Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
NTP Monogr. 2019 Jun(6). doi: 10.22427/NTP-MGRAPH-6.
Sarin (CASRN: 107-44-8) is a highly toxic organophosphorus nerve agent that was developed for chemical warfare during World War II and continues to be used in conflicts. Immediate effects of sarin exposure are well known, and although there are suggestions in the literature of neurological effects persisting after the initial signs have subsided, long-term neurological effects of acute exposure to sarin are not well characterized in humans.
The National Toxicology Program (NTP), on behalf of the National Institutes of Health (NIH) Countermeasures Against Chemical Threats program, conducted a systematic review to evaluate the evidence for long-term neurological effects in humans and nonhuman animals following acute exposure to sarin. (The terms "animal" and "animals" refer to nonhuman animals.).
A systematic review protocol was developed and utilized for this evaluation that followed the Office of Health Assessment and Translation approach for conducting literature-based health assessments. Any effect observed 24 hours after exposure (including days to years after exposure) was considered long term for this assessment. Because effects might vary based on time after exposure, the development of hazard conclusions was considered for three different time periods: initial (>24 hours-7 days after exposure), intermediate (8-364 days after exposure), and extended (greater than or equal to 1 year after exposure) periods.
The literature search and screening process identified 32 data sets within the 34 human studies and 47 data sets within the 51 animal studies (from 6,837 potentially relevant references) that met the objective and the inclusion criteria. Four main health effect categories of neurological response were identified as having sufficient data to reach hazard conclusions: (1) cholinesterase levels; (2) visual and ocular effects; (3) effects on learning, memory, and intelligence; and (4) morphology and histopathology in nervous system tissues. (This section of the abstract has been abridged.).
Hazard conclusions were considered for the four main health effect categories at all three time periods after exposure. The conclusions with the highest level of evidence for each time period were used to reach the overall conclusions. NTP concludes that acute sarin exposure is known to be a neurological hazard to humans in the initial time period of >24 hours-7 days after exposure based on suppression of cholinesterase. NTP concludes that acute sarin exposure is suspected to be a neurological hazard to humans in the intermediate time period of 8 days-1 year after exposure based on multiple effects, including suppression of cholinesterase, visual and ocular effects, and morphological and histological changes in nervous system tissues. NTP concludes that acute sarin exposure is suspected to be a neurological hazard to humans in the extended time period of greater than or equal to 1 year after exposure based on multiple effects, including effects on learning and memory and morphological and histopathological changes in nervous system tissues.
This evaluation identified data gaps that contribute to lower confidence in the bodies of evidence for some endpoints and time periods after exposure. Future targeted research to assess the long-term neurological effects of sarin exposure should address areas with low confidence in the findings. Future research would benefit from the use of well-characterized human exposure data, use of exposed and appropriately matched control populations for neurological tests, and animal models that address the inconsistencies identified in this review using study design, conduct, and reporting practices to minimize bias. Given the hazard conclusions from this review, additional research on the four main health effect categories above may impact the confidence in the conclusions. Research may also be informative on a diverse range of neurological endpoints, identified in this report's appendices, for which there is inadequate evidence to determine whether there is an association with acute sarin exposure. Another area of research that the available data do not address is the effects of sarin on developing and aging brains. The current data are insufficient to assess if there are any susceptible populations.
沙林（化学物质登记号：107-44-8）是一种剧毒有机磷神经毒剂，在第二次世界大战期间被开发用于化学战，并且仍在冲突中使用。沙林暴露的即时影响是众所周知的，尽管文献中有迹象表明在初始症状消退后神经学影响仍持续存在，但急性暴露于沙林后的长期神经学影响在人类中尚未得到充分描述。
国家毒理学计划（NTP）代表美国国立卫生研究院（NIH）的化学威胁应对计划进行了一项系统评价，以评估急性暴露于沙林后人类和非人类动物长期神经学影响的证据。（术语“动物”指非人类动物。）
制定并使用了一个系统评价方案进行此评估，该方案遵循健康评估与转化办公室基于文献进行健康评估的方法。对于此评估，暴露后24小时（包括暴露后数天至数年）观察到的任何影响都被视为长期影响。由于影响可能因暴露后的时间而异，因此针对三个不同时间段考虑得出危害结论：初始阶段（暴露后>24小时至7天）、中间阶段（暴露后8至364天）和延长阶段（暴露后大于或等于1年）。
文献检索和筛选过程在34项人体研究中确定了32个数据集，在51项动物研究（来自6837篇潜在相关参考文献）中确定了47个数据集，这些数据集符合目标和纳入标准。确定了四个主要的神经学反应健康影响类别有足够的数据得出危害结论：（1）胆碱酯酶水平；（2）视觉和眼部影响；（3）对学习、记忆和智力的影响；（4）神经系统组织的形态学和组织病理学。（摘要的此部分已缩写。）
考虑了暴露后所有三个时间段四个主要健康影响类别的危害结论。使用每个时间段证据水平最高的结论得出总体结论。NTP得出结论，基于胆碱酯酶的抑制，已知急性沙林暴露在暴露后>24小时至7天的初始时间段对人类是一种神经危害。NTP得出结论，基于多种影响，包括胆碱酯酶的抑制、视觉和眼部影响以及神经系统组织的形态学和组织学变化，怀疑急性沙林暴露在暴露后8天至1年的中间时间段对人类是一种神经危害。NTP得出结论，基于多种影响，包括对学习和记忆的影响以及神经系统组织的形态学和组织病理学变化，怀疑急性沙林暴露在暴露后大于或等于1年的延长时间段对人类是一种神经危害。
该评估确定了一些数据差距，这些差距导致对暴露后某些终点和时间段的证据体系信心较低。未来评估沙林暴露长期神经学影响的针对性研究应针对研究结果信心较低的领域。未来的研究将受益于使用特征明确的人类暴露数据、使用暴露组和适当匹配的对照组进行神经学测试，以及使用研究设计、实施和报告实践来解决本评价中确定的不一致性以尽量减少偏差的动物模型。鉴于本评价的危害结论，对上述四个主要健康影响类别的进一步研究可能会影响对结论的信心。研究也可能有助于了解本报告附录中确定的各种神经学终点，目前尚无足够证据确定其与急性沙林暴露是否存在关联。现有数据未涉及的另一个研究领域是沙林对发育中和衰老大脑的影响。目前的数据不足以评估是否存在任何易感人群。
