Total body irradiation models in NHPs – consideration of animal sex and provision of supportive care to advance model development

Harmonized animal models are an indispensable tool for the development of safe and effective medical countermeasures (MCMs) against radiation injury, and rhesus macaques (referred herein as NHPs) play a critical role in FDA approval of radiation medical countermeasures for acute and delayed radiation syndromes. Reliance on such models requires that they be well characterized, which consists, in part, of a reproducible dose to mortality response relationship (DRR). However, data describing the DRR for both male and female NHPs from the same study are scarce. Furthermore, the level of supportive care and the use of blood transfusions may shift the DRR, yet such information can be difficult to compare across publications. To address these knowledge gaps, the DRRs of two different NHP total body irradiation (TBI) models are compared in this paper, one which is reliant on the use of male animals provided blood transfusions, and the other which incorporates both sexes wherein animals are not provided transfusions. Studies were conducted using NHPs (Macacca mulatta) receiving TBI, with survival reported over a 60 days. Two primary studies, incorporating both male and female animals not receiving blood transfusions as a provision of supportive care, were compared to two previously published studies, which incorporated only male animals provided blood transfusions as a part of the supportive care regimen. Criterion for euthanasia, and all other provisions of supportive care were comparable. Linear probit plots estimating the lethal dose (LD) and upper and lower limits of the 95% confidence interval (CI) for 10, 30, 50, 70 and 90% mortality, were compared between individual studies and the two models presented. Comparison of probit estimates reveals two important findings. (1) Females have higher mortality than males at identical radiation doses, and (2) blood transfusions increased survival of male animals at lower doses but not at high doses of radiation exposure. The use of single sex animal models may lead to an incomplete understanding of potential sex differences in the dose to mortality response of the TBI model. Consistent use of both sexes and type of supportive care will improve the transferability and reliability of NHP-TBI models currently in use, assist in the selection of radiation doses for single dose lethality studies, and allow investigators to determine the effectiveness of a particular MCM.标准化协调动物模型是研发安全有效的辐射损伤医学对策（MCMs）的不可或缺工具，而恒河猴（本文中以非人灵长类动物（NHPs）指代）在美國食品药品监督管理局（FDA）批准用于急性与延迟性辐射综合征的辐射医学对策审评中发挥着关键作用。对这类模型的应用依赖于其良好的特性表征，其中一项核心内容便是可重复的剂量-死亡率反应关系（DRR）。然而，来自同一研究、同时涵盖雌雄两性非人灵长类动物的DRR相关数据仍较为匮乏。此外，支持治疗的强度与输血手段均可能改变剂量-死亡率反应关系，但此类信息在不同出版物间难以进行横向比较。为填补这些认知空白，本文对两种不同的非人灵长类动物全身照射（TBI）模型的剂量-死亡率反应关系进行了对比：其一为仅使用接受输血支持的雄性动物模型，其二则涵盖雌雄两性且未对动物实施输血干预。本研究以接受全身照射的猕猴（Macacca mulatta）为实验对象，对其60天内的存活情况进行了记录。本研究纳入两项未实施输血支持、涵盖雌雄两性动物的原创研究，并将其与两项既往发表的研究进行对比——后者仅纳入接受输血支持作为治疗方案一部分的雄性动物。两组研究的安乐死判定标准及其余所有支持治疗方案均保持一致。针对10%、30%、50%、70%及90%死亡率对应的致死剂量（LD）以及95%置信区间（CI）的上下限，本文通过线性概率单位图进行估算，并在各项独立研究与所提出的两种模型间展开对比。对概率单位估算结果的对比揭示了两项重要结论：其一，在相同辐射剂量下，雌性动物的死亡率高于雄性动物；其二，在较低辐射剂量下，输血可提升雄性动物的存活率，但在高辐射剂量下并无此效果。仅使用单一性别动物模型，可能导致对全身照射模型剂量-死亡率反应关系中潜在性别差异的认知不全面。统一使用雌雄两性动物并规范支持治疗方案，将提升当前所用非人灵长类动物全身照射模型的可推广性与可靠性，有助于单剂量致死性研究中辐射剂量的选择，同时也便于研究者评估特定辐射医学对策的有效性。