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.

中文翻译：

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保留骨髓（Leg-out PBI）的部分身体照射大鼠模型，专为 FDA 批准缓解急性和迟发性辐射损伤的对策而设计。

本研究的目的是开发保留骨髓的部分身体照射（腿外 PBI）大鼠模型，以测试急性辐射综合征（ARS）和急性辐射暴露延迟效应（DEARE）的医疗对策（MCM）根据 FDA 动物规则。在雌性和雄性 WAG/RijCmcr 大鼠中以 12.5-14.5 Gy 的剂量开发腿部外伸 PBI 模型。大鼠接受包括液体和抗生素在内的支持治疗。通过第 7 天的致死率和第 10 天的腹泻评分来评估胃肠道 ARS (GI-ARS)。分析第 1-42 天之间的差异血细胞计数，了解造血 ARS (H-ARS) 的自然史。在第 28-110 天之间测量致死率和呼吸间隔 (BI)，以评估肺部延迟损伤 (L-DEARE)。通过测量第 90-180 天之间血尿素氮 (BUN) 的升高来评估肾损伤 (K-DEARE)。雌性和雄性大鼠的 LD50/30（包括 GI-ARS 和 H-ARS 的致死率）分别为 14.0 Gy 和 13.5 Gy，而仅 GI-ARS 的 LD50/7 分别为 14.3 Gy 和 13.6 Gy。120 d (LD50/120) 期间的全因死亡率（包括 ARS 和 L-DEARE）分别为 13.5 Gy 和 12.9 Gy。次要终点证实了腿外 PBI 后出现四种不同的后遗症，分别是胃肠道、造血、肺和肾毒性。腿部外翻 PBI 的成年大鼠模型显示出辐射损伤的急性和长期后遗症，这已在人类辐射暴露案例研究中报告过。女性和男性之间的 DRR 存在性别差异。这些大鼠模型对于根据 FDA 动物规则制定和批准减轻辐射损伤的对策最有用。