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Abstract
Purpose
To describe the dose response relationship and natural history of radiation injury in the Wistar rat and its suitability for use in medical countermeasures (MCM) testing.
Materials & Methods
In two separate studies, male and female rats were exposed to partial body irradiation (PBI) with 5% bone marrow sparing. Animals were X-ray irradiated from 7 to 12 Gy at 7–10 weeks of age. Acute radiation syndrome (ARS) survival at 30 days and delayed effects of acute radiation exposure (DEARE) survival at 182 days were assessed. Radiation effects were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging of lung, whole-body plethysmography, and histopathology.
Results
Rats developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in mortality at doses ≥8Gy in males and ≥8.5 Gy in females. DEARE mortality occurred at doses ≥8Gy for both sexes. Findings indicate lung, kidney, and/or liver injury, and persistent hematological dysregulation, revealing multi-organ injury as a DEARE.
Conclusion
The Wistar rat PBI model is suitable for testing MCMs against hematopoietic and gastrointestinal ARS. DEARE multi-organ injury occurred in both sexes irradiated with 8–9Gy, also suggesting suitability for polypharmacy studies addressing the combination of ARS and DEARE injury.
Correction Statement
This article has been republished with minor changes. These changes do not impact the academic content of the article.
Acknowledgements
We would like to thank Meetha Medhora, Heather Himburg, Brian Fish, and Tracy Gasperetti at the Medical College of Wisconsin for the many discussions of the technical details regarding rat PBI models, and the toxicology support staff (TSS) at SRI for their impeccable work over the course of two years during the conductance of the studies presented here.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Tyler Beach
Tyler Beach, PhD, is a Research Scientist, Study Director, and Co-investigator at SRI International focusing on the development of animal models and medical countermeasures against radiation.
James Bakke
James Bakke, BS, is a Research Scientist and Study Director at SRI International focusing on efficacy and safety toxicology studies and animal model development for advancement of radiation countermeasure candidates in a variety of animal species.
Ed Riccio
Ed Riccio, BS, is a retired Program Director for the Genetic Toxicology Testing Program at SRI International.
Harold S. Javitz
Harold S. Javitz is a Senior Biostatistician at SRI International and conducts statistical analyses for toxicology and radiation studies.
Denise Nishita
Denise Nishita, BS, is a Research Associate and Study Director in the Molecular Toxicology group at SRI International, conducting pre-clinical toxicology and efficacy studies of medical countermeasures against radiation.
Shweta Kapur
Shweta Kapur, MS, is a Research Associate in the Molecular Toxicology group at SRI International, supporting toxicology studies, animal model development, and efficacy studies of medical countermeasures against radiation.
Deborah I. Bunin
Deborah I. Bunin, PhD, is Director of Molecular Toxicology at SRI International and conducts pre-clinical toxicology and efficacy studies of medical countermeasures against radiation.
Polly Y. Chang
Polly Y. Chang, PhD, is Scientific Director of the Nonclinical Development Program in SRI’s Biosciences Division and serves as Principal or co-Investigator on a number of NIH, BARDA, NASA, and commercially sponsored grants/contracts. She is actively engaged in radiation biology research and product development of medical countermeasures against radiation.