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

OBJECTIVE: 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. METHODS: 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 day 7 and diarrhea scoring to day 10. Differential blood counts were analyzed between days 1–42 for the natural history of hematopoietic ARS (H-ARS). Lethality and breathing intervals (BI) were measured between days 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 days 90–180. RESULTS: The LD(50/30), including both lethality from GI-ARS and H-ARS, for female and male rats is 14.0 Gy and 13.5 Gy respectively, while the LD(50/7) for only GI-ARS is 14.3 Gy and 13.6 Gy respectively. The all-cause mortality, including ARS and L-DEARE, through 120 days (LD(50/120)) is 13.5 Gy and 12.9 Gy respectively. Secondary end points confirmed occurrence of 4 distinct sequelae representing GI, hematopoietic, lung and kidney toxicities after leg-out PBI. CONCLUSION: Adult rat models of leg-out PBI developed 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.