A Dose-Dependent Hematological Evaluation of Whole-Body Gamma-Irradiation in the Göttingen Minipig (original) (raw)
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PLoS ONE, 2011
Background: The animal efficacy rule addressing development of drugs for selected disease categories has pointed out the need to develop alternative large animal models. Based on this rule, the pathophysiology of the disease in the animal model must be well characterized and must reflect that in humans. So far, manifestations of the acute radiation syndrome (ARS) have been extensively studied only in two large animal models, the non-human primate (NHP) and the canine. We are evaluating the suitability of the minipig as an additional large animal model for development of radiation countermeasures. We have previously shown that the Gottingen minipig manifests hematopoietic ARS phases and symptoms similar to those observed in canines, NHPs, and humans.
International Journal of Radiation Biology, 2020
Animal models that accurately reflect human responses to radiation injury are needed for advanced mechanistic investigation and development of effective therapeutics. The rabbit is an established animal model accepted by the FDA for studies of cardiovascular disease, lipid metabolism, the development of anticoagulants, testing of bone implants, and the development of treatments for infectious diseases such as HIV. The purpose of this study was to investigate the New Zealand White (NZW) Rabbit model as a model of acute radiation exposure because of its established similarity to human vascular, immune, and coagulation responses. Materials & Methods: Two sequential studies were performed in a total of 81 male NZW rabbits, 16-20 weeks of age. All animals underwent clinical observations and peripheral blood analyses following a single dose of 0, 6,7,8,8.5, 9, or 10 Gy of total body irradiation via a 6 MV Linear accelerator photon source on Day 0. Animals were treated with timed release fentanyl patch (Day 0-30), subcutaneous hydration (Day 1, Study 2 only), and oral sulfamethoxazole/trimethoprim 30mg/kg once daily (Days 3-30) and were followed for 30 days or to time of mortality.
The Effects of Gamma and Proton Radiation Exposure on Hematopoietic Cell Counts in the Ferret Model
Gravitational and space research : publication of the American Society for Gravitational and Space Research, 2013
Exposure to total-body radiation induces hematological changes, which can detriment one's immune response to wounds and infection. Here, the decreases in blood cell counts after acute radiation doses of γ-ray or proton radiation exposure, at the doses and dose-rates expected during a solar particle event (SPE), are reported in the ferret model system. Following the exposure to γ-ray or proton radiation, the ferret peripheral total white blood cell (WBC) and lymphocyte counts decreased whereas neutrophil count increased within 3 hours. At 48 hours after irradiation, the WBC, neutrophil, and lymphocyte counts decreased in a dose-dependent manner but were not significantly affected by the radiation type (γ-rays verses protons) or dose rate (0.5 Gy/minute verses 0.5 Gy/hour). The loss of these blood cells could accompany and contribute to the physiological symptoms of the acute radiation syndrome (ARS).
Significance of Bioindicators to Predict Survival in Irradiated Minipigs
Health Physics, 2014
The minipig is emerging as a potential alternative non-rodent animal model. Several biological markers e.g. blood counts, laboratory parameter and clinical signs have been proposed for rapid triage of radiation victims. Here, we focus on the significance of bio-indicators for prediction of survivors after irradiation and compared it with human data; relationship between these biomarkers and radiation dose is not part of this study. Male Gottingen minipigs (age 4-5 months, weight 9-10 kg) were irradiated (or sham-irradiated) bilaterally with gamma-photons (Cobalt-60, 0.5-0.6 Gy/min) in the dose range of 1.6-12 Gy. Peripheral blood cell counts, laboratory parameters, and clinical symptoms were collected up to 10 days after irradiation and analyzed using logistic regression analysis and calculating ROC curves. In moribund pigs parameters such as decreased lymphocyte/granulocyte counts, increased C-reactive protein, alkaline phosphatase values as well as increased citrulline values and body temperature significantly (p<0.002 up to p<0.0001) discriminated non-survivors from survivors with high precision (ROC ≥ 0.8), but most predictive within the first three days after exposure was a combination of decreased lymphocyte counts and increased body temperature observed as early as 3 h after radiation exposure (ROC: 0.93-0.96, p<0.0001). Sham-irradiated animals (corresponding to "worried wells") could be easily discriminated from dying pigs, thus pointing to the diagnostic significance of our analysis. These data corroborate with earlier findings performed on human radiation victims suffering from severe hematological syndrome and provide further evidence for the suitability of the minipig model as a potential alternative non-rodent animal model.
Military Medicine, 2002
In some radiation accidents, exposure doses are delivered over days or even months. In all cases the organ system most relevant to a patient's survival is the hematopoietic tissue. There appears to be a threshold of approximately 10 mSv per day above which hematopoietic effects become apparent and hematopoietic failure may occur. Experimental observations in dogs demonstrate that exposure to chronic v-Irradiation may be tolerated for over a year if the daily dose does not exceed 7 mSv to 18 mSv. The pathophysiological mechanisms are being studied by hematological measures and biomathematical models. The results are in accordance with the assumption of excess cell loss and progressive diminution of the stem cell pool over time until a "turbulence region," with an increased probability of system failure, is approached. Diagnostic procedures require a thorough hematological assessment that includes the stem cell compartment. Therapeutic options include administration of hematopoietic growth factors and stem cell transplantation.
Low-dose radiation effects: Experimental hematology and the changing paradigm
Experimental Hematology, 2003
This review looks at the emerging field of nontargeted radiation effects and their impact on low-dose radiation risk assessment and radiotherapy. It identifies the major role of experimental hematologists and cytogeneticists in changing the old view of radiation action on living things. It also considers the history of radiobiology, seeking to explain why it is only now that we are
Health physics, 2015
Since controlled clinical studies on drug administration for the acute radiation syndrome are lacking, clinical data of human radiation accident victims as well as experimental animal models are the main sources of information. This leads to the question of how to compare and link clinical observations collected after human radiation accidents with experimental observations in non-human primate (NHP) models. Using the example of granulocyte counts in the peripheral blood following radiation exposure, approaches for adaptation between NHP and patient databases on data comparison and transformation are introduced. As a substitute for studying the effects of administration of granulocyte-colony stimulating factor (G-CSF) in human clinical trials, the method of mathematical modeling is suggested using the example of G-CSF administration to NHP after total body irradiation.
International Journal of Radiation Biology, 2019
Purpose: Incidents, such as nuclear facility accidents and the release of a 'dirty bomb', might result in not only external irradiation of personnel, but additional internal exposures through concomitant inhalation and/or ingestion of radioactive particulates. The purpose of this study was to define the impact of such a combination of radiation injuries on the hematopoietic niche. Material and methods: To assess changes in the murine hematopoietic system, we used a combined exposure of total body irradiation (TBI, 6 Gy) followed immediately by an internal (intraperitoneal) administration of 100 mCi of soluble 137 Cs. We then evaluated acute survival in combined versus single modality exposure groups, as well as assessing hematopoietic function at 12 and 26 week time points. Results: Acutely, the combination of external and internal exposures led to an unexpected delay in excretion of 137 Cs, increasing the absorbed dose in the combined exposure group and leading to mortality from an acute hematopoietic syndrome. At 12 weeks, all exposure paradigms resulted in decreased numbers of phenotypic hematopoietic stem cells (HSCs), particularly the short-term HSCs (ST-HSC); long-term HSCs (LT-HSC) were depleted only in the internal and combined exposure groups. At 26 weeks, there was significant anemia in both the TBI alone and combined exposure groups. There were decreased numbers in both the LT-and ST-HSCs and decreased functionality, as measured by competitive repopulation, was seen in all radiation groups, with the greatest effects seen in the internal and combined exposure groups. Conclusions: Our data indicate that a combined injury of sublethal external irradiation with internal contamination induces significant and persistent changes in the hematopoietic system, as may have been predicted from the literature and our own group's findings. However, a novel observation was that the combined exposure led to an alteration in the excretion kinetics of the internal contamination, increasing the acute effects beyond those anticipated. As a result, we believe that a combined exposure poses a unique challenge to the medical community during both the acute and, possibly, delayed recovery stages.
Effects of Proton Radiation Dose, Dose Rate and Dose Fractionation on Hematopoietic Cells in Mice
Radiation Research, 2010
The present study evaluated the acute effects of radiation dose, dose rate and fractionation as well as the energy of protons in hematopoietic cells of irradiated mice. The mice were irradiated with a single dose of 51.24 MeV protons at a dose of 2 Gy and a dose rate of 0.05-0.07 Gy/min or 1 GeV protons at doses of 0.1, 0.2, 0.5, 1, 1.5 and 2 Gy delivered in a single dose at dose rates of 0.05 or 0.5 Gy/min or in five daily dose fractions at a dose rate of 0.05 Gy/min. Sham-irradiated animals were used as controls. The results demonstrate a dose-dependent loss of white blood cells (WBCs) and lymphocytes by up to 61% and 72%, respectively, in mice irradiated with protons at doses up to 2 Gy. The results also demonstrate that the dose rate, fractionation pattern and energy of the proton radiation did not have significant effects on WBC and lymphocyte counts in the irradiated animals. These results suggest that the acute effects of proton radiation on WBC and lymphocyte counts are determined mainly by the radiation dose, with very little contribution from the dose rate (over the range of dose rates evaluated), fractionation and energy of the protons. Acute radiation sickness has a sequence of a phased syndrome that varies with radiation dose, dose rate and quality and individual radiation sensitivity (1). The acute effects are
Evidence of disseminated intravascular coagulation in a porcine model following radiation exposure
Life Sciences in Space Research, 2014
Recent evidence has suggested that disseminated intravascular coagulation (DIC) plays an integral role in death at the LD 50 dose of either gamma or solar particle event (SPE)-like proton radiation in ferrets. In these studies, Yucatan minipigs were evaluated to determine whether they were susceptible to the development of radiation induced DIC. Yucatan minipigs were exposed to a dose of 2.5 Gray (Gy) with X-rays and monitored over the course of 30 days. Evidence of DIC was evaluated by way of thromboelastometry parameters, platelet counts, fibrinogen concentration, and the d-dimer assay. Pigs exposed to X-rays developed signs of DIC within 2 days' post-irradiation. The development of DIC was exacerbated over the course of the studies, and one of the pigs died at day 14 and another had to be euthanized on day 16 post-irradiation. For both of these pigs, DIC was evident at the time of death. The following observations were indicated or were suggestive of DIC: whole blood clotting was impaired (as evidenced by thromboelastometry alterations), there were decreased platelet counts, elevated d-dimer concentrations in the blood, and/or hemorrhaging and the presence of fibrin in tissues observed during post-mortem examination. The extrapolation of data from these studies, in combination with other published data, have led to the hypothesis that there could be a correlation between the propensity to develop DIC, as indicated by hemorrhaging at death at relatively low doses of radiation, and the LD 50 for a particular species. Our data suggest that the development of DIC may contribute to death at the LD 50 dose in large mammals.