Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans☆
Introduction
In early March 1991 US troops participating in the Gulf War (GW) detonated a munitions storage pit at Khamisiyah, Iraq, later found to contain stockpiled sarin (GB; o-isopropyl methylphosphonoflouridate) and cyclosarin (GF; cyclohexyl methylphosphonoflouridate). Both of these compounds are acetylcholinesterase inhibitors that are lethal and/or incapacitating upon acute, high level exposure. Symptoms of acute exposure to these compounds may include miosis (narrowing of the pupil of the eye), blurred vision, nausea, vomiting, weakness, and dizziness (Brown and Brix, 1998, Marrs et al., 1996). Published reports and theatre medical records of 1991 GW veterans in the vicinity of Khamisiyah have failed to provide evidence of clinical effects of sarin or cyclosarin toxicity at the time of exposure (Riddle et al., 2003). However, a small but growing body of research examining low-level sarin exposure in animals (Henderson et al., 2002, van Helden et al., 2003, van Helden et al., 2004a, van Helden et al., 2004b) suggests long-term central nervous system effects and evidence of anticholinesterase inhibition occur at levels lower than those that produce miosis and other acute symptoms or that would trigger current field system alarms. Also, long-term delayed or residual effects have been observed in persons performing rescue and police work following the Japanese sarin attacks in 1994 and 1995 (e.g., Miyaki et al., 2005).
A terrorist attack in March of 1995 exposed more than 5500 people to sarin released within the Tokyo subway system (Suzuki et al., 1995). Although a follow-up investigation of 640 of those initially exposed revealed no obvious clinical effects 3 months after the incident (Okumura et al., 1996), differences were noted between the exposed clinical cases and control individuals 6–8 months later. These findings included differences in visual evoked potential measures (Murata et al., 1997), postural parameters (e.g., sway) in females (Yokoyama et al., 1996), and on a neurobehavioral test of psychomotor functioning after adjustment for post-traumatic stress disorder (PTSD) symptoms (Yokoyama et al., 1998). Subsequent investigations of Tokyo subway rescue workers and police officers 3 and 7 years after the event suggest possible long-term neurobehavioral effects (Miyaki et al., 2005, Nishiwaki et al., 2001). These later Japanese findings, although intriguing, are not conclusive: the studies involved small sample sizes requiring pooling across time points and the neurobehavioral task battery used was not consistent with the previous Japanese studies.
In 2000, the Institute of Medicine (IOM, 2000) convened a panel to review the possible long-term effects of sarin and cyclosarin exposure in GW veterans. The committee's conclusions, which were reevaluated and reiterated in 2004 (IOM, 2004), stated that subclinical effects are reasonable to hypothesize although there is inadequate/insufficient evidence to determine whether an association exists because few studies of long-term health effects in humans have been conducted.
In this report we test the hypothesis that low-level exposure from the 1991 Khamisiyah incident is associated with central nervous system effects 4–5 years after GW deployment, specifically with poorer performances on neuropsychological tasks assessing the domains of visuospatial abilities and psychomotor functioning. The analyses were conducted to focus on the specific question of toxicological significance concerning the effects of sarin and cyclosarin on neurobehavioral functioning in humans rather than address the role of the Khamisiyah incident and its association with GW veterans’ illnesses in general.
This study provides a unique perspective on the study of neurobehavioral effects associated with the Khamisiyah detonation in two ways: (1) dose–effect relationships were examined using estimated sarin and cyclosarin exposure levels rather than self-report, and (2) objective outcome data were obtained prior to the 1996 public announcement that the munitions pit detonation at Khamisiyah involved stockpiled sarin and cyclosarin (Directorate for Deployment Health Support of the Special Assistant to the Under Secretary of Defense (Personnel and Readiness) for Gulf War Illness Medical Readiness, and Military Deployments, April 2002). Aside from studies looking at depleted uranium effects (McDiarmid et al., 2000), this investigation of 1991 GW postwar health issues is the first to examine relationships between objectively measured health outcomes (neurobehavioral test performances) and exposure estimates of a pertinent GW event in a dose-dependent manner.
Section snippets
Materials and methods
This report focuses on neuropsychological test performances of a subset of 1991 GW veterans from the Devens Cohort Study who underwent a comprehensive in-person evaluation between the fall of 1994 and summer of 1996 (3.5–5 years after GW deployment) (Proctor et al., 1998, White et al., 2001, Wolfe et al., 1999).
The Devens Cohort Study was first initiated in the spring of 1991 with a survey study of almost 3000 GW veterans, representing close to 100 different military units, who returned home
Exposure characterization
In June 1996, the Presidential Advisory Committee and the National Security Council requested that the Central Intelligence Agency model any potential chemical warfare agent release events during the GW, including those associated with the detonation of specific bunkers and ammunitions pits at Khamisiyah, at al Muthanna, and Muhammidiyat (Presidential Advisory Committee on Gulf War Veterans’ Illness, 1996). Using meteorological data and estimates of atmospheric transport and diffusion, initial
Description of neuropsychological test battery and assessment of mood
Neuropsychological tests were used to assess five cognitive domains: simple attention, executive function, psychomotor functioning, visuospatial abilities, and short-term memory (Table 1). Mood states at the time of testing were assessed using the Profile of Mood States (POMS; McNair et al., 1971). The test battery was designed to included tasks with known sensitivity to neurotoxicants hypothesized to be present in the 1991 GW environment, well-established psychometric properties, and
Analyses
Statistical analyses were conducted with SAS, version 8 (SAS Institute, 1999). Outlier values were reviewed for each of the primary covariate and outcome variables. Extreme values (more than 3 standard deviations (S.D.) from the group mean) were top- (or bottom-) coded and assigned the value corresponding with the 3 S.D. level. (Overall, less than 2% of cases required any truncation of values.) Transformations of the outcomes measures were also considered in an effort to yield approximate
Results
As described above in Section 2, the high exposure group included 23 persons with cumulative exposure levels that ranged between greater than 0.072 and 0.144 mg min/m3. The moderate exposure group included 47 persons with cumulative exposure levels between 0.01296 and 0.072 mg min/m3. There were 70 persons in the low-to-no group (defined as exposure levels less than 0.01296 mg min/m3 or the GPL).
There were few significant demographic or descriptive differences among persons in the three exposure
Discussion
This is the first published study to examine the relationship between low-level sarin and cyclosarin exposure and objective neurobehavioral performances in 1991 GW veterans. Significant dose-response relationships between exposure and less proficient neuropsychological task performances for psychomotor dexterity and visuospatial abilities (Purdue Pegboard and Block Designs) were present 4–5 years following exposure. Similar results within these same functional domains have been observed in
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Acknowledgements
This research project was supported by the Department of Veterans Affairs through a center grant (October 1994–March 2000) to the Boston Environmental Hazards Center, VA Boston Healthcare System. We also would like to acknowledge Jack Heller, Ph.D. and Christopher Weir of the Directorate of Health Risk Management, US Army Center for Health Promotion and Preventive Medicine, Aberdeen Proving Ground, MD for providing the data regarding estimated exposure dosage information for individual units
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Grant sponsor: This research was carried out at the Boston Environmental Hazards Center, under grant support from the Department of Veterans Affairs (DVA) Office of Research and Development (1994–2000).
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The current primary affiliation for Drs. Proctor and Heaton is the US Army Research Institute for Environmental Medicine. The work described in the manuscript was performed while they both were at the VA Boston Heathcare System.