Acute Radiation Mortality Research Articles

Initial Characterization of the Growth Stimulation and Heat-Shock-Induced Adaptive Response in Developing Lake Whitefish Embryos after Ionizing Radiation Exposure.

Ionizing radiation is known to effect development during early life stages. Lake whitefish (Coregonus clupeaformis) represent a unique model organism for examining such effects. The purpose of this study was to examine how ionizing radiation affects development in lake whitefish embryos and to investigate the presence of an adaptive response induced by heat shock. Acute exposure to 137Cs gamma rays was administered at five time points corresponding to major developmental stages, with doses ranging from 0.008 to 15.5 Gy. Chronic gamma-ray exposures were delivered throughout embryogenesis within a custom-built irradiator at dose rates between 0.06 and 4.4 mGy/day. Additionally, embryos were given a heat shock of 3, 6 or 9°C prior to a single acute exposure. Radiation effects were assessed based on survival, development rate, morphometric measurements and growth efficiency. Embryos showed high resistance to acute exposures with an LD50/hatch of 5.0 ± 0.7 Gy immediately after fertilization, increasing to 14.2 ± 0.1 Gy later in development. Chronic irradiation at all dose rates stimulated growth, with treated embryos up to 60% larger in body mass during development compared to unirradiated controls. Chronic irradiation also accelerated the time-to-hatch. A heat shock administered 6 h prior to irradiation reduced mortality by up to 25%. Overall, low-dose chronic irradiation caused growth stimulation in developing lake whitefish embryos and acute radiation mortality was reduced by a heat-shock-induced adaptive response.

Radiomitigation and Tissue Repair Activity of Systemically Administered Therapeutic Peptide TP508 Is Enhanced by PEGylation.

TP508 is a synthetically derived tissue repair peptide that has previously demonstrated safety and potential efficacy in phase I/II clinical trials for the treatment of diabetic foot ulcers. Recent studies show that a single injection of TP508 administered 24h after irradiation significantly increases survival and delays mortality in murine models of acute radiation mortality. Thus, TP508 is being developed as a potential nuclear countermeasure. Because of the short plasma half-life of TP508, we hypothesize that increasing the peptide bioavailability would increase TP508 efficacy or reduce the dosage required for therapeutic effects. We, therefore, evaluated the covalent attachment of various sizes of polyethylene glycol to TP508 at either its N-terminus or at an internal cysteine. A size-dependent increase in TP508 plasma half-life due to PEGylation was observed in blood samples from male CD-1 mice using fluorescently labeled TP508 and PEGylated TP508 derivatives. Biological activity of PEGylated TP508 derivatives was evaluated using a combination of biologically relevant assays for wound closure, angiogenesis, and DNA repair. PEG5k-TP508 enhanced wound closure after irradiation and enhanced angiogenic sprouting in murine aortic ring segments relative to equimolar dosages of TP508 without enhancing circulating half-life. PEG30k-TP508 extended the plasma half-life by approximately 19-fold while also showing enhanced biological activity. Intermediate-sized PEGylated TP508 derivatives had enhanced plasma half-life but were not active in vivo. Thus, increased half-life does not necessarily correlate with increased biological activity. Nevertheless, these results identify two candidates, PEG5k-TP508 and PEG30k-TP508, for potential development as second-generation TP508 injectable drugs.

Dose Protraction and Acute Radiation Mortality in the Chicken: A Reappraisal of Injury Accumulation Kinetics

The kinetics of injury accumulation during a single exposure to /sup 60/ Co gamma rays is described in the adult rooster and 3-wk chicken, and the results compared with those previously reported for the 3-day chick. Single exposure periods vary from 30 to 1440 min, with exposures in the lethal range for early (0 to 2 day) and for later (3 to 30 day) acute mortality. For early mortality, an empirical model based on a constant repair or reversal rate during irradiation describes the dose-- time relations. Individual repair rates are assumed to be normally distributed and independent of exposure rate. In addition, there appears to be little influence of age between 3 days and 6 mo. For the later (3 to 30 day) mortality, repair or reversal processes operating during irradiation are time limited as well as rate limited, with an effective period of about 360 min. The effectiveness of dose protraction decreases with age. (auth)

Major and Trace Elements as Bioindicators of Acute Insect Radiosensitivity

LEVY, R., CROMROY, H. L., AND CORNELL, J. A. Major and Trace Elements as Bioindicators of Acute Insect Radiosensitivity. Radiat. Res. 56, 130-139 (1973). Simple regression analyses of 20 species of insects representing the orders Anoplura, Coleoptera, Diptera, Hemiptera, Hymenoptera, Orthoptera, and Thysanura indicated that the total body concentration of several major and trace elements could be used as bioindicators or biopredictors of acute (LD50(24 hr)) radiosensitivity for a species population when insects were subdivided into groups based on laboratory diets. The groups were divided into cockroaches, blood feeders, and stored product beetles based on their broad dietary. Statistical models based on insect total body potassium, magnesium, and copper (i.e., copper/iron ratio) for the 3 groups, respectively, were found to be effective in predicting or estimating acute radiation mortality for related insect species having

Age at X-Irradiation and Acute Radiation Mortality in the Adult Male Rat

Male rats received whole-body single doses of 250-kVp x-rays at various ages ranging from young adulthood to old age. From probit analysis, the ${\rm LD}_{50(30)}$ values for groups exposed at 3 or 7 months of age were 851 and 900 R, respectively. After adjustment for the natural mortality rate, ${\rm LD}_{50(30)}$ values for groups exposed at 17, 21, or 24 months of age were 776, 806, and 747 R, respectively. The mean survival time at the ${\rm LD}_{50(30)}$ for the group exposed at 3 months of age exceeded those for groups irradiated at older ages. The slope of the dose versus survival curve for the youngest group was almost twice that for groups exposed at older ages, reflecting increased variability of the population at older ages. These findings indicate that age at exposure is an important variable to be considered in establishing parameters of acute radiation mortality in adult animals.

The Effect of High-Pressure Oxygen on Acute Radiation Mortality in Mice

Groups of mice were x-irradiated in either air at 1 atmosphere or pure oxygen at 3 atmospheres to assess to effect of exposure in high-pressure oxygen on acute radiation injury. Exposure in air resulted in an ${\rm LD}_{50(30)}$ value of 617 R, while exposure in 3 atmospheres of oxygen resulted in an ${\rm LD}_{50(30)}$ of 540 R. These data indicate sensitization of 13% due to the presence of high-pressure oxygen. The ${\rm LD}_{50(5)}$ values were 1025 R for exposure in air and 900 R following irradiation in high-pressure oxygen, resulting in a sensitizing effect of 12% for acute gastrointestinal radiation. injury.

Acute Radiation Mortality in Mice Inoculated with Pigmented or Non-Pigmented Pseudomonas

SUMMARY Different groups of lethally-irradiated and normal control mice were inoculated with a pigmented Pseudomonas (P. aeruginosa), or a non-pigmented Pseudomonas (P. stutzeri), by intraperitoneal and oral routes. Thirty-two of 50 mice receiving P. aeruginosa died within 8 days after irradiation, and 29 of the 32 showed pigmented P. aeruginosa on heart blood culture. Fewer early deaths were seen with oral administration of the organisms than with intraperitoneal administration. Two out of 50 mice given P. stutzeri died within 8 days of exposure to X-rays. Neither showed the organism on heart blood culture. No pigment reversion for cither organism was demonstrated in vivo. These results indicate that P. stutzeri is not involved in the early-death syndrome in X-irradiated mice.

Antibiotic Therapy after Exposure to X-Rays

The role of infection and its treatment postirradiation has been reported by many investigators (1-5). It is considered to be an important factor contributing to the death of animals exposed to levels of ionizing radiation severe enough to cause depression of hematopoietic tissue, inhibition of antibody formation, and, therefore, increased susceptibility to bacterial invasion. Numerous investigators have reported antibiotic therapy to be only a temporary measure employed to prevent death during the period after irradiation when the animal's defense mechanisms are inadequate to cope with this problem (4, 6). If the irreparable damage is so great that these mechanisms cannot be eventually restored, the antibiotics merely serve to prolong survival, but the animal eventually dies. Penicillin-streptomycin and chloramphenicol have been shown to be beneficial when administered after various doses of ionizing radiation (4, 7-9). Penicillinstreptomycin is generally accepted as an effective antibiotic with few toxic effects; however, published opinions differ on the toxic effects of chloramphenicol in human beings and animals not exposed to irradiation (10-14). It seemed appropriate, therefore, to study the effects of antibiotics on acute radiation mortality, and also to determine whether the effects of chloramphenicol are summated with those of the radiation injury.

Discrimination among injury processes reflected in acute radiation mortality.

SummarySeveral modes of injury that contribute to acute radiation lethality may be distinguished in two complementary ways: (1) by pathological examination and (2) by analysis of the kinetics of death after single exposures of varying degrees of protraction. The analytical approach is discussed, and statistical procedures are applied to 30-day mortality in 3–4 day chicks after 60Co γ-irradiation for exposure times varying from 3 to 1440 min. Kinetic analysis suggests that two irreversible (time-independent) processes lead to different kinds of injury. Time-dependent effects are taken to reflect reversible injury mechanisms. Three different processes of this kind are distinguished, each characterized by an accumulation of injury during exposure at a rate proportional to dose-rate and a constant (linear) reversal, or reduction, of the radiation effects.

Comparative Aspects of Acute Radiation Mortality in Birds

SummaryAdult parakeets and pigeons, given doses of 60Co γ-rays in the 30-day lethal range, showed a peak of mortality at 9 to 11 days; and the early mortality (0 to 2 days after exposure), which is characteristic of the chicken, was not seen. Bone-marrow aplasia was the principal histological finding. When the duration of the exposure was increased from 4 to 480 min, there was a progressive decrease in dose effectiveness, but further increase of the exposure time to 1440 min led to no further decrease in dose effectiveness. These data are described in terms of time-dependent (reversible) and time-independent (irreversible) processes. A linear reversal of the time-dependent injury processes is in agreement with available data. The time constant associated with the reversible process in the parakeet and pigeon (τ = 295 ± 25 min) is in close agreement with the value reported earlier for the chick.

Sex hormones as protective agents against radiation mortality in mice.

Summary1. In dba mice diethylstilbestrol and estradiol benzoate reduce the acute radiation mortality. The androgens, testosterone propionate and depotestosterone cyclopentyl-propionate, afford no protection against acute lethal radiation dose. 2. The estrogens afford protection when given for 7 days before or after the irradiation. 3. No toxic effects due to estrogens or androgens were seen in the administration of the hormones for 7 days after irradiation.

Mouse-strain differences in response to radiation.

Summary1. The acute radiation mortality of mice exposed to x-rays shows that there are radiosensitive regions in the mouse head. 2. The L.D.-50% at 12 days for acute mortality due to whole-body exposure to x-rays is essentially the same for 4 mouse strains and is about 528 r. 3. The sensitivity of the head region varies with mouse strain. In the most sensitive strain, the dba, the M.L.D. for head exposure is the same as for whole-body exposure. Up to more than a 4-fold decrease in head sensitivity in the strains is found in the following order: dba, Marsh, C57 black, and C3H mice.