1
Introduction

The Gulf War in 1990–1991 was considered a brief and successful military operation, with few injuries or deaths of US troops. The war began in August 1990, and the last US ground troops returned home by June 1991. Although most Gulf War veterans resumed their normal activities, many soon began reporting a variety of nonexplained health problems that they attributed to their participation in the Gulf War, including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash.

In response to concerns about the veterans’ health problems, the Department of Veterans Affairs (VA) requested that the Institute of Medicine (IOM) review the scientific and medical literature on the long-term adverse health effects of agents to which the Gulf War veterans may have been exposed. In 1998, IOM and the VA entered into a contract for a series of studies that would provide conclusions about the strength of the association between exposure to the agents of concern and health outcomes as observed in the epidemiologic literature.

Congress, also responding to the growing concerns of ill veterans, passed legislation in 1998 for a study similar to that previously requested by the VA (the Persian Gulf War Veterans Act of 1998, PL 105–277, and the Veterans Programs Enhancement Act of 1998, PL 105–368). The legislation directed the secretary of veterans affairs to enter into an agreement with IOM to review the literature on 33 agents related to service in the Gulf War and to assess the strength of associations between exposure to those agents and long-term adverse health effects as noted in the published literature. The legislation directs the secretary to consider the IOM conclusions when making decisions about compensation.

In response to those requests, IOM has convened three committees to evalu-



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Gulf War and Health: Updated Literature Review of Sarin 1 Introduction The Gulf War in 1990–1991 was considered a brief and successful military operation, with few injuries or deaths of US troops. The war began in August 1990, and the last US ground troops returned home by June 1991. Although most Gulf War veterans resumed their normal activities, many soon began reporting a variety of nonexplained health problems that they attributed to their participation in the Gulf War, including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headache, and rash. In response to concerns about the veterans’ health problems, the Department of Veterans Affairs (VA) requested that the Institute of Medicine (IOM) review the scientific and medical literature on the long-term adverse health effects of agents to which the Gulf War veterans may have been exposed. In 1998, IOM and the VA entered into a contract for a series of studies that would provide conclusions about the strength of the association between exposure to the agents of concern and health outcomes as observed in the epidemiologic literature. Congress, also responding to the growing concerns of ill veterans, passed legislation in 1998 for a study similar to that previously requested by the VA (the Persian Gulf War Veterans Act of 1998, PL 105–277, and the Veterans Programs Enhancement Act of 1998, PL 105–368). The legislation directed the secretary of veterans affairs to enter into an agreement with IOM to review the literature on 33 agents related to service in the Gulf War and to assess the strength of associations between exposure to those agents and long-term adverse health effects as noted in the published literature. The legislation directs the secretary to consider the IOM conclusions when making decisions about compensation. In response to those requests, IOM has convened three committees to evalu-

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Gulf War and Health: Updated Literature Review of Sarin ate the health effects of various chemicals used in the Gulf War. The first evaluated the health effects of depleted uranium, pyridostigmine bromide, sarin and cyclosarin, and vaccines (anthrax and botulinum toxoid) and produced Gulf War and Health, Volume 1, hereafter referred to as GW1 (IOM, 2000a). The second reviewed the health effects of solvents and pesticides and produced Gulf War and Health, Volume 2, hereafter referred to as GW2 (IOM, 2003a). The third is reviewing the health effects of the combustion products of oil-well fires, fuels, and synthetic compounds potentially used as propellants for Scud missiles. Sarin (GB; o-isopropyl methylphosphonofluoridate) and cyclosarin (GF; cyclohexyl methylphosphonofluoridate) are highly toxic organophosphorus (OP) nerve agents produced for chemical-warfare. They were first synthesized in Germany before and during World War II (Somani, 1992), and the first military use of sarin occurred in the Iran–Iraq conflict in the 1980s (Brown and Brix, 1998). Sarin and cyclosarin exert many of their effects by irreversibly binding to and inactivating acetylcholinesterase (AChE), the enzyme responsible for metabolizing the neurotransmitter acetylcholine (ACh). The inactivation of AChE results in an increase in ACh at cholinergic synapses (Gunderson et al., 1992) and overstimulation of muscles and nerves. After sufficient exposure to sarin or other OP nerve agents, that overstimulation causes what has been termed the acute cholinergic syndrome (see Chapter 2). Because of continued concerns of veterans, especially in light of recent toxicologic studies of low-dose exposure to sarin, the VA requested that IOM update its evaluation of the health effects of sarin. In response to that request, IOM convened the Committee on Gulf War and Health: Updated Literature Review of Sarin, which is responsible for the present report. The committee consists of several members of the committee responsible for GW2 (IOM, 2003a), which evaluated the health effects of pesticides and solvents used in the Gulf War. POTENTIAL US TROOP EXPOSURE During a cease-fire period in March 1991, troops from the US 37th and 307th engineering battalions destroyed enemy munitions throughout the occupied areas of southern Iraq (PAC, 1996). A large storage complex at Khamisiyah, Iraq, which contained more than 100 bunkers, was destroyed. Two sites in the complex—one of the bunkers and another site called the “pit”—contained stacks of 122-mm rockets loaded with sarin and cyclosarin (Committee on Veterans Affairs, 1998). According to the most recent estimates, 371 kg of sarin and cyclosarin combined was released (Winkenwerder, 2002). US troops performing demolitions were unaware of the presence of nerve agents because their detectors, being sensitive only to lethal or near-lethal concentrations of nerve agents (CDC, 1999), did not sound any alarms before demolition. It was not until October 1991 that inspectors from the United Nations Special Commission (UNSCOM) confirmed

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Gulf War and Health: Updated Literature Review of Sarin the presence of a mixture of sarin and cyclosarin at Khamisiyah (Committee on Veterans Affairs, 1998). No air monitoring was conducted at the time of the Khamisiyah demolition. At the request of the Presidential Advisory Committee (PAC), the Central Intelligence Agency (CIA) and the Department of Defense (DOD) used models to estimate ground-level concentrations of sarin and cyclosarin as a function of distance and direction from the detonation sites and then to estimate the extent of potential exposure of US military personnel to the nerve agents (PAC, 1996). The models produced a series of geographic maps of the Khamisiyah area that overlay known troop unit locations with the projected path of the sarin–cyclosarin plume. Initially, however, because of the complexity of the modeling that needed to be done, CIA–DOD estimated that any noticeable effects of sarin and cyclosarin would possibly have been seen within 25 km of the demolition site. The CIA–DOD report estimated, on the basis of troop locations, that about 10,000 US troops had been within 25 km and thus might have been exposed to sarin or cyclosarin over a period of hours (CIA–DOD, 1997). Given the uncertainties in that estimate, CIA–DOD doubled the distance and, again on the basis of unit locations, estimated that roughly 20,000 troops were within 50 km. In 1997, DOD mailed a survey to the 20,000 troops who were within 50 km of Khamisiyah; of the 7,400 respondents, more than 99% reported no acute effects that could be correlated with exposure to sarin or cyclosarin (CIA–DOD, 1997). The survey was attached to a letter from the secretary of veterans affairs indicating that chemical weapons had been present at Khamisiyah at the time of the demolitions. The letter also urged survey recipients to call the Gulf Incident Hotline with any additional information about the Khamisiyah incident or to report illnesses they attributed to their service in the Gulf War. The CIA–DOD models integrated four components: UNSCOM reporting and intelligence summaries of the amount, purity, and type of chemical-warfare agents stored at Khamisiyah. Results of experiments1 performed later at Dugway Proving Ground to simulate the demolition at Khamisiyah and thus estimate the amount of sarin and cyclosarin released, the release rate, and the type of release (instantaneous, continuous, or fly-out). A combination of dispersion models that incorporated meteorologic conditions at the time (including wind direction) to simulate the transport and diffusion of the plume so that agent concentrations downwind could be estimated. 1   These experiments used a substitute chemical (triethyl phosphate) to simulate chemical-warfare agent and measured agent release concentrations after replicating the rockets in the pit, terrain, original warhead design, stacking of rockets, and other relevant information.

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Gulf War and Health: Updated Literature Review of Sarin Unit location information to determine the position of troops in relation to the plume’s path (CIA–DOD, 1997). Potential exposure was categorized as a “first-noticeable-effects” level and a “general-population” level. At the first-noticeable-effects level, for which the lower limit was set at 1 mg-min/m3, the estimated exposure would be high enough to cause watery eyes, runny nose, tightness of chest, sweating, muscle twitching, or other early signs of exposure to OP compounds. The general-population level, for which the upper limit was set at 0.01296 mg-min/m3, was the “dosage below which the general population, including children and older people, could be expected to remain 72 hours with no effects”. Between those two was the “area of low-level exposure” (CIA–DOD, 1997). The models indicated that the plume of air concentrations that were the first-noticeable-effects levels would have dispersed to below 1 mg-min/m3 within 3 days of the demolition. The plume of air concentrations in the low-level range dispersed to be in the general-population level within 5 days of the demolition. Taking the potential first-noticeable-effects exposures and the potential low-level exposures into account, and eliminating the counting of the same troops on multiple days, CIA–DOD estimated that nearly 99,000 troops might have been exposed to sarin or cyclosarin above the general-population level over the course of 4 days after the demolition of the pit at Khamisiyah. Those CIA–DOD findings were challenged in a US Senate report (Committee on Veterans’ Affairs, 1998). The Senate report took issue with the methodology, especially the reconstruction of the pit site, with the nature of the demolition, and with the number of exposed troops. At the request of the Senate Committee on Veterans’ Affairs, the Air Force Technical Applications Center (AFTAC) prepared another exposure model. The AFTAC report summary—the only portion of the report made public—indicates that AFTAC used models different from those used by CIA–DOD to simulate atmospheric chemistry (Committee on Veterans’ Affairs, 1998). The report indicated additional geographic areas of low-level exposure not modeled by CIA–DOD. Neither the AFTAC nor the CIA–DOD report described above appears to have undergone independent peer review. A second CIA–DOD model, revised from the first and peer-reviewed, was completed in 2000 (Rostker, 2000), and a final report was released in 2002 (Winkenwerder, 2002). The second CIA–DOD model differed from the first in that it incorporated updated unit location and personnel data, revised meteorologic models, reduced estimates of nerve-agent release, combined toxicity of sarin and cyclosarin (the first model used only sarin), and adjusted the general population level to account for a briefer duration of troops’ potential exposure. Troops were considered exposed at an exposure rate of 0.0432 mg-min/m3 for sarin and 0.0144 mg-min/m3 for cyclosarin. Neither of the models found any troops to have been exposed above first-

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Gulf War and Health: Updated Literature Review of Sarin noticeable-effects levels at which concentrations would have been high enough to induce a particular type of chemical alarm to sound and visible signs of the acute cholinergic syndrome among troops. No medical reports by the US Army Medical Corps at the time of the release were consistent with signs and symptoms of acute exposure to sarin (PAC, 1996). That is in accordance with the results of the survey completed by 7,400 troops within 50 km of Khamisiyah: no reports of cholinergic effects (CIA–DOD, 1997). Two other storage sites in central Iraq, Muhammadiyat and Al Muthanna, sustained damage from air attacks during the Gulf War. Munitions containing 2.9 metric tons of sarin–cyclosarin and 1.5 metric tons of mustard gas were damaged at Muhammadiyat, and munitions containing 16.8 metric tons of sarin–cyclosarin were damaged at Al Muthanna (PAC, 1996). Atmospheric modeling by CIA–DOD determined that the nearest US personnel—400 km away—were outside the range of contamination (PAC, 1996). In summary, exposure models indicate that sarin–cyclosarin release occurred in March 1991 as a result of US demolition of a storage depot in Khamisiyah, Iraq. Exposure models indicate that the degree of exposure of US troops in the path of the sarin–cyclosarin plume was low. Two other storage sites in central Iraq that contained sarin, cyclosarin, and mustard gas were damaged in air attacks, but modeling indicates that all US troops were outside the range of contamination from those sites. All that information is consistent with the absence of reports of symptoms of an acute cholinergic syndrome by medical personnel or veterans. PREVIOUS IOM CONCLUSIONS ON SARIN AND CYCLOSARIN GW1 (IOM, 2000a) evaluated the health effects of the chemical-warfare agents sarin and cyclosarin. The GW1 committee was unable to formulate conclusions about cyclosarin, because of the paucity of toxicologic and human studies. After a review of the literature on sarin, the committee reached three conclusions, as follows: There is sufficient evidence of a causal relationship between exposure to sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to sarin exposure and resolves in days to months. The acute cholinergic syndrome has been recognized for decades and has been documented in human studies summarized in this chapter. The syndrome is evident seconds to hours after exposure and usually resolves in days to months. The syndrome is produced by sarin’s irreversible inhibition of AChE. Inactivation of the enzyme leads to the accumulation of ACh at cholinergic synapses. Excess ACh results in widespread overstimulation of muscles and nerves. At high doses, convulsions and death can occur.

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Gulf War and Health: Updated Literature Review of Sarin There is limited/suggestive evidence of an association between exposure to sarin at doses sufficient to cause acute cholinergic signs and symptoms and subsequent long-term health effects. Many health effects are reported to persist after sarin exposure: fatigue, headache, visual disturbances (asthenopia, blurred vision, and narrowing of the visual field), asthenia, shoulder stiffness, symptoms of posttraumatic stress disorder, and abnormal results (of unknown clinical significance) on the digit symbol test of psychomotor performance, electroencephalographic records of sleep, event-related potential, visual evoked potential, and computerized posturography. Those conclusions were based on retrospective studies of three exposed populations in which the cholinergic signs and symptoms were documented as acute effects of exposure. The findings in those studies were based on comparisons with control populations—one of industrial workers accidentally exposed to sarin in the United States and two of civilians exposed during terrorism episodes in Japan. The health effects listed above were documented at least 6 months after sarin exposure, and some persisted for up to 3 years, depending on the study. Whether the health effects noted above persist beyond 3 years had not been studied. There is inadequate/insufficient evidence to determine whether an association does or does not exist between exposure to sarin at low doses insufficient to cause acute cholinergic signs and symptoms and subsequent long-term adverse health effects. On the basis of findings in a study of nonhuman primates and in studies of humans exposed to OP insecticides, it is reasonable to hypothesize the occurrence of long-term adverse health effects of exposure to low concentrations of sarin. Studies of low exposure of workers have found that OP insecticides are associated with a higher prevalence of neurologic or psychiatric symptoms. However, no well-controlled human studies have looked expressly at sarin’s long-term health effects at doses that do not produce acute signs and symptoms. CHARGE TO THE PRESENT COMMITTEE The present committee was charged to review the peer-reviewed literature published since earlier IOM reports on health effects associated with exposure to sarin and related compounds, including relevant epidemiologic studies. With regard to the toxicologic literature, the committee used review articles to obtain and present a broad overview of the toxicology of sarin and cyclosarin and to assess biologic plausibility with respect to the compounds in question and health effects; individual toxicologic research papers were evaluated as warranted. The committee based determinations on the strength of the evidence of associations between the compounds and human health effects. If published, peer-reviewed

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Gulf War and Health: Updated Literature Review of Sarin information was available on the magnitude of sarin and cyclosarin exposure of Gulf War veterans, the committee addressed the potential health risks posed to the veterans. The committee also considered other relevant issues, such as exposure to multiple chemicals and genetic susceptibilities. The committee’s review included recommendations for additional scientific studies to resolve continued scientific uncertainty as warranted. The committee was not charged with determining whether a unique Gulf War syndrome exists, nor was it to make judgments regarding magnitudes of exposure of veterans to the putative agents. Moreover, the committee was not charged to focus on broader issues, such as the potential costs of compensation for veterans or policies regarding such compensation. Those decisions remain the responsibility of the secretary of veterans affairs. This report does, however, provide an assessment of the scientific evidence regarding health effects that may be associated with exposures to specific agents that were present in the Gulf War. The secretary may consider those health effects as the VA develops a compensation program for Gulf War veterans. APPROACH TO THE CHARGE The committee’s first step was to identify the literature that it would review. The search was conducted by using the names of sarin and cyclosarin and their synonyms. The search resulted in the retrieval of about 250 titles published from the time of preparation of GW1 (IOM, 2000a) to November 2003. Those titles and abstracts were reviewed to determine their relevance to the committee’s charge; potentially relevant studies were retrieved and evaluated. The literature was also searched for epidemiologic studies on OP compounds published since the last literature search for the preparation of GW2 (March, 1999), and such studies were reviewed. The committee used only published, peer-reviewed titles to draw its conclusions. Although the process of peer review by fellow professionals enhances the likelihood that a study has reached valid conclusions, it does not guarantee it. Accordingly, committee members read each study and considered its relevance and quality. The committee did not collect original data or perform any secondary data analysis. A great deal of research, including much epidemiologic work, has been conducted on the health effects of other OP compounds that are used as insecticides. As discussed in Chapter 2, most of the acute effects of sarin are thought to be mediated by inhibition of AChE, a common mechanism among OP compounds that leads to the acute cholinergic syndrome. Because of that common mechanism of action, it is possible that studies of those insecticides could provide some insight into potential health effects of sarin and cyclosarin. The mechanisms underlying any possible effects of low doses of the insecticides and nerve agents, however, are not yet understood. Therefore, the committee did not base its conclusions of the results of studies of the insecticides. Despite not using the

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Gulf War and Health: Updated Literature Review of Sarin OP insecticide data in its conclusion, the committee reviewed the OP epidemiology literature. The committee responsible for GW2 (IOM, 2003a) reviewed the literature on OP compounds. The present committee reviewed relevant epidemiology studies published since the preparation of that report. Animal studies had a small role in the committee’s assessment of association between putative agents and health outcomes. As with previous committees, this committee used animal data for making assessments of biologic plausibility in support of the epidemiologic data rather than as part of the weight of evidence to determine the likelihood that an exposure to a specific agent might cause a long-term outcome. The committee classified the evidence of an association between exposure to sarin and cyclosarin and a specific health outcome into five categories (Box 1-1). The categories closely resemble those used by previous committees that evaluated the effects of chemicals related to the Gulf War (IOM, 2000a, 2003a) and those used by several IOM committees that have evaluated vaccine safety (IOM, 1991, 1994a), herbicides used in Vietnam (IOM, 1994b, 1996, 1999, 2001, 2003b), and indoor pollutants related to asthma (IOM, 2000b). The committee’s conclusions, presented in Chapter 4, represent its collective judgment. The committee endeavored to express its judgment as clearly and precisely as the available data allowed, and it used the established categories of association from previous IOM studies because they have gained wide acceptance over more BOX 1-1 Categories of Evidence Sufficient Evidence of a Causal Relationship Evidence from available studies is sufficient to conclude that a causal relationship exists between exposure to a specific agent and a specific health outcome in humans, and the evidence is supported by experimental data. The evidence fulfills the guidelines for sufficient evidence of an association (below) and satisfies several of the guidelines used to assess causality: strength of association, dose–response relationship, consistency of association, biologic plausibility, and a temporal relationship. Sufficient Evidence of an Association Evidence from available studies is sufficient to conclude that there is a positive association. A consistent positive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance1 and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive associations, and the studies are sufficiently free of bias, including adequate control for confounding.

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Gulf War and Health: Updated Literature Review of Sarin Limited/Suggestive Evidence of an Association Evidence from available studies suggests an association between exposure to a specific agent and a specific health outcome in human studies, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality2 study reports a positive association that is sufficiently free of bias, including adequate control for confounding. Other corroborating studies provide support for the association, but they are not sufficiently free of bias, including confounding. Alternatively, several studies of less quality show consistent positive associations, and the results are probably not3 due to bias, including confounding. Inadequate/Insufficient Evidence to Determine Whether an Association Exists Evidence from available studies is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans. Limited/Suggestive Evidence of No Association Evidence from well-conducted studies is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any magnitude. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. The possibility of a very small increase in risk after exposure studied cannot be excluded. 1   Chance refers to sampling variability. 2   Factors used to characterize high-quality studies include the statistical stability of an association, whether or not dose–response or other trends were demonstrated, whether or not the association was among numerous comparisons that were made, and the quality of the assessments of exposure and outcome. Specifically, the quality of exposure assessment refers to specificity and sensitivity in relation to the association of interest. For instance, for insecticides, studies assessing specific insecticides (such as chlorpyrifos) have more specificity than those assessing classes of insecticides (such as organophosphorus), which in turn are more specific than those assessing pesticides more generally. With respect to sensitivity, studies are judged by the instruments used to measure exposure. Biologic monitoring data are theoretically the most preferable but are almost never obtainable in the context of a nonpersistent chemical and a disease with long latency, such as cancer. Other kinds of efforts can obtain sensitive measures of exposure, such as use of occupational or environmental monitoring data, use of more extensive industrial hygiene assessments, use of interview techniques that help to minimize recall bias (for example, photos of products and home and workplace walkthroughs). Similarly, there are questions about quality of outcome assessment—whether an outcome has been verified by a medical diagnosis in a consistent fashion. 3   Factors used to make this judgment include data on the relationship between potential confounders and related health end points in a given study, information on subject selection, and classification of exposure.

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Gulf War and Health: Updated Literature Review of Sarin than a decade by Congress, government agencies, researchers, and veterans groups. The five categories describe different levels of association and sound a recurring theme: the validity of an association is likely to vary with the extent to which the authors reduced common sources of error in drawing inferences—chance variation, bias, and confounding. Accordingly, the criteria for each category express a degree of confidence based on the extent to which sources of error were reduced. As the committee began its evaluation, neither the existence nor the absence of an association was presumed. Rather, the committee weighed the strengths and weaknesses of the available evidence, including studies reviewed in GW1 and recent studies, to reach conclusions. It should be noted that although causation and association are often used interchangeably, they are not the same; an association can indicate an increase in risk even if exposure to the putative agent is not the sole or even primary cause. Epidemiologic studies can establish statistical associations between exposure to specific agents and health effects, and associations are generally estimated by using relative risks or odds ratios. To conclude that an association exists, it is necessary for exposure to an agent to be followed by the health outcome more frequently than it would be expected to by chance alone. Furthermore, it is almost always necessary to find that the effect occurs consistently in several studies. Epidemiologists seldom consider a single study sufficient to establish an association; rather, it is desirable to replicate the findings in other studies to draw conclusions about the association. Results of separate studies are sometimes conflicting. It is sometimes possible to attribute discordant study results to such characteristics as soundness of study design, quality of execution, and the influence of different forms of bias. Studies that result in a statistically precise measure of association suggest that the observed result was unlikely to be due to chance. When the measure of association does not show a statistically precise effect, it is important to consider the size of the sample and whether the study had the power to detect an effect of a given size. Epidemiology concerns itself with the study of the determinants, frequency, and distribution of disease in human populations. A focus on populations distinguishes epidemiology from medical disciplines that focus on the individual. Epidemiologic studies examine the relationship between exposures to agents of interest in a studied population and the development of health outcomes, so they can be used to generate hypotheses for study or to test hypotheses posed by investigators. Epidemiology study designs differ in their ability to provide valid estimates of an association (Ellwood, 1998). Randomized controlled trials yield the most robust type of evidence; cohort or case–control studies are more susceptible to bias. Cross-sectional studies generally provide a lower level of evidence than cohort and case–control studies. Determining whether a given statistical association rises to the level of causation requires inference (Hill, 1965). As discussed by

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Gulf War and Health: Updated Literature Review of Sarin the International Agency for Research on Cancer in the preamble of its monographs evaluating cancer risks (for example, IARC, 2004), a strong association in an epidemiology study, an association being seen in a number of different studies, an increase risk of disease with increasing amount of exposure or a decline in risk of disease after cessation of exposure, and specificity of an effect all strengthen the likelihood that an association seen in epidemiology study is a causal effect. Inferences from epidemiology studies, however, are often limited to population associations in many cases because of a lack of exposure information. Exposures are not controlled in epidemiology studies and, in some cases, there is large uncertainty in the assessment of the exposure. That is especially the case for the available epidemiology studies of sarin. To assess explanations other than causality, one must bring together evidence from different studies and apply well-established criteria (which have been refined over more than a century) (Evans, 1976; Hill, 1965; Susser, 1973, 1977, 1988, 1991; Wegman et al., 1997). The strengths and limitations of the various epidemiology designs, the issues to be considered when assessing epidemiology studies, and the outcomes measured in the studies are discussed in detail in Chapter 2 of GW2 (IOM, 2003a). By examining numerous epidemiologic studies, the committee addressed the question, “Does the available evidence support a causal relationship or an association between exposure to a specific agent and a health outcome?” An association between a specific agent and a specific health outcome does not mean that exposure to the agent invariably results in the health outcome or that all cases of the health outcome result from exposure to the agent. Such complete correspondence between agent and disease is the exception in large populations (IOM, 1994b). The committee evaluated the data and based its conclusions on the strength and coherence of the data in the selected studies. ORGANIZATION OF REPORT The remainder of this report is organized into three chapters and an appendix. Chapter 2 reviews the relevant animal and in vitro toxicology data to provide background on the mechanism of action of sarin and cyclosarin and to permit evaluation of the biologic plausibility of any effects seen in the epidemiologic literature. Chapter 3 reviews relevant epidemiologic studies published since GW1 to provide the basis of the committee’s conclusions on the health effects of sarin and cyclosarin. The committee’s overall conclusions on the health effects of sarin and cyclosarin, with summaries of the studies and the rationale that lead to those conclusions, are presented in Chapter 4. As discussed above, sarin and cyclosarin are OP compounds and therefore have some mechanisms of action in common with OP insecticides, which have been more thoroughly studied than the chemical-warfare agents. In light of those similarities, in Appendix A the committee has summarized the conclusions on OP insecticides

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Gulf War and Health: Updated Literature Review of Sarin from GW2 and reviewed epidemiologic data on those insecticides published since GW2 (IOM, 2003a). REFERENCES Brown MA, Brix KA. 1998. Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents. Journal of Applied Toxicology 18(6):393–408. CDC (Centers for Disease Control and Prevention). 1999. Background Document on Gulf War-Related Research for the Health Impact of Chemical Exposures During the Gulf War: A Re-search Planning Conference. Atlanta, GA: CDC. CIA–DOD (Central Intelligence Agency and Department of Defense). 1997. Modeling the Chemical Warfare Agent Release at the Khamisiyah Pit. Washington, DC: CIA–DOD. Committee on Veterans Affairs (US Senate). 1998. Report of the Special Investigation Unit on Gulf War Illnesses. 105th Congress, 2nd session. Washington, DC: US Government Printing Office. S.PRT 105-139. Ellwood JM. 1998. Critical Appraisal of Epidemiological Studies and Clinical Trials. 2nd ed. Oxford, UK: Oxford University Press. Evans AS. 1976. Causation and disease: The Henle-Koch postulates revisited. Yale Journal of Biology and Medicine 49(2):175–195. Gunderson CH, Lehmann CR, Sidell FR, Jabbari B. 1992. Nerve agents: A review. Neurology 42(5):946–950. Hill AB. 1965. The environment and disease: Association or causation? Proceedings of the Royal Society of Medicine 58:295–300. IARC (International Agency for Research on Cancer). 2004. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Tobacco Smoke and Involuntary Smoking. Volume 83. Lyon, France: IARC. IOM (Institute of Medicine). 1991. Adverse Effects of Pertussis and Rubella Vaccine. Washington, DC: National Academy Press. IOM. 1994a. DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis. Washington, DC: National Academy Press. IOM. 1994b. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000a. Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, and Vaccines. Washington, DC: National Academy Press. IOM. 2000b. Clearing the Air: Asthma and Indoor Air Exposures. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003a. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. IOM. 2003b. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. PAC (Presidential Advisory Committee on Gulf War Veterans’ Illnesses). 1996. Presidential Advisory Committee on Gulf War Veterans’ Illnesses: Final Report. Washington, DC: US Government Printing Office. Rostker B. 2000. US demolition of operations at Khamisiyah. Washington, DC: Department of Defense, December 7. http://www.gulflink.osd.mil/khamisiyah/index.html. Somani SM. 1992. Chemical Warfare Agents. New York: Academic Press.

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Gulf War and Health: Updated Literature Review of Sarin Susser M. 1973. Causal Thinking in the Health Sciences: Concepts and Strategies of Epidemiology. New York: Oxford University Press. Susser M. 1977. Judgement and causal inference: Criteria in epidemiologic studies. American Journal of Epidemiology 105(1):1–15. Susser M. 1988. Falsification, verification, and causal inference in epidemiology: Reconsideration in the light of Sir Karl Popper’s philosophy. In: Rothman KJ, ed. Causal Inference. Chestnut Hill, MA: Epidemiology Resources. Pp. 33–58. Susser M. 1991. What is a cause and how do we know one? A grammar for pragmatic epidemiology. American Journal of Epidemiology 133(7):635–648. Wegman DH, Woods NF, Bailar JC. 1997. Invited commentary: How would we know a Gulf War syndrome if we saw one? American Journal of Epidemiology 146(9):704–711. Winkenwerder W. 2002. US demolition operations at Khamisiyah. Final Report. Washington, DC: Department of Defense. http://www.gulflink.osd.mil/khamisiyah/index.html.