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.     

Metabolic indices of proteolysis of the blood serum in dogs in the early period following uniform whole-body gamma irradiation

Free amino acid concentration and proteinase inhibitor content were studied during the first 48 h following whole-body uniform gamma irradiation of dogs (LD30/50 and LD90/45). The contribution of metabolic profile features to individual radiosensitivity is discussed on the basis of the retrospective analysis of the initial level of metabolic indices in animals survived and died after irradiation. The comparison of the dynamics of changes in the indices under study in the animals died after exposure to different radiation doses permitted to suggest the important role that early hyperactivation of proteolysis played in the development of metabolism decompensation which promoted the fatal outcome of the affection.     

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.     

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.     

16,16-Dimethyl prostaglandin E2 increases survival in mice following irradiation

16,16-Dimethyl prostaglandin E2 (DiPGE2), a stable analog of PGE2, increases the LD50/30 survival in CD2F1 male mice when given prior to ionizing radiation. Subcutaneous administration of 40 micrograms of DiPGE2 30 min prior to 60Co gamma irradiation extends the LD50/30 from 9.39 Gy in the control animals to 16.14 Gy in DiPGE2 treated, with a dose reduction factor of 1.72 [95% confidence limits: 1.62, 1.82]. The degree of protection is dependent on both the time of administration and the dose of the prostaglandin. Ten micrograms administered 5 min prior to receiving a lethal dose of 10 Gy provides 90% survival but only 10% survival if administered 30 min prior to irradiation. Experiments to determine the in vivo concentration of DiPGE2 in organs postinjection show increased levels over time, but these are not correlated with protection. At 30 min after injection, as much as 80% of the DiPGE2 present in the spleen and plasma is unmetabolized. These results suggest that the protection results from the physiologic action of DiPGE2 rather than direct in vivo detoxification of radicals.     

Melatonin and protection from whole-body irradiation: survival studies in mice

The radioprotective ability of melatonin was investigated in mice exposed to an acute whole-body gamma radiation dose of 815 cGy (estimated LD50/30 dose). The animals were observed for mortality over a period of 30 days following irradiation. The results indicated 100% survival for unirradiated and untreated control mice, and for mice treated with melatonin or solvent alone. Forty-five percent of mice exposed to 815 cGy radiation alone, and 50% of mice pretreated with solvent and irradiated with 815 cGy were alive at the end of 30 days. Irradiated mice which were pretreated with 125 mg/kg melatonin exhibited a slight increase in their survival (60%) (p=0.3421). In contrast, 85% of irradiated mice which were pretreated with 250 mg/kg melatonin were alive at the end of 30 days (p=0.0080). These results indicate that melatonin (at a dose as high as 250 mg/kg) is non-toxic, and that high doses of melatonin are effective in protecting mice from lethal effects of acute whole-body irradiation.     

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.     

Pharmacological PI 3-kinase inhibitors induce radioprotective effect in Drosophila melanogaster imago

Phosphatidylinositol 3-kinase (PI3K) signaling cascade is involved in many cell processes that are required for radioresistance, including proliferation, survival, growth, metabolism, and death. At the whole organism level PI3K signaling cascade is involved in lifespan control. In this study the contribution of PI3-signaling cascade to radioresistance of Drosophila melanogaster imago was investigated. It is shown that pretreatment with Pl3-kinase specific inhibitor LY294002 (5, 100 micromol/l) and wortmannin (5 micromol/1) leads to increase of male and female survival after acute irradiation in dose of 30 Gy. The obtained results demonstrate that PI3K specific inhibition induces radioprotective effect on Drosophila melanogaster imago.     

The reticulocyte count and reticulocytogram of rat peripheral blood at early periods following non-uniform (fractionated) x-ray irradiation

A study was made of the dynamics of changes in the number of reticulocytes in the peripheral blood and of reticulocytograms in rats subjected to partial (front or hind body parts) X-irradiation with LD100/10, LD50/30, and LD0/30. The degree of the post-irradiation reticulocytopenia and modification of reticulocytograms was a function of radiation dose as observed 1-3 h following irradiation of the front part and 48 h after irradiation of the hind part of the animal body.     

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.     

Characteristics of mouse hematopoietic stem cells in the phase of enhanced radioresistance after sublethal irradiation

Haemopoietic stem cells of mice which displayed an increased radioresistance 12 days following sublethal irradiation, exhibited higher proliferative, granulocyte-repopulating and migration activities as compared with those of intact animals.     

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.     

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.     

Increase in endogenous spleen colonies without recovery of blood cell counts in radioadaptive survival response in C57BL/6 mice

The radioadaptive survival response induced by a conditioning exposure to 0.45 Gy and measured as an increase in 30-day survival after mid-lethal X irradiation was studied in C57BL/6N mice. The acquired radioresistance appeared on day 9 after the conditioning exposure, reached a maximum on days 12-14, and disappeared on day 21. The conditioning exposure 14 days prior to the challenge exposure increased the number of endogenous spleen colonies (CFU-S) on days 12-13 after the exposure to 5 Gy. On day 12 after irradiation, the conditioning exposure also increased the number of endogenous CFU-S to about five times that seen in animals exposed to 4.25-6.75 Gy without preirradiation. The effect of the interval between the preirradiation and the challenge irradiation on the increase in endogenous CFU-S was also examined. A significant increase in endogenous CFU-S was observed when the interval was 14 days, but not 9 days. This result corresponded to the increase in survival observed on day 14 after the challenge irradiation. Radiation-inducted resistance to radiation-induced lethality in mice appears to be closely related to the marked recovery of endogenous CFU-S in the surviving hematopoietic stem cells that acquired radioresistance by preirradiation. Preirradiation enhanced the recovery of the numbers of erythrocytes, leukocytes and thrombocytes very slightly in mice exposed to a sublethal dose of 5 Gy, a dose that does not cause bone marrow death. There appears to be no correlation between the marked increase in endogenous CFU-S and the slight increase or no increase in peripheral blood cells induced by the radioadaptive response. The possible contribution by some factor, such as Il4 or Il11, that has been reported to protect irradiated animals without stimulating hematopoiesis is discussed.     

The late effects of radiation on hematopoietic stem cells and the possibility of their modification]

In experiments with mice it has been found that a radioprotective agent, mexamine (two different forms), administered prior to a whole-body single exposure at a dose of LD0/30 increases the average life of animals and the number of exoCFUs 8 days and has no influence on the number of exoCFUs 12 days. Mexamine does not modify the decrease of haemopoietic colonies in sizes in recipients, mice survived acute radiation sickness being used as donors. The share of CFUs 8 days at the stage of DNA synthesis has been shown to increase with age, as well as in animals which lived for 14 months after irradiation.     

Modifying effect of deep hypoxia on neutron-irradiated mice

Deep hypoxia was shown to influence the survival of animals, the state of the small intestine mucosa and the haemopoietic system. DMF (LD50/30) was 2.49 and 1.66 with X- and neutron radiation, respectively. As to haemopoietic stem cells X-irradiated in vivo, D0 was 0.96 +/- 0.04 Gy (control) and 2.82 +/- 0.14 Gy (anoxia). With neutron irradiation, D0 was 0.44 +/- 0.01 Gy and 0.8 +/- 0.03 for the control and experimental animals respectively.     

Radiomodifying properties of the synthetic analog of prostaglandin F2 alpha-estrofan

Estrofan (0.1 to 5 mg/kg) administered to rats and mice 5 min prior to gamma irradiation with doses of 8.5 to 9.5 Gy (LD90/30) increases the survival rate up to 30-40 per cent. The drug is ineffective when administered 30 and 60 min before irradiation.     

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.     

Radiation protection effectiveness of various zootoxins

A study was made of the effectiveness of a new class of radioprotective agents, polypeptides, obtained from zootoxins of scorpion, tarantula, Lathrodectes tredecimguttatus, and bee under conditions of a short-term and long-term irradiation. The peptide fraction of the scorpion venom, butoxin, was most radioprotective: it provided 65% survival after LD98/30. Butoxin exerted a stimulatory effect on the hypophysis-adrenal system and haemopoiesis of intact and irradiated animals.     

Aggressive behavior and radiosensitivity in rats'

This paper aims to present the study of rats' individual radiosensitivity dependence on their individual aggressiveness. On total irradiation in sublethal doses (1.0, 1.5 and 3.5 Gy) and in doses close to LD50/30 (6, 7 and 8 Gy) there was investigated comparative radiosensitivity of non-aggressive and aggressive rats of Wistar line, as well as that of non-aggressive individuals during provoked aggressiveness by means of blocking serotonin synthesis with intraperitoneal (i/p) injection of 400 mg/kg of parachlorphenylalanine (pCPA). Muricidity served as a criterion for aggressiveness and as a criterion of radiosensitivity--cumulative function of survival, the changes of behavior in "Open feald", serotonine and catecholamine content in various brain structures and the dose dependence on the radiation modification of muricidity. It has been found that after 1 Gy total X-irradiation the rats do not lose aggressiveness. Nevertheless the ethalogical parameters change in considerable degree. In the doses of 1.5 and 3.5 Gy muricidity is eluminated in 15-18 and 5-9 days, correspondingly. I/p injection of pCPA after the elimination of aggressiveness provokes transient muricidity in the same terms and duration as it is in case of non-aggressive rats. The elimination of muricidity is associated with changes in content and distribution of biogenic amines in various structures of brain, as well as with reduction of locomotor and reference-research activity, on the one hand and with an increase of emotionality and stereotype activity, on the other hand. After X-irradiation in 6, 7 and 8 Gy the regression coefficients of the dependence of functions type of survival on irradiation dose in aggressive rats is significantly reliable both in comparison with non-aggressive rats and animals with provoked aggressiveness. The change of mortality-rate per unit of changing irradiation dose not depend on blocking of serotonin synthesis, which deficit is one of the distinct determinant of aggressiveness, on the one hand, and higher radiosensitivity, on the other hand. The obtained data allow to suppose that elimination of muricidity after the irradiation of rats in the sublethal doses is conditioned not only by the consequenses of radiation damage of neurobiological structures responsible for the organization of aggressive behavior but the activation of serotonergic system in the process of restitution after radiation trauma. On the other hand, higher radiosensitivity of aggressive rats compared with non-aggressive ones is connected with low serotonin content, thiols and some other biologically active substances which are endogenous radioprotectors determining individual radioresistance.