Brian L Fish1,2, Thomas J MacVittie3,4, Aniko Szabo5, John E Moulder1, Meetha Medhora1,6,7,8,9,2. 1. a Departments of Radiation Oncology , Medical College of Wisconsin (MCW) , Milwaukee , USA. 2. g Research Service , Zablocki Veterans Affairs Medical Center , Milwaukee , USA. 3. h Department of Radiation Oncology , University of Maryland, School of Medicine , Baltimore , USA. 4. i Charles River Laboratories , Durham , USA . 5. f Division of Biostatistics , Medical College of Wisconsin (MCW) , Milwaukee , USA. 6. b Departments of Pulmonary Medicine , Medical College of Wisconsin (MCW) , Milwaukee , USA. 7. c Departments of Physiology , Medical College of Wisconsin (MCW) , Milwaukee , USA. 8. d Departments of Cardiovascular , Medical College of Wisconsin (MCW) , Milwaukee , USA. 9. e Departments of Cancer Center , Medical College of Wisconsin (MCW) , Milwaukee , USA.
Abstract
PURPOSE: Defined animal models are needed to pursue the FDA Animal Rule for approval of medical countermeasure for radiation injuries. This study compares WAG/RijCmcr rat and non-human primate (NHP) models for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). MATERIALS AND METHODS: Irradiation models include total body irradiation, partial body irradiation with bone marrow sparing and whole thorax lung irradiations. Organ specific sequelae of radiation injuries were compared using dose-response relationships. RESULTS AND CONCLUSIONS: Rats and NHP manifest similar organ dysfunctions after radiation, starting with acute gastrointestinal (GI-ARS) and hematopoietic (H-ARS) syndromes followed by lung, heart and kidney toxicities. Humans also manifest these sequelae. Latencies for injury were earlier in rats than in NHP. After whole thorax lung irradiations (WTLI) up to 13 Gy, there was recovery of lung function from pneumonitis in rats. This has not been evaluated in NHP. The latency, incidence, severity and progression of radiation pneumonitis was not influenced by early multi-organ injury from ARS in rats or NHP. Rats developed more severe radiation nephropathy than NHP, and also progressed more rapidly. Dosimetry, anaesthesia, environment, supportive care, euthanasia criteria etc., may account for the alterations in radiation sensitivity observed between species.
PURPOSE: Defined animal models are needed to pursue the FDA Animal Rule for approval of medical countermeasure for radiation injuries. This study compares WAG/RijCmcr rat and non-human primate (NHP) models for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). MATERIALS AND METHODS: Irradiation models include total body irradiation, partial body irradiation with bone marrow sparing and whole thorax lung irradiations. Organ specific sequelae of radiation injuries were compared using dose-response relationships. RESULTS AND CONCLUSIONS:Rats and NHP manifest similar organ dysfunctions after radiation, starting with acute gastrointestinal (GI-ARS) and hematopoietic (H-ARS) syndromes followed by lung, heart and kidney toxicities. Humans also manifest these sequelae. Latencies for injury were earlier in rats than in NHP. After whole thorax lung irradiations (WTLI) up to 13 Gy, there was recovery of lung function from pneumonitis in rats. This has not been evaluated in NHP. The latency, incidence, severity and progression of radiation pneumonitis was not influenced by early multi-organ injury from ARS in rats or NHP. Rats developed more severe radiation nephropathy than NHP, and also progressed more rapidly. Dosimetry, anaesthesia, environment, supportive care, euthanasia criteria etc., may account for the alterations in radiation sensitivity observed between species.
Entities:
Keywords:
Probit; bone marrow sparing; partial body irradiation; radiation dose response relationship; radiation nephropathy; radiation pneumonitis; whole thorax lung irradiation
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