation processes.