The National Toxicology Program, on behalf of the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program, recently conducted a systematic review to evaluate the evidence for long-term neurological effects in humans and animals following acute exposure to sarin.
Sarin is a highly toxic organophosphorus nerve agent that was developed for chemical warfare during World War II and continues to be used as a weapon. Long-term neurological effects of acute exposure to sarin are not well characterized. Previous reviews of potential health effects of sarin have generally not assessed individual study quality or considered multiple evidence streams (human, animal, and mechanistic data). In addition, the interpretation of effects of sarin in some previous reviews was compounded by concurrent exposure to multiple chemicals, such as assessments of health effects in military personnel during the Gulf War or other conflicts.
The literature search and screening process identified 32 datasets within the 34 human studies and 47 datasets within the 51 animal studies (from 6,837 potentially relevant references) that met the objective and the inclusion criteria.
Neurological Response Health Effect Findings
Author’s note: These are select summary points curated from the report. Please read the full NTP draft for complete context of the findings.
Cholinesterase Levels
There is a high level of evidence from the human studies that sarin decreased cholinesterase levels in the initial time period and a moderate level of evidence for decreased cholinesterase from experimental animal studies. The evidence for potential effects on cholinesterase in the extended period is inadequate with no experimental data and only a single study in humans.
Visual and Ocular Effects
Case reports or case series have reported that subjects exposed to sarin occupationally or via terrorist attacks complained of vision problems for weeks to years after exposure. There is a consistent pattern of findings that pupil constriction from acute sarin exposure gradually normalizes in the following week to several months. There is a moderate level of evidence from human studies that sarin has negative effects on vision in the intermediate time period including decreases in visual evoked potentials.
Learning, Memory, and Intelligence
Experimental studies in rats found consistent sarin-related effects on learning and memory that were apparent for days, weeks, and months after sarin exposure. The evidence from human studies for effects on learning and memory during the initial period is inadequate. In the extended period, there is a moderate level of evidence that sarin exposure is associated with impaired learning and memory based on epidemiological studies and a low level of evidence from experimental animal studies.
Morphology and Histopathology in Nervous System Tissues
Although there were no experimental animal studies available to evaluate morphological and histological changes at the extended time period after exposure, one cross-sectional study and one case report, which evaluated adults from the Tokyo subway attack, provide evidence that acute exposure to high levels of sarin is associated with morphological and histological changes in human nervous system tissues in the years following sarin exposure.
Key Data Gaps
Rapid Research Response
Because wartime and terrorist use of chemical weapons are rare and unpredictable events, there could be value to developing a rapid research response capability so that emergency response would include the latest treatment knowledge for the victims. The response could also collect vital human clinical data soon after chemical exposures.
Well designed, pre-planned, epidemiological studies would add valuable data to the body of evidence that would be likely to impact conclusions or the confidence in the conclusions reached in this systematic review, given the lack of human data on many endpoints and time periods.
More rigorous human data would add greater confidence to conclusions reached in this evaluation across all outcomes described above except in the body of evidence for suppression of cholinesterase activity in the initial time period, which already is rated as high confidence and a high level of evidence.
Data on other persistent symptoms and neurological effects would also be valuable, as a range of effects have been reported, but the evidence was inadequate to evaluate these health outcomes due to serious limitations in the bodies of evidence (e.g., heterogeneity in the endpoints examined, too few human or animal studies, small sample sizes, serious risk-of-bias concerns).
Human Cohort Studies
Prospective longitudinal cohort studies would be the most informative to better assess neurological effects associated with sarin exposure. Studies that assess visual and ocular effects 1 year or more after exposure in humans would address a data gap in reaching conclusions. However, studies that evaluate measurable results beyond pupil size and self-reported symptoms would add value to the assessment of potential visual and ocular effects resulting from acute sarin exposure. Human cohort studies would be invaluable in characterizing the relationship between ChE activity and neurological effects over time, as well as the potential relationship between acute sarin exposure and the development of PTSD as it relates to other neurological effects.
Animal Model Dose-Response Effects Over Time
Because of the ability to conduct controlled-exposure studies, experimental animal studies are particularly important for addressing research gaps identified by this systematic review, especially for identifying specific effects that could be targeted for medical mitigation. Animal studies indicate differences in inhibition and recovery of ChE activity in different areas of the brain; however, the data are insufficient to identify if there are particularly vulnerable areas of the brain. Future research could focus on these effects to help identify potentially vulnerable areas that could be targeted. Studies in appropriate animal models are also needed for rigorous, well-controlled experimental assessments of the dose-response relationship between sarin exposure and long-term neurological effects.
Sarin Effects on Special Populations
Another gap in both the human and animal data are the effects of sarin on the developing and aging brain. It currently cannot be assessed if children, the very young, or the very old are more susceptible populations.
Peer-Review Meeting
The review and draft report will be discussed in a webcast peer review meeting on 4 Feb 2019. Registration is required for attendance and to present oral comments. The webcast is open to the public.
Document: Draft NTP Monograph on Systemic Review of Evidence of Long-Term Neurological Effects Following Acute Exposure to the Organophosphorus Nerve Agent Sarin (.pdf)
