Radiation resistance of animals subjected to lethal irradiation with chemical protection

The data are presented on radioresistance of mice 1, 5 and 9 months after irradiation (LD95-99/30) in conditions of protection with cystamine. It was shown that the resistance of these animals to repeated irradiation with LD50/30 is considerably lower than that of the animals not exposed previously. The radioresistance and such indices of the haemopoietic system status as quantity of caryocytes and colony-forming capacity of the bone marrow are compared.     

An analysis of the lymphocytes with anomalous nuclei in the peripheral blood of rats subjected to gamma irradiation

The share of lymphocytes with abnormal nuclei in the peripheral rat blood was found to increase during the first 24 h following irradiation with doses LD0, LD50, and LD100. With LD50 the index under study significantly varied in survived, died and control animals. It is suggested that the occurrence of abnormal nuclei in the peripheral rat blood is the result of the two processes, namely, the mitotic division and apoptotic death of cells.     

Radiation-induced rectal complications are not influenced by age: a dose fractionation study in the rat

Radiation-induced complications of the rectum are an important dose-limiting factor in radiotherapy of pelvic malignancies. In general, animal studies demonstrated no differences in acute and late normal tissue toxicity with age, but little is known about rectal complications in relation to age. For this purpose, an extensive histological and dose fractionation study was carried out on the rectum of young (12 weeks) and older (77-80 weeks) rats. In this paper, the results of dose fractionation are presented in relation to age at the time of irradiation. Young and older animals were irradiated with single and fractionated doses. After irradiation, rectal complications could lead to occlusion and stenosis, eventually resulting in the clinical symptoms of a megacolon and a possible fistula. For each dose group, cumulative survival rates were obtained with Kaplan-Meier analysis, from which dose-effect curves and the associated LD(50) values for a megacolon/fistula were calculated. The majority of responders died between 8 and 24 weeks after irradiation, irrespective of age. For both age groups, only the fractionation data showed a reduction in the mean latency with increasing dose. In the older age group, 39% of the responders developed a fistula compared to 26% for the younger animals. The LD(50) values increased from around 30 Gy after single doses to nearly 65 Gy after 10 fractions. The increases in LD(50) values with the number of fractions were independent of the age of the rats. For each of the dose fractionation schedules, log-rank testing indicated no significant differences in cumulative survival rates between younger and older animals (P > 0.10). The high alpha/beta ratios obtained for both the young and older animals strongly suggested that the late rectal complications were a consequence of early epithelial injury. Associated histological findings indicated that blood vessel damage, which was already evident at a high incidence at 4 weeks after irradiation, could also play a significant role in the occurrence of consequential late injuries. In conclusion, data obtained for the latent period of rectal occlusion, for the dose-effect curves, for the log-rank testing of cumulative survival rates, and for the alpha/beta ratios strongly support the hypothesis that the incidence of radiation-induced rectal complications is independent of age. Late rectal complications could be a consequence of radiation-induced acute injury.     

Effect of gemcitabine on the tolerance of the lung to single-dose irradiation in C3H mice.

In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung carcinomas, severe pulmonary toxicity was observed. In this framework, the objective of this study was to investigate the effect of dFdC on the tolerance of the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung tolerance was assessed by the LD50 at 7-180 days after irradiation. For irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h interval between administration of dFdC and irradiation, the LD50 reached 13.29 (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached 13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung tolerance after single-dose irradiation. However, a proper phase I-II trial should be designed before any routine use of combined dFdC and radiotherapy in the thoracic region.     

Changes in the sensitivity of mice to the action of gamma irradiation by Viscum album L. polysaccharides]

The influence of water-soluble polysaccharides of Viscum album L. on the survival of mice subjected to whole-body gamma-irradiation has been investigated. Polysaccharides were shown to exert a radioprotective effect which was a function of both the radiation dose and the drug dose and time of its injection. The maximum radioprotective efficacy of polysaccharides was observed after their injection 15 min before irradiation. A single intraperitoneal administration of polysaccharides (25 mg/kg) before irradiation with LD50/30 and LD100/10-12 increased the 60-day survival rate up to 95% and 27% respectively. The postirradiation injection of polysaccharides prevented death of 80% of mice given LD50 and increased the average life expectancy of animals irradiated with absolutely lethal doses.     

Effects of interleukin 11 (IL-11) on early post-implantation development of the rat

The development of embryos, trophoblast and decidua of IL-11-treated rats were examined in vivo, while ectoplacental cones (EPC) were studied in vitro. Female Wistar rats were injected daily with buffer (C), 1 mg/kg IL-11 (HD) daily or 30 microgram/kg (LD) IL-11 twice a week. On day 9 of pregnancy, embryonic tissue volume was reduced in IL-11-treated animals, but EPC volume was elevated, compared to controls. Mitotic indices were reduced in embryos (P<0.05 for LD, P<0.001 for HD) and in EPCs of both groups. Pycnotic indices were elevated in LD (NS) and HD (P<0.05) embryos, but decreased in EPCs of the LD group (P<0.01). Morphological abnormalities were observed in decidua, embryo and trophoblast. In HD, EPC attachment was impaired after 1 day culture but proliferation was stimulated after 5 days. Defective decidualization in IL-11 treated rats may therefore result in abnormal development of embryo and trophoblast.     

The radioprotective effect of extracts of Archangelica officinalis Hoffm. and Ledum palustre L. on mice

A single injection of Archangelica officinalis Hoffm. and Ledum palustre L. extracts to mice 5-15 min before irradiation with a median lethal dose increased their survival rate. The most favourable effect was produced by a combination of the two preparations: by day 30 100% of animals survived after a dose of 6 Gy (LD50/30); 70% survived after a dose of 7.5 Gy (LD90/30), and 25% after a dose of 8 Gy (LD100/12). DMF for the extract mixture was 1.48.     

Deoxyribonuclease activity in the tissues of X-ray irradiated animals with alloxan diabetes

Fractionated X-irradiation (a cumulative dose of 12.9 mC/kg) of animals with alloxan diabetes caused different, with respect to direction and degree, changes in liver nuclease system than those observed in intact animals after similar irradiation. This indicates that insulin is involved in a metabolic response of the organism to irradiation with relatively small doses.     

Experimental chemotherapy of radiation injury with synthetic lysophospholipid analogs in mice

Synthetic lysophospholipids represent a variety of analogs of the naturally occurring 2-lysophosphatidylcholine. Some of these compounds showed significant therapeutic effects on the survival of mice following radiation injury when administered after various doses of whole-body X irradiation. Such therapeutic effects were discernible even when the treatment was given 6 hr after irradiation, and both intravenous and oral application were effective. Intravenous application of 2 X 25 mg/kg lysophospholipid after whole-body X irradiation around the LD50 resulted in significantly higher numbers of surviving animals. The mode of action remains speculative.     

Estimation of the influence of physical and biological factors on the development of the hematopoietic type of radiation sickness in dogs and two types of monkeys

In this investigation, the analysis of radiobiological experiments on 532 dogs and two types of monkeys (101 animals), irradiated totally in the 1.0 to 6.0 Gy dose range at different irradiation facilities, has been carried out. LD50 values at X-ray and gamma-neutron exposure were close to each other (2.35 and 2.83 Gy, respectively) while at gamma-radiation exposure LD(50/45) increased to 3.09 Gy. Comparison of LD(50/45) values for different kinds of animals allowed us to draw a conclusion of approximately equal radiosensitivities of dogs and Macaca fascicularis monkeys (LD(50/30-45) - 3.09 Gy and 3.17 Gy, respectively); Macaca rhesus monkeys revealed higher radioresistance (LD(50/30-45) - 5.03Gy). Analysis of the influence of several biological factors has not displayed any significant differences in the values of LD(50/45) and average lifespan of male and female dogs. Higher radiosensitivity of dogs with body weight less than 12 kg and lower radiosensitivity of dogs in summer time compared to other seasons have been shown. Dogs at the age of 2 to 3 years appeared to be more radioresistant than animals of the other age.     

The modifying action of the Japanese pagoda tree (Sophora japonica) and pantocrine in radiation lesions

A study was made of the effect of Sophora japonica and pantocrine on irradiated (2.5 Gy) human lymphoblastoid cells. The radioprotective effect was manifested with the preparations injected separately after irradiation. The highest radioprotective effect was produced by the mixture of the preparations, the injection 15 min after irradiation being more effective than preinjection. The protective effect of the agents was studied on mongrel mice after the administration thereof for the purposes of protection protection-and-treatment and treatment. Sophora japonica and pantocrine were shown to increase the survival rate of lethally exposed mice (LD90/30) when administered in a combination 5-15 min before irradiation and when used for the purposes of protection--and--treatment: 53.3% and 50% of animals, respectively, survived by day 30 following irradiation. DMF was 1.25.     

Effect of sodium humate on animals irradiated with lethal doses

A therapeutic effect of natrium humate given to experimental mongrel rats exposed to 60Co-gamma-radiation of lethal doses has been studied. A single administration of natrium humate, 5-10 min following irradiation with a dose of 193.5 mC/kg (LD100/30) leads to a 43.3 per cent survival of animals after 60 days; with a dose of 232.2 mC/kg (LD100/8) there is a trend toward the increase in the life span of exposed rats.     

Regenerative effects of tetrachlorodecaoxide in BD IX rats after total-body gamma irradiation

Tetrachlorodecaoxide (TCDO) was tested for its effects in BD IX rats when combined with a single dose nearing LD50 of total-body irradiation (gamma rays, 60Co). In pilot tests we found that TCDO administrations prior to or immediately after irradiation led to a very high mortality rate (up to 90%), whereas the initiation of TCDO treatment on Day 2, 3, or 4 after irradiation lowered the death rate noticeably, with optimum results when TCDO application was started on Day 4. In our major experiment on 100 BD IX rats, it was demonstrated that the following treatment schedule considerably decreased the death rate (from 44 to 4%): 15.5 mumol TCDO/kg body wt/day on Days 4-6 after irradiation and 7.75 mumol/kg body wt/day on Days 7-11. The animals treated with TCDO showed only mild anemia in the peripheral blood, accompanied by reticulocytosis and low-grade leukocytopenia. Examination of the bone marrow on Day 12 after irradiation revealed X-ray-induced agranulocytosis in the animals that had received only physiological saline solution, whereas in the bone marrow of the animals treated with TCDO there was erythropoiesis as well as myelopoiesis. In addition, the degree of hair loss and depigmentation occurring about 1 month after irradiation was considerably reduced by TCDO. From these results it can be postulated that TCDO has two different effects: as an oxygen donator it causes radiosensitization in the tissue when given before or immediately after irradiation; as an agent stimulating phagocytes and tissue regeneration, it promotes regeneration very effectively when damage is already evident in the tissue.     

Comparative kinetics of the early repair of intestines and lung in mice after fast neutron and gamma-ray irradiation

Early repair (Elkind) after d(50) + Be neutron and gamma irradiation is assessed by determining the additional dose Dr necessary to reach a given biological effect when a single fraction Ds is split into 2 equal fractions 2Di separated by a time interval "i". LD50 at 180 days after thoracic irradiation is used as an evaluation of late pulmonary tolerance; LD50 at 5 days after abdominal irradiation is used as an evaluation of early intestinal tolerance. Dr is reduced but still important after neutron irradiation as compared to gamma irradiation. For LD50/180, after fast neutron irradiation Dr reaches 66, 90, 64, 162, 195, 150 cGy for "i" = 1, 2, 3, 5, 4, 12, and 24 hours respectively; after gamma irradiation, Field and Hornsey reported Dr = 390, 530, and 376 cGy for "i" = 2, 6, and 24 hours respectively; after neutron irradiation, they reported Dr = 190 cGy for "i" = 24 hours. For LD50/5, after fast neutron irradiation, Dr = 14, 45, 43, and 133 cGy for "i" = 1,5, 3,5, 5,5 and 24 hours respectively. Early repair is faster after gamma irradiation: Dr reaches a maximum for "i" = 3-4 hours. For neutrons, Dr reaches its maximum at 24 hours for both criteria.     

Interaction between photoperiod and an endogenous seasonal factor in influencing the diel locomotor activity of the benthic polychaete Nereis virens Sars

The locomotor activity of Nereis virens Sars associated with food prospecting was investigated in response to photoperiod and season using an actograph. Experimental animals which had been reared under natural photoperiods were exposed to two constant photoperiodic treatments, LD 16:8 and LD 8:16, in both the autumn and winter and in the absence of tidal entrainment. Autocorrelation analysis of rhythmicity showed that during the autumn, animals under the LD 16:8 photoperiod displayed a strong nocturnal rhythm of activity, whereas animals under the LD 8:16 photoperiod showed only a weak nocturnal activity rhythm. This is believed to represent an autumn feeding cessation that is triggered when the animals pass through a critical photoperiod LD(crit) <12:>12. Later in the winter, however, animals exposed to both photoperiodic treatments showed strong rhythms of foraging activity irrespective of the imposed photoperiod. It is suggested that the autumn cessation may maximize the fitness of N. virens, a spring-breeding semelparous organism, by reducing risk during gamete maturation, while spontaneous resurgence of activity after the winter solstice permits animals that are not physiologically competent to spawn to accrue further metabolic reserves. This response is believed to be initiated by a seasonal (possibly circannual) endogenous oscillator or interval timer.     

Hepatic injury after whole-liver irradiation in the rat

Radiation-induced hepatic injury in rats, which is characterized by marked ascites accompanied by liver necrosis, fibrosis, and vein lesions, is described in this study. These adverse sequelae are produced within 30 days after irradiation if there is surgical removal of two-thirds of the liver immediately after whole-liver irradiation. The LD50/30 day and median survival time after liver irradiation and two-thirds partial hepatectomy is 24 Gy and 17 days, respectively. Death is preceded by reduction in liver function as measured by [131I]-labeled rose bengal clearance. Prior to death, liver sepsis and endotoxemia were detected in most irradiated, partially hepatectomized animals. Pretreatment of the animals with endotoxin and/or antibiotic decontamination of the GI tract, which increase the host resistance to infection and endotoxemia, resulted in increased survival time, but no irradiated, partially hepatectomized animal survived beyond 63 days. The combination of these treatments resulted in additive effects leading to 38% survival at 100 days. These treatments did not, however, prevent the eventual development of radiation-induced liver pathology. This suggests that sepsis and endotoxemia resulting from the bacteria in the intestine are the immediate cause of death after 30-Gy liver irradiation and partial hepatectomy. It is concluded that the hepatectomized rat model is an economical and scientifically manageable experimental system to study a form of radiation hepatitis that occurs in compromised human livers.     

Nonmonotonous Changes in Metabolic Parameters of Tissues and Cells under Action of Ionizing Radiation on Animal

A nonmonotonous relationship between changes of metabolic parameters of tissues and cells of animal and radiation dose were discussed. Under acute irradiation of animals the nonmonotonous dose-response curve for metabolic parameters of tissues and cells were found. The nonmonotonous dose-response curves of metabolic and functional tissues and cells parameters were also revealed upon chronic irradiation of animals at a low dose-rate. The nonmonotonous shape of dose-response curves may be explained on the basis of nonmonotonous kind of the time-course of metabolic response after irradiation. Living cells were supposed to possess a fundamental property in response to action of different stress agents by nonmonotonous changes of cell metabolism. This response was damping in time oscillation of the value of metabolic parameters around the normal level. Amplitudes and periods of oscillations in these changes of metabolic parameters could be observed. In case of chronic irradiation at a low dose-rate the metabolic and functional parameters showed some modified oscillation during irradiation. The nonmonotonous type of changes in metabolic and functional parameters of tissue and cell by chronic low dose-rate irradiation threw some new light on the peculiarities of biological effects of chronic irradiation.     

Effects of photoperiod on gluconeogenic activity and total lipid concentration in organs of crabs, Neohelice granulata, challenged by salinity changes

Abstract. This study assessed the effects of long (LD) or short (SD) days on the conversion of [¹⁴C]-glycerol to [¹⁴C]-glucose and total lipid concentration in organs of the crab Neohelice granulata challenged by a change in external salinity. In the 20‰-acclimated crabs, no difference was found in the concentration of total lipids in the muscle, hepatopancreas, gills, or hemolymph between crabs acclimated to SD or LD. In SD crabs, the total lipid levels in the anterior and posterior gills did not decrease during an osmotic challenge. Only in the posterior gills did the total lipid levels decrease during acclimation to the 34‰ medium in LD animals. The total lipid concentration in the hemolymph decreased after 1 d of osmotic stress in SD, and increased in the hepatopancreas. In LD crabs, the lipid contents decreased gradually in muscle, and in the hepatopancreas on day 3 after transfer to 34‰ medium. In 20‰-acclimated crabs, the gluconeogenesis activity in both sets of gills was higher in LD than in SD animals. The gluconeogenesis capacity decreased in both sets of gills on the first day of osmotic challenge in SD, and in the posterior gills on the third day in LD crabs. These results suggest that in organs of N. granulata , photoperiod affects the metabolic adjustments to an osmotic challenge.     

Effect of Pseudomonas contamination or antibiotic decontamination of the GI tract on acute radiation lethality after neutron or gamma irradiation

The influence of antibiotic decontamination of Pseudomonas contamination of the GI tract prior to whole-body neutron or gamma irradiation was studied. It was observed that for fission neutron doses greater than 5.5 Gy, cyclotron-produced neutron doses greater than 6.7 Gy, and 137Cs gamma-ray doses greater than 14.4 Gy, the median survival time of untreated rats was relatively constant at 4.2 to 4.5 days, indicating death was due to intestinal injury. Within the dose range of 3.5 to 5.5 Gy of fission neutrons, 4.9 to 6.7 Gy of cyclotron-produced neutrons, and 9.6 to 14.4 Gy of gamma rays, median survival time of these animals was inversely related to dose and varied from 12 to 4.6 days. This change in survival time with dose reflects a transition in the mechanisms of acute radiation death from pure hematopoietic, to a combination of intestinal and hematopoietic, to pure intestinal death. Decontamination of the GI tract with antibiotics prior to irradiation increased median survival time 1 to 5 days in this transitional dose range. Contamination of the intestinal flora with Pseudomonas aeruginosa prior to irradiation reduced median survival time 1 to 5 days in the same radiation dose range. Pseudomonas-contaminated animals irradiated within this transitional dose range had maximum concentrations of total bacteria and Pseudomonas in their livers at the time of death. However, liver bacteria concentration was usually higher in gamma-irradiated animals, due to a smaller contribution of hematopoietic injury in neutron-irradiated animals. The effects of both decontamination of the GI tract and Pseudomonas contamination of the GI tract were negligible in the range of doses in which median survival time was dose independent, i.e., in the pure "intestinal death" dose range. Finally, despite the marked changes in survival time produced by decontamination or Pseudomonas contamination in the "transitional dose range," these treatments had little effect on ultimate survival after irradiation as measured by the LD50/5 day and the LD50/30 day end points. The implications of these results with respect to treatment of acute radiation injury after whole-body irradiation are discussed.     

Cyclic nucleotides and lipids in the realization of the radioprotective effect of ceruloplasmin

Ceruloplasmin administered 60 min before irradiation diminished cAMP and cGMP levels, which were increased by irradiation at LD50 and LD100, and normalized cAMP/cGMP ratio in the rat liver during the first 24 h following irradiation with a dose of 6.24 Gy. The content of phospholipids increased and that of cholesterol decreased under the effect of ceruloplasmin leading to normalization of the molar cholesterol/phospholipid ratio in the rat liver on the 7th day of radiation sickness (LD50, 6.24 Gy).