NTP monograph on the systematic review of long-term neurological effects following acute exposure to sarin.

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 (greater than or equal to 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. (This section of the abstract has been abridged.).

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 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.

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.