Critical Reviews in Toxicology ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/itxc20 A national toxicology program systematic review of the evidence for long-term effects after acute exposure to sarin nerve agent David A. Jett , Christopher A. Sibrizzi , Robyn B. Blain , Pamela A. Hartman , Pamela J. Lein , Kyla W. Taylor & Andrew A. Rooney To cite this article: David A. Jett , Christopher A. Sibrizzi , Robyn B. Blain , Pamela A. Hartman , Pamela J. Lein , Kyla W. Taylor & Andrew A. Rooney (2020): A national toxicology program systematic review of the evidence for long-term effects after acute exposure to sarin nerve agent, Critical Reviews in Toxicology, DOI: 10.1080/10408444.2020.1787330 To link to this article: https://doi.org/10.1080/10408444.2020.1787330 Published online: 05 Aug 2020. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=itxc20 CRITICAL REVIEWS IN TOXICOLOGY https://doi.org/10.1080/10408444.2020.1787330 REVIEW ARTICLE A national toxicology program systematic review of the evidence for long-term effects after acute exposure to sarin nerve agent a b b b c d David A. Jett , Christopher A. Sibrizzi , Robyn B. Blain , Pamela A. Hartman , Pamela J. Lein , Kyla W. Taylor d and Andrew A. Rooney a b c National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; ICF, Fairfax, VA, USA; School of d Veterinary Medicine, University of California, Davis, Davis, CA, USA; Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NC, USA ABSTRACT ARTICLE HISTORY Sarin is a highly toxic nerve agent that was developed for chemical warfare during World War II and is Received 2 March 2020 used in present conflicts. Immediate effects of acute sarin exposure are established; however, whether Revised 22 June 2020 effects persist after initial signs have subsided is debated. The National Toxicology Program (NTP) con- Accepted 22 June 2020 ducted a systematic review to evaluate the evidence for long-term neurological effects following acute KEYWORDS (<24 hour) exposure to sarin. The literature search and screening process identified 32 data sets within Sarin; long-term effects; the 34 human studies and 47 data sets within the 51 animal studies (from 6837 potentially relevant chemical weapon; nerve references) that met the objective and the inclusion criteria. Four main health effect categories of agent; National neurological response were identified as having sufficient data to reach hazard conclusions: (1) cholin- Toxicology Program esterase levels; (2) visual and ocular effects; (3) effects on learning, memory, and intelligence; and (4) morphology and histopathology in nervous system tissues. NTP concluded that acute sarin exposure is known to be a neurological hazard to humans in the period following exposure up to 7 days and sus- pected to be a hazard week to years after exposure, given a lower level of evidence in later time peri- ods. Effects included reduced cholinesterase, visual and ocular effects, impaired learning and memory, and altered nervous system morphology. Further mechanistic, targeted animal studies, translational research, and rapid research responses after human exposures may reduce uncertainties on long-term consequences of sarin. Abbreviations: AChE: acetylcholinesterase; ChE: cholinesterase; CNS: central nervous system; DRL: dif- ferential reinforcement of low rates; EEG: electroencephalogram; FOB: functional observational battery; GB: sarin [two-character identifier]; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; HAWC: Health Assessment Workspace Collaborative; MRI: magnetic resonance imaging; NIH: National Institutes of Health; NTP: National Toxicology Program; OHAT: Office of Health Assessment and Translation; OPNA: organophosphorus nerve agent; PECO: population, exposure, com- parator, and outcome; PTSD: post-traumatic stress disorder; VEP: visual evoked potential. Table of contents 1. Introduction ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 2 3.2.2. Animal evidence for cholinesterase effects ... ... 8 2. Material and methods ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 4 3.2.3. Data integration and hazard conclusions for 2.1. Protocol development and literature search ... ... ... ... 4 cholinesterase inhibition ... ... ... ... ... ... ... ... ... ... ... 9 2.2. Screening process and data extraction ... ... ... ... ... ... 5 3.3. Visual and ocular effects ... ... ... ... ... ... ... ... ... ... ... ... ... 9 2.3. Quality assessment of individual studies ... ... ... ... ... 5 3.3.1. Human evidence for visual/ocular effects ... ... 9 2.4. Assessment of body of evidence and confi- 3.3.2. Animal evidence for visual/ocular effects ... 10 dence rating ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 3.3.3. Data integration and hazard conclusions for 2.5. Integration of evidence to develop hazard identifica- visual and ocular effects ... ... ... ... ... ... ... ... ... ... 10 tion conclusions ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 3.4. Effects on learning, memory, and intelligence ... ... 10 3. Results ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 3.4.1. Human evidence of learning, memory, and 3.1. Literature search results in human and ani- intelligence effects ... ... ... ... ... ... ... ... ... ... ... ... ... 10 mal evidence... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 6 3.4.2. Animal evidence of learning, memory, and 3.2. Cholinesterase inhibition effects ... ... ... ... ... ... ... ... ... 8 intelligence effects ... ... ... ... ... ... ... ... ... ... ... ... ... 11 3.2.1. Human evidence for cholinesterase effects ... 8 CONTACT David A. Jett [email protected] National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, NSC, Room 2143, Bethesda, MD 20892-9527, USA This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 USC. 105, no copyright protection is available for such works under US Law. 2 D. A. JETT ET AL. 3.4.3. Data integration and hazard conclusions for the Tokyo subway incident in 1995 when members of the learning, memory, and intelligence ... ... ... ... ... 11 terrorist group Aum Shinrikyo released sarin into rail cars 3.5. Effects on morphology and histopathology ... ... ... 11 resulting in several fatalities and over a thousand victims 3.5.1. Human evidence of morphology and histopath- needing immediate medical attention (Yanagisawa ology effects ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 12 et al. 2006). Studies of incidents where sarin attacks and exposure 3.5.2. Animal evidence of morphology and histopath- have occurred indicate that survivors of the initial lethal ology effects ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 12 effects of sarin may suffer long-term serious health effects. 3.5.3. Data integration and hazard conclusions for Neurological effects seem to be the most commonly reported morphology and histopathology effects ... ... ... 12 long-term effect, but the data, especially in humans, are 4. Discussion ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 12 sparse and heterogeneous. In partnership with the National 4.1. What is the biological plausibility of long-term neuro- Institutes of Health (NIH) Countermeasures Against Chemical logical effects? ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 12 Threats (CounterACT) program, the National Toxicology 4.2. Limitations to the systematic review ... ... ... ... ... ... 13 Program (NTP) in the USA conducted a comprehensive sys- 4.3. The systematic review results suggest specific data tematic review to evaluate the evidence for long-term neuro- gaps and research needs ... ... ... ... ... ... ... ... ... ... ... ... 14 logical effects following acute exposure to sarin. This article 4.3.1. Mechanistic research ... ... ... ... ... ... ... ... ... ... ... 14 will summarize the NTP monograph on sarin, which is an 4.3.2. Natural history studies in animal models ... 14 extensive, peer-reviewed systematic review that evaluates the strength of the available data for evidence of potential long- 4.3.3. Targeted animal studies ... ... ... ... ... ... ... ... ... 14 term neurological effects associated with acute sarin expos- 4.3.4. Translational research ... ... ... ... ... ... ... ... ... ... 14 ure. The original protocol, literature search results, and full 4.3.5. A robust clinical research response after human detailed monograph can be found on the NTP website at exposures ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 15 https://ntp.niehs.nih.gov/go/sarin (NTP 2019). Notes ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 15 The NTP systematic review was initiated because of obser- Acknowledgements... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 15 vations in the literature of long-term neurological effects of Declaration of interest ... ... ... ... ..