This study was carried out to determine acute oral toxicity and histopathological effects associated with consumption of Euphorbia heterophylla ethanolic extract using 9 to 10 weeks old Albino mice randomized in six groups. The five groups were orally administered with single graded doses of plant extract at 1500, 2000, 2500, 3500 and 4000 mg/kg body weight while the sixth group was administered 1 ml of physiological saline and the animals were observed for toxicity signs and death. Viscera organs were obtained after cervical dislocation for histopathological assessment. The graded extracts induced dose-dependent toxicity signs with major clinical manifestation prior to death including: polyurea, circling, paralysis, thirst, loss of appetite and gait, tachypnea, dehydration and stupor. The major dosedependent histopathological lesions included: Hemorrhages, congestion, peri-vascular degeneration and necrosis in viscera organs in the groups that received 2000 to 4000 mg/kg body weight. The 24 h median lethal dose was 2831 mg/kg body weight and the 95% confidence interval of median lethal dose was 2490 to 3218 mg/kg body weight and R 2 is 0.96 indicating E. heterophylla is of low toxicity. The study demonstrated the toxicity potential associated with uncontrolled use of this plant by the communities. Toxicological studies of sub chronic and chronic toxicity, as well as in vitro mutagenicity and genotoxicity need to be conducted considering the well claimed prolonged use of the plant extract to assess the effect prolonged use on animals.

The objective of the current study was to establish a mouse model of acute radiation syndrome (ARS) after total-body irradiation with 2.5% bone marrow sparing (TBI/BM2.5) that progressed to the delayed effects of acute radiation exposure, specifically pneumonitis and/or pulmonary fibrosis (DEARE-lung), in animals surviving longer than 60 days. Two hundred age and sex matched C57L/J mice were assigned to one of six arms to receive a dose of 9.5 to 13.25 Gy of 320 kV X-ray TBI/BM2.5. A sham-irradiated cohort was included as an age- and sex-matched control. Blood was sampled from the facial vein prior to irradiation and on days 5, 10, 15, 20, 25, and 30 postirradiation for hematology. Respiratory function was monitored at regular intervals throughout the in-life phase. Animals with respiratory dysfunction were administered a single 12-day tapered regimen of dexamethasone, allometrically scaled from a similar regimen in the non-human primate. All animals were monitored daily for up to 224 days postirradiation for signs of organ dysfunction and morbidity/mortality. At euthanasia due to criteria or at the study endpoint, wet lung weights were recorded, and blood sampled for hematology and serum chemistry. The left lung, heart, spleen, small and large intestine, and kidneys were processed for histopathology. A dose-response curve with the estimated lethal dose for 10–99% of animals with 95% confidence intervals was established. The median survival time was significantly prolonged in males as compared to females across the 10.25 to 12.5 Gy dose range. Animal sex played a significant role in overall survival, with males 50% less likely to expire prior to the study endpoint compared to females. All animals developed pancytopenia within the first one- to two-weeks after TBI/BM2.5 followed by a progressive recovery through day 30. Fourteen percent of animals expired during the first 30-days postirradiation due to ARS (e.g., myelosuppression, gastrointestinal tissue abnormalities), with most deaths occurring prior to day 15. Microscopic findings show the presence of radiation pneumonitis as early as day 57. At time points later than day 70, pneumonitis was consistently present in the lungs of mice and the severity was comparable across radiation dose arms. Pulmonary fibrosis was first noted at day 64 but was not consistently present and stable in severity until after day 70. Fibrosis was comparable across radiation dose arms. In conclusion, this study established a multiple organ injury mouse model that progresses through the ARS phase to DEARE-lung, characterized by respiratory dysfunction, and microscopic abnormalities consistent with radiation pneumonitis/fibrosis. The model provides a platform for future development of medical countermeasures for approval and licensure by the U.S. Food and Drug Administration under the animal rule regulatory pathway.

Purpose: The hemorrhagic syndrome is a major cause of morbidity and mortality associated with the acute radiation syndrome (ARS). We previously characterized the dose-response relationship for total body irradiation (TBI)-induced ARS in the New Zealand White (NZW) rabbit. Thrombocytopenia, hemorrhage, and anemia were strongly associated with morbidity/mortality during the first three weeks post-TBI. The objective of the current study was to further characterize the natural history of thrombocytopenia, hemostatic dysfunction and hemorrhage in the rabbit model at a TBI dose range to induce ARS. Methods: Fifty male NZW rabbits were randomized to receive 7.0 or 7.5 Gy of 6 MV-derived TBI. Sham-irradiated controls (n ¼ 6) were included as a comparator. Animals were treated with minimal supportive care including pain medication, antibiotics, antipyretics for temperature >104.8 F, and fluids for signs of dehydration. Animals were culled at predetermined timepoints post-TBI, or for signs of imminent mortality based on pre-defined euthanasia criteria. Hematology parameters, serum chemistry, viscoelasticity of whole blood, coagulation tests, and coagulation factor activities were measured. A gross exam of vital organs was performed at necropsy. Results: Findings in this study include severe neutropenia during the first week post-TBI followed by thrombocytopenia and severe acute anemia with petechial hemorrhages of the skin and hemorrhage of the vital organs during the second to third weeks post-TBI. Abnormalities in whole blood viscoelastometry were observed concurrent with thrombocytopenia and hemorrhage. Antithrombin activity was significantly elevated in animals after exposure to 7.5 Gy, but not 7.0 Gy TBI. Conclusions: The hemorrhagic syndrome in the rabbit model of TBI recapitulates the pathogenesis described in humans following accidental or deliberate exposures. The rabbit may present an alternative to the rodent model as a small animal species for characterization of the full spectrum of multiorgan injury following TBI and early testing of promising medical countermeasures.