Introduction
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.
Objective
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.)
Methods
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 (≥1 year after exposure) periods.
Results and evidence synthesis
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.
Cholinesterase levels
Taken together, the human and animal bodies of evidence provide a consistent pattern of findings in the initial period after exposure that acute sarin exposure is associated with decreased cholinesterase levels. This is supported by similar findings in the intermediate period. There is a high level of evidence from the human studies that sarin decreased cholinesterase levels in the initial time period (primarily supported by two controlled exposure studies) and a moderate level of evidence for decreased cholinesterase from experimental animal studies. The evidence for cholinesterase effects in the intermediate period is more limited with a low level of evidence from human case report studies, and a moderate level of evidence 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
The human body of evidence in the initial period provides a moderate level of evidence that acute sarin exposure constricts pupil diameter in humans and decreases the pupil: iris ratio from 24 hours through the first week following exposure. There is a consistent pattern of findings that this decrease 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 potential. There is inadequate evidence of decreased pupil size in animals in the initial and intermediate periods. In addition to changes in pupil diameter and response, 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. The evidence for visual and ocular effects in the extended period is limited, with a low level of evidence in humans from one prospective study and four case reports with serious risk-of-bias concerns and an inadequate level of evidence in animals from a single study with very serious risk-of-bias concerns that did not report an effect.
Effects on learning, memory and intelligence
The majority of the human data on learning and memory evaluated potential effects in the extended period. Taken together, the human and animal bodies of evidence provide some evidence that acute exposure to sarin is associated with effects on learning and memory. There was a low level of evidence from experimental animal studies during all three time periods. Experimental studies in rats found some evidence of 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 with no studies identified, and there is a low level of evidence that sarin affects memory during the intermediate period. 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
Collectively, the human and animal bodies of evidence provide a consistent pattern of findings that acute exposure to high doses of sarin is associated with morphological and histological changes in nervous tissue across all three time periods. Conclusions for the initial and intermediate periods are based on a moderate level of evidence from experimental animal studies that sarin exposure affects nervous tissue within the first 7 days and through 90 days thereafter. The evidence from human studies for the initial and intermediate time periods is inadequate with only a single case report identified. 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.
Other neurological effects, including activity and strength, anxiety and fear, avoidance and depression, electroencephalogram, sleep disruption, other neurological symptoms, and other sensory effects are included in this review. However, the evidence for these effects was not considered in reaching conclusions due to having few studies on a given outcome, inconsistency in findings, heterogeneity of the data, and study limitations.
Discussion and conclusions
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 ≥1 year after exposure based on multiple effects, including effects on learning and memory and morphological and histopathological changes in nervous system tissues.
Data gaps
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.
National Toxicology Program (NTP). 2019. NTP monograph on the systematic review of long-term neurological effects of sarin. Research Triangle Park, NC: National Toxicology Program. NTP Monograph 06. https://doi.org/10.22427/NTP-MGRAPH-6