Rat Models of Partial-body Irradiation with Bone Marrow-sparing (Leg-out PBI) Designed for FDA Approval of Countermeasures for Mitigation of Acute and Delayed Injuries by Radiation. Health Phys 2021 Oct 01;121(4):419-433
Date
09/22/2021Pubmed ID
34546222Pubmed Central ID
PMC8577554DOI
10.1097/HP.0000000000001444Scopus ID
2-s2.0-85117425987 (requires institutional sign-in at Scopus site) 20 CitationsAbstract
The goal of this study was to develop rat models of partial body irradiation with bone-marrow sparing (leg-out PBI) to test medical countermeasures (MCM) of both acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE) under the FDA animal rule. The leg-out PBI models were developed in female and male WAG/RijCmcr rats at doses of 12.5-14.5 Gy. Rats received supportive care consisting of fluids and antibiotics. Gastrointestinal ARS (GI-ARS) was assessed by lethality to d 7 and diarrhea scoring to d 10. Differential blood counts were analyzed between d 1-42 for the natural history of hematopoietic ARS (H-ARS). Lethality and breathing intervals (BI) were measured between d 28-110 to assess delayed injury to the lung (L-DEARE). Kidney injury (K-DEARE) was evaluated by measuring elevation of blood urea nitrogen (BUN) between d 90-180. The LD50/30, including both lethality from GI-ARS and H-ARS, for female and male rats are 14.0 Gy and 13.5 Gy, respectively, while the LD50/7 for only GI-ARS are 14.3 Gy and 13.6 Gy, respectively. The all-cause mortalities, including ARS and L-DEARE, through 120 d (LD50/120) are 13.5 Gy and 12.9 Gy, respectively. Secondary end points confirmed occurrence of four distinct sequelae representing GI, hematopoietic, lung, and kidney toxicities after leg-out PBI. Adult rat models of leg-out PBI showed the acute and long-term sequelae of radiation damage that has been reported in human radiation exposure case studies. Sex-specific differences were observed in the DRR between females and males. These rat models are among the most useful for the development and approval of countermeasures for mitigation of radiation injuries under the FDA animal rule.
Author List
Fish BL, MacVittie TJ, Gao F, Narayanan J, Gasperetti T, Scholler D, Sheinin Y, Himburg HA, Hart B, Medhora MAuthors
Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinYuri M. Sheinin MD, PhD Associate Professor in the Pathology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acute Radiation SyndromeAnimals
Bone Marrow
Female
Hematopoietic System
Male
Radiation Exposure
Radiation Injuries, Experimental
Rats
