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. Issue 4 (October 2021)

• Record Type: Journal Article
• Authors: Fish, Brian L.; MacVittie, Thomas J.; Gao, Feng; Narayanan, Jayashree; Gasperetti, Tracy; Scholler, Dana; Sheinin, Yuri; Himburg, Heather A.; Hart, Barry; Medhora, Meetha
• Is Part Of: Health physics. Volume 121:Issue 4(2021)
• Publication Date: 2021-10
• Subjects: biological indicators -- health effects -- radiation effects -- rat; Biophysics -- Periodicals; Health Physics -- periodicals; Radiation Protection -- periodicals; Radiotherapy -- periodicals; Medische fysica; Electronic journals; 612.01448
• DOI: 10.1097/HP.0000000000001444
• Languages: English
• ISSNs: 0017-9078

Abstract

Abstract : Abstract: 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. Abstract : Supplemental digital content is available in the text.