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INTRODUCTION

On August 2, 1990, Iraq invaded Kuwait. Operation Desert Shield, the buildup of coalition forces in the Persian Gulf region led by the United States, began in response to that invasion. Operation Desert Storm began on January 16, 1991, with an air offensive, and the 4-day ground war was over by February 28; a ceasefire was signed in April 1991. During the war almost 700,000 US troops were deployed to the Persian Gulf region, although by June 1991 only about 50,000 US troops remained in the region. Although brief with relatively few injuries and deaths among the coalition, the legacy of the war has been a continuing plethora of health problems for many veterans even 20 years after the war. Numerous exposures have been implicated as the cause of these problems, ranging from oil-well fires to the use of the prophylactic antinerve agent pyridostigmine bromide (PB). These health problems, particularly a constellation of symptoms that have been termed multisymptom illness or Gulf War illness, continue to plague as many as a third of the veterans who were deployed to the Gulf War. Furthermore, these unexplained illnesses are seen in veterans from several of the countries that formed the coalition forces, including the United Kingdom (UK), Australia, Canada, and Denmark. Numerous researchers have studied the variety of health outcomes presented by Gulf War veterans and attempted to identify possible exposures that may have caused or contributed to those outcomes.

BACKGROUND

In 1998, in response to the growing concerns of Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The NAS assigned the study to the Institute of Medicine (IOM).

The Persian Gulf War legislation directs the IOM to study diverse biologic, chemical, and physical agents. Exposures to many of the Gulf War agents have been extensively studied and characterized, primarily in occupational settings (for example, exposure to pesticides, solvents, and fuels), but exposures to others have not been as well studied and characterized in human populations (for example, exposure to nerve agents and vaccines).



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1 INTRODUCTION On August 2, 1990, Iraq invaded Kuwait. Operation Desert Shield, the buildup of coalition forces in the Persian Gulf region led by the United States, began in response to that invasion. Operation Desert Storm began on January 16, 1991, with an air offensive, and the 4- day ground war was over by February 28; a ceasefire was signed in April 1991. During the war almost 700,000 US troops were deployed to the Persian Gulf region, although by June 1991 only about 50,000 US troops remained in the region. Although brief with relatively few injuries and deaths among the coalition, the legacy of the war has been a continuing plethora of health problems for many veterans even 20 years after the war. Numerous exposures have been implicated as the cause of these problems, ranging from oil-well fires to the use of the prophylactic antinerve agent pyridostigmine bromide (PB). These health problems, particularly a constellation of symptoms that have been termed multisymptom illness or Gulf War illness, continue to plague as many as a third of the veterans who were deployed to the Gulf War. Furthermore, these unexplained illnesses are seen in veterans from several of the countries that formed the coalition forces, including the United Kingdom (UK), Australia, Canada, and Denmark. Numerous researchers have studied the variety of health outcomes presented by Gulf War veterans and attempted to identify possible exposures that may have caused or contributed to those outcomes. BACKGROUND In 1998, in response to the growing concerns of Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, or preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The NAS assigned the study to the Institute of Medicine (IOM). The Persian Gulf War legislation directs the IOM to study diverse biologic, chemical, and physical agents. Exposures to many of the Gulf War agents have been extensively studied and characterized, primarily in occupational settings (for example, exposure to pesticides, solvents, and fuels), but exposures to others have not been as well studied and characterized in human populations (for example, exposure to nerve agents and vaccines). 11

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12 GULF WAR AND HEALTH Given the large number of agents to study, IOM divided the task into several reviews, which are now complete: Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM, 2000); Gulf War and Health, Volume 2: Insecticides and Solvents (IOM, 2003); Gulf War and Health: Updated Literature Review of Sarin (IOM, 2004); Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants (IOM, 2005); Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature (IOM, 2006a); Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (IOM, 2006b); Gulf War and Health, Volume 5: Infectious Disease (IOM, 2007); Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress (IOM, 2008); and Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury (IOM, 2009). In 2005, the Department of Veterans Affairs (VA) requested that the IOM appoint a committee, the Committee on Gulf War and Health: A Review of the Medical Literature Relative to Gulf War Veterans’ Health, to review that body of literature and to summarize what was known about the then current status of the veterans’ health. In 2006 the committee produced a report, Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War that summarized the overall health effects in veterans and noted which health outcomes are more evident in Gulf War veterans than in their nondeployed counterparts, irrespective of the specific exposures experienced by the deployed veterans. This current report is an update of Volume 4, covering the literature published since 2006 on the health effects seen in veterans deployed to the Persian Gulf in 1990-1991. THE GULF WAR SETTING1 In Gulf War and Health, Volume 4, that committee’s charge was not to review the scientific evidence on the possible health effects of various agents to which Gulf War veterans were potentially exposed, but rather to look at the prevalence of the various health effects seen in Gulf War deployed veterans and to determine if that prevalence was greater than that seen in veterans who served in the military during the Gulf War but were not deployed. The current committee (the Update committee) is also not charged with looking at whether a specific exposure could cause a health effect, but like the Volume 4 committee, the Update committee recognized that its members needed to have an appreciation of the Gulf War experience, including the magnitudes of possible exposures for all the military forces that served in the gulf, including those deployed to the region after the war ended. Therefore, in addition to reviewing studies from the United States, the committee reviewed studies of Gulf War veterans from Australia, Canada, Denmark, the United Kingdom, Kuwait, and France. The information in this section provides a context for the many scientific articles that the current committee reviewed and an appreciation (albeit limited) of the collective experience of Gulf War veterans. It is compiled from many sources including Gunby (1991), Hyams et al. (1995), IOM (1995, 1996, 1999), Joellenbeck et al. (1998), Lawler et al. (1997), NIH Technology Assessment Workshop Panel (1994), PAC (1996, 1997), Persian Gulf Veterans Coordinating Board (1995), Ursano and Norwood (1996), and VA (1998). 1 This section is adapted from Gulf War and Health, Volume 1 (IOM, 2000) and Gulf War and Health, Volume 4 (IOM, 2006).

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INTRODUCTION 13 Deployment The pace of the buildup for the Gulf War was unprecedented. Within 5 days after Iraq invaded Kuwait, the United States began moving troops into the region as part of Operation Desert Shield. By September 15, 1990, the number of American servicemembers reached 150,000 and included nearly 50,000 reservists. Within the next month, another 60,000 troops arrived in the Persian Gulf region; in November, an additional 135,000 reservists and National Guard members were called up. By February 24, 1991, more than 500,000 US troops had been deployed to the Persian Gulf region. In addition to the US troops, a coalition force of 34 member countries was eventually assembled. The Gulf War reflected many changes from previous wars, particularly in the demographic composition of military personnel and the uncertainty of conditions for many reservists. Of the nearly 700,000 US troops who fought in Operation Desert Shield and Operation Desert Storm, almost 7% were women and about 17% (106,000) were from National Guard and reserve units. Military personnel were, overall, older than those who had participated in previous wars with a mean age of 28 years. Seventy percent of the troops were non- Hispanic/white; 23% were black, and 5% were Hispanic (Joseph, 1997). Rapid mobilization exerted substantial pressure on those who were deployed, disrupting lives, separating families, and, for reserve and National Guard units, creating uncertainty about whether jobs would be available when they returned to civilian life. Living Conditions Combat troops were crowded into warehouses and tents on arrival in the gulf region and then often moved to isolated desert locations. Most troops lived in tents and slept on cots lined up side by side, affording virtually no privacy or quiet. Sanitation was often primitive, with strains on latrines and communal washing facilities. Hot showers were infrequent, the interval between laundering uniforms was sometimes long, and desert flies were a constant nuisance, as were scorpions and snakes. Military personnel worked long hours and had narrowly restricted outlets for relaxation. Troops were ordered not to fraternize with local people, and alcoholic drinks were prohibited in deference to religious beliefs in the host countries. A mild, traveler’s type of diarrhea affected more than half of the troops in some units. Fresh fruits and vegetables from neighboring countries were identified as the cause and were removed from the diet. Thereafter, the diet consisted mostly of packaged foods and bottled water. For the first 2 months of troop deployment (August and September 1990) the weather was extremely hot, with air temperatures as high as 115°F and sand temperatures reaching 150°F. Except for coastal regions, the relative humidity was less than 40%. Troops had to drink large quantities of water to prevent dehydration. Although the summers were hot and dry, temperatures in winter (December-March) were low, with wind-chill temperatures at night dropping to well below freezing. Wind and blowing sand made protection of skin and eyes imperative. Goggles and sunglasses helped somewhat, but visibility was often poor. Environmental and Chemical Exposures The most visually dramatic environmental event of the Gulf War was the smoke from more than 750 oil-well fires in Kuwait. Smoke plumes from individual fires rose and combined to form giant plumes that could be seen for hundreds of kilometers. As noted in Volume 4, it has

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14 GULF WAR AND HEALTH been difficult to correlate veterans’ self-reports of exposure to the smoke with dispersion models based on troop location information (IOM, 2006b). There were additional potential sources of exposure to petroleum-based combustion products. Kerosene, diesel, and leaded gasoline were used in unvented tent heaters, cooking stoves, and portable generators. Exposures to tent-heater emissions were not specifically documented, but a simulation study was conducted after the war to determine exposure (Cheng et al., 2001). Petroleum products, including diesel fuels, were also used to suppress sand and dust, and petroleum fuels were used to aid in the burning of waste and trash. Pesticides, including dog flea collars, were widely used by troops in the Persian Gulf to combat the region’s ubiquitous insect and rodent populations, and although guidelines for use were strict, there were many reports of misuse. The pesticides used included methyl carbamates, organophosphates, pyrethroids, and chlorinated hydrocarbons. The use of those pesticides is covered in several reports (for example, DoD, 2001; RAND, 2000); however, objective information regarding individual levels of pesticide exposure is generally not available, and reports by individual veterans as to their use of and possible exposure to pesticides are subject to considerable recall bias. Many exposures could have been related to particular occupational activities in the Gulf War. The majority of occupational chemical exposures appear to have been related to repair and maintenance activities, including battery repair (corrosive liquids), cleaning and degreasing (solvents, including chlorinated hydrocarbons), sandblasting (abrasive particles), vehicle repair (asbestos, carbon monoxide, and organic solvents), weapon repair (lead particles), and welding and cutting (chromates, nitrogen dioxide, and heated metal fumes). In addition, troops painted vehicles and other equipment used in the gulf with a chemical-agent-resistant coating either before being shipped to the gulf or at ports in Saudi Arabia. Working conditions in the field were not ideal and recommended occupational-hygiene standards might not have been followed at all times. Exposure of US personnel to depleted uranium (DU) occurred as the result of friendly- fire incidents, cleanup operations, and accidents (including fires). Other personnel might have inhaled DU dust through contact with DU-contaminated tanks or munitions. Assessment of DU exposure, especially high exposure, is considered to be more accurate than assessment of exposure to most other agents because of the availability of biologic monitoring information. Threat of Chemical and Biologic Warfare When US troops arrived in the gulf, they had no way of knowing whether they would be exposed to biologic and chemical weapons. Iraq previously had used such weapons in fighting Iran and in attacks on the Kurdish minority in Iraq. Military leaders feared that the use of such weapons in the gulf could result in the deaths of tens of thousands of Americans. Therefore, in addition to the standard vaccinations before military deployment, about 150,000 troops received anthrax vaccine and about 8,000 troops received botulinum toxoid vaccine. In some cases, vaccination records were kept, and they provide an objective measure of exposure in addition to self-reporting by troops. Troops were also given blister packs of 21 tablets of pyridostigmine bromide (PB) to protect against agents of chemical warfare, specifically nerve gas. Troops were to take PB on the orders of a commanding officer when a chemical-warfare attack was believed to be imminent. Chemical sensors and alarms were distributed throughout the region to warn of such attacks. The alarms were extremely sensitive and could be triggered by many substances, including some

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INTRODUCTION 15 organic solvents, vehicle exhaust fumes, and insecticides. Alarms sounded often and troops responded by donning the confining protective gear and ingesting PB as an antidote to nerve gas. In addition to the alarms, there were widespread reports of dead sheep, goats, and camels, which troops were taught could be indication of the use of chemical or biologic weapons. The sounding of the alarms, the reports of dead animals, and rumors that other units had been hit by chemical warfare agents caused the troops to be concerned that they would be or had been exposed to such agents. Despite the small numbers of US personnel injured or killed during combat in the Gulf War, the troops, as in any war, faced the fear of death, injury, or capture by the enemy. After the war, there was the potential for other exposures, including US demolition of a munitions storage complex at Khamisiyah, Iraq, which—unbeknownst to demolition troops at the time—contained stores of sarin and cyclosarin. The potential exposures to sarin and cyclosarin from the Khamisiyah incident have been the subject of specific modeling and health outcome studies. Depending on the dispersion model used to estimate the sarin and cyclosarin plume and troop unit locations, the number of Gulf War veterans who may have been exposed to the nerve agents ranged from an initial estimate of 10,000 troops within 25 km of Khamisiyah in 1997 to more than 100,000 troops using a 2000 model. However, more than 35,000 troops originally considered to have been exposed and notified that they may have been within the plume were subsequently considered to have been unexposed and 37,000 troops were newly identified as being in the hazard area (IOM, 2006b), adding to the confusion of how many troops were actually exposed to nerve agents and at what levels. As stated in Volume 4, “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” (IOM, 2006b). CHARGE TO THE COMMITTEE The charge to the Volume 4 committee and to the current IOM committee (Update committee) is different from charges to other IOM Gulf War and Health committees in that the Volume 4 and Update committees were not asked to associate health outcomes with specific biologic, chemical, or other agents believed to have been present in the gulf, but rather to examine health outcomes related to deployment to the gulf region in general. The specific charge to the Update committee, as requested by the VA, was to review, evaluate, and summarize the literature on the following health outcomes noted in the 2006 report that seem to appear at higher incidence or prevalence in Gulf War-deployed veterans: cancer (particularly brain and testicular cancer), amyotrophic lateral sclerosis and other neurologic diseases (for example, Parkinson’s disease and multiple sclerosis), birth defects and other adverse pregnancy outcomes, and postdeployment psychiatric conditions. The committee also was to review studies on cause- specific mortality in Gulf War veterans as recommended in the 2006 report. Finally, the committee was to examine the literature to identify any emerging health outcomes. Thus, the current committee has limited its review to epidemiologic studies of health outcomes published since the last literature search conducted for Volume 4 and those studies included in Volume 4. The studies must compare the health status of Gulf War veterans compared with nondeployed veterans or veterans deployed elsewhere such as Bosnia. Because the committee was not attempting to link health outcomes to any exposures other than deployment to a war zone, for which there is no known animal model, the committee did not review toxicologic, animal, or experimental studies. Where studies attempted to associate health

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16 GULF WAR AND HEALTH effects with specific exposures, such as oil-well fire smoke or nerve gas agents, those studies were also considered. COMMITTEE’S APPROACH TO ITS CHARGE The committee began its evaluation by holding two public sessions. At those sessions, the committee heard from the VA and from Gulf War veterans about health outcomes that had been identified in Gulf War veterans during the past 20 years. During the second public session, the committee also heard presentations about health outcomes that were of particular concern to female veterans, a presentation from the chair of the IOM committee that had prepared Gulf War and Health, Volume 4, and from representatives of the VA Research Advisory Committee on Gulf War Veterans’ Illnesses, who discussed that committee’s findings and recommendations. Those sessions helped the committee to put its efforts in context and to clarify an approach to its task. The committee sought to characterize and weigh the strengths and limitations of the available evidence. It did not address policy issues, such as decisions regarding the potential costs of compensation. Extensive searches of the epidemiologic literature published since 2005 were conducted using the same search strategy as that used for Volume 4; over 1000 potentially relevant references were retrieved. After an assessment of the titles and abstracts of the initial searches, the committee focused on some 400 potentially relevant epidemiologic studies for review and evaluation. The committee adopted a policy of using only peer-reviewed published literature as the basis for its conclusions, with the exception of some government reports. The process of peer review by fellow professionals increases the likelihood of high quality but does not guarantee the validity of a study or the ability to generalize its findings. Accordingly, committee members read each study critically and considered its relevance and quality. The committee did not collect original data, nor did it perform any secondary data analysis. To be comprehensive in its approach to the epidemiologic literature, the committee also reviewed the studies that had been included in Volume 4 as primary or secondary studies. The Volume 4 committee did not draw conclusions as to the strength of association between an exposure, that is, deployment to the Gulf War, and a particular health effect. However, Volume 4 did indicate what health outcomes had a greater prevalence in deployed veterans compared with nondeployed veterans. The Update committee has been asked to make a determination on the strength of the association between being deployed to the Gulf War and specific health effects. To make such a determination, the committee needed to review the studies cited in Volume 4 to assess whether those studies would still be classified as primary or secondary. The committee then considered the epidemiologic studies identified in the updated literature search. These studies were also reviewed and classified as primary or secondary according to the criteria discussed below and in more detail in Chapter 2. Once the committee had assessed the studies cited in Volume 4 and evaluated the new studies identified from the updated literature, it reviewed the entire body of relevant literature using a weight-of-the-evidence approach and determined the strength of the association between being deployed to the Gulf War and a specific health outcome based on the primary studies and supported by the secondary studies.

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INTRODUCTION 17 COMPLEXITIES IN RESOLVING GULF WAR AND HEALTH ISSUES Investigations of the health effects of past wars have often focused on narrowly defined hazards or health outcomes, such as infectious diseases (for example, typhoid and malaria) during the Civil War, specific chemical hazards (for example, mustard gas in World War I and Agent Orange and other herbicides in Vietnam), and combat injuries. A discussion of the possible health effects of Gulf War service, however, involves many complex issues, some of which are explored below. They include exposure to multiple biologic and chemical agents as described above, limitations of exposure information collected during or modeled after deployment, individual variability factors, and illnesses that are often nonspecific and lack defined medical diagnoses or treatment protocols. The committee was not tasked with addressing those issues, but it presents them in this introductory chapter to acknowledge the difficulties faced by veterans, researchers, policymakers, and others in reaching an understanding about the veterans’ ill health. Multiple Exposures and Chemical Interactions Although Operation Desert Shield and Operation Desert Storm were relatively brief, military personnel were potentially exposed to numerous harmful agents simultaneously. These include agents administered as preventive measures (such as PB, vaccines, pesticides, and insecticides), hazards of the natural environment (such as sand and endemic diseases), job- specific agents (such as paints, solvents, and diesel fumes), war-related agents (such as smoke from oil-well fires and DU), and hazards from cleanup operations (such as sarin and cyclosarin). Thus, military personnel might have been exposed to various agents at various doses for various periods. Many of the exposures are not specific to the Gulf War, but the number and combination of agents to which the veterans might have been exposed make it difficult to determine whether any agent or combination of agents is the cause of many Gulf War veterans’ illnesses. The veterans also experienced numerous psychological stressors such as uncertainty about the presence of chemical and biological agents, seeing dead or wounded combatants and civilians, and anxiety about their families and jobs at home. The impacts of these psychologic stressors are discussed in more depth in Gulf War and Health, Volume 6. Limitations of Exposure Information Determining whether Gulf War veterans face an increased risk of illness because of their exposures during the war requires extensive information about each exposure, such as the actual agents, the duration of exposure, the route of entry, the internal dose, and documentation of adverse reactions. But very little is known about most Gulf War exposures. After the ground war, an environmental-monitoring effort was initiated primarily because of concerns related to smoke from oil-well fires and exposure to sarin and cyclosarin rather than for the other agents to which the troops might have been exposed. Consequently, exposure data on other agents are lacking or are severely limited. At the request of the DoD, the RAND Corporation conducted a postwar survey to assess possible exposures to pesticides (RAND, 2000). Various exposure assessment tools have been used in research to fill gaps in exposure information, but there are problems in reconstruction of past exposure events. For example, veterans have been surveyed to obtain recollections about agents to which they might have been exposed, although survey results might be limited by recall bias. Models have been refined to

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18 GULF WAR AND HEALTH estimate exposures to sarin and cyclosarin, but it is difficult to incorporate intelligence information, meteorologic data, transport and dispersion data, and troop-unit location information accurately (see Volume 4, Chapter 2, Exposures in the Persian Gulf). Extensive efforts have been made to model and obtain information on potential exposures to DU, smoke from oil-well fires, and other agents. Although modeling efforts are important for discerning the details of exposures of Gulf War veterans, they require external review and validation. Furthermore, even if there were accurate troop location data, the location of individual soldiers would be very uncertain. Because of the limitations in the exposure data, it is difficult to determine the likelihood of increased risk for disease or other adverse health effects in Gulf War veterans that are due specifically to biologic and chemical agents. Although many studies have assessed military personnel exposures to various preventive agents including PB and pesticides during the Gulf War, these studies have been based on individuals’ recall of the measures they received or took, frequently under stress situations, and have rarely been verified by in situ measurements or records. This potential for recall bias also contributes to the difficulty in identifying specific causes of the veterans’ health problems. Individual Variability Differences among people in their genetic, biologic, psychologic, and social vulnerabilities add to the complexities in determining health outcomes related to specific agents. People with increased sensitivity to some agents will have different health outcomes than people who are less sensitive. For example, a person who is a poor metabolizer of a particular substance, depending on his or her genetic makeup, might be at higher or lower risk for specific health effects if exposed to the substance. For example, researchers are investigating the genotypes that code for two forms of an enzyme that differ in the rate at which they hydrolyze particular organophosphates (including sarin) (Costa et al., 1999). Lower hydrolyzing activity would mean that despite identical exposure to sarin, more sarin would be bioavailable in people who are poor metabolizers and could result in increased anticholinesterase effects. See Appendix A for a discussion of the metabolism of chemical agents. VOLUME 4 CONCLUSIONS In Gulf War and Health, Volume 4 (IOM, 2006b), no associations were found between being deployed to the Gulf War and any health effects, nor were any associations found between specific exposures that may have occurred during deployment and health effects. The committee that prepared that volume, however, did report that Gulf War veterans, regardless of the country they served, consistently reported higher rates of nearly all symptoms examined than their nondeployed counterparts. This was true for veterans from the United States, the United Kingdom, Canada, Australia, and Denmark. The Volume 4 committee found that the majority of studies of Gulf War veterans relied on self-reports of symptoms and medical conditions. Fewer studies used objective measures or diagnostic medical tests to confirm the veterans’ reports. The committee recognized that many of the veterans symptoms were subjective—for example, headache, joint pain—and could not be evaluated other than by self-report, but other symptoms and medical conditions—for example, fibromyalgia, irritable bowel syndrome—had diagnostic criteria or laboratory tests that could be used to make or verify a diagnosis. Therefore, the Volume 4 committee grouped the health effects in Gulf War veterans on the basis of whether the

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INTRODUCTION 19 health effects were based primarily on symptoms and self-reports, or on objective measures and diagnostic medical tests. Box 1-1 summarizes of the Volume 4 findings and recommendations. BOX 1-1 Brief Summary of Findings and Recommendations Outcomes Based Primarily on Symptoms or Self-Reports • No unique syndrome, unique illness, or unique symptom complex in deployed Gulf War veterans was found. Veterans of the Gulf War report higher rates of nearly all symptoms or sets of symptoms than their nondeployed counterparts; 29% of veterans meet a case definition of “multisymptom illness,” as compared with 16% of nondeployed veterans. • Multisymptom-based medical conditions reported to occur more frequently among deployed Gulf War veterans include fibromyalgia, chronic fatigue syndrome, and multiple chemical sensitivity. • Deployment places veterans at increased risk for symptoms that meet diagnostic criteria for a number of psychiatric illnesses, particularly posttraumatic stress disorder (PTSD), anxiety, depression, and substance abuse. In addition, co-morbidities were reported among a number of veterans, with PTSD, depression, anxiety, and/or substance abuse. • Studies of Gulf War deployed veterans vs nondeployed have not demonstrated differences in cognitive and motor measures as determined through neurobehavioral testing. • Studies of returning Gulf War veterans with at least one of the symptoms most commonly reported by Gulf War veterans (for example, fatigue, memory loss, confusion, inability to concentrate, mood swings, somnolence, gastrointestinal distress, muscle and joint pain, skin/mucous membrane complaints) found poorer performance on cognitive tests when compared to returning Gulf War veterans who did not report such symptoms. • Other symptoms that appear to be self-reported more often by deployed veterans are gastrointestinal symptoms, particularly dyspepsia; dermatologic conditions, particularly atopic dermatitis and warts; and joint pains (arthralgias). Outcomes with Objective Measures or Diagnostic Medical Tests • Studies of mortality provide evidence for a modest increase in transportation-related injuries and mortalities among Gulf War deployed compared to nondeployed veterans in the decade immediately following deployment. However, studies with longer follow-up indicate that the increased injury rate was likely to have been restricted to the first several years after the war. • With regard to all-causes of hospitalization, excess hospitalizations did not occur among veterans of the Gulf War who remained on active duty through 1994. However, Gulf War veterans who left the military reported worse health outcomes than those who remained. • The studies do not demonstrate consistent evidence of increased overall cancer in the Gulf War veterans compared to nondeployed veterans. Studies of testicular cancer produced inconsistent results, but the latency period for many cancers may not have been reached among Gulf War veterans. • Studies indicate that Gulf War veterans might be at increased risk for amyotrophic lateral sclerosis (ALS). • There does not appear to be an increase in the prevalence of peripheral neuropathy in deployed versus non- deployed veterans, as defined by history, physical examination, and electrophysiologic studies. • It does not appear that there is a difference in the prevalence of cardiovascular disease or diabetes between deployed and nondeployed veterans. • Overall there is no consistent pattern of one or more birth defects with a higher prevalence for the offspring of male or female Gulf War veterans. Only one set of defects, urinary tract abnormalities, has been found to be increased in more than one well-designed study. • Respiratory symptoms are strongly associated with Gulf War deployment when using comparison groups of non- deployed veterans in most studies addressing this question. However, studies with objective pulmonary function measures find no association between respiratory illnesses with Gulf War deployment across the four cohorts in which this has been investigated.

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20 GULF WAR AND HEALTH Outcomes with Objective Measures or Diagnostic Medical Tests Associated with Specific Gulf War Exposures • Among studies that examined pulmonary outcomes in associations with specific exposures in the Gulf War Theater, exacerbation of asthma associated with oil-well fire smoke has been indicated. • With respect to nerve agents at Khamisiyah, no study using objective estimates of exposure has found associations with pulmonary function measures or physician-diagnosed respiratory disease. Another study indicated that there might be an increase in brain cancer among such veterans; however, the exposure models are highly uncertain. Recommendations • Pre- and post-deployment screening of health status. • Assessment of exposures. • Surveillance for adverse health outcomes, specifically cancer, ALS, birth defects, adverse pregnancy outcomes, post-deployment psychiatric outcomes, and mortality. Organization of the Report Chapter 2 provides a brief background in epidemiology and describes the committee’s methods for choosing the epidemiologic studies that are reviewed in later chapters. Chapter 3 describes the major Gulf War cohorts and provides information about the numerous studies that have been derived from them; the chapter includes a summary table that lists all the original cohorts and their derivative studies. The original table of studies was provided in Volume 4 and has been updated here. Chapter 4 describes and analyzes the studies of health outcomes in Gulf War veterans; it also provides the basis for the committee’s conclusions and recommendations, which are presented in Chapter 5. Appendix A briefly reviews the toxicity of cholinesterase inhibitors such as organophosphate pesticides and the adverse health outcomes that might result from exposure to them. Brief biographical sketches of the committee members are provided in Appendix B. REFERENCES Cheng, Y. S., Y. Zhou, J. Chow, J. Watson, and C. Frazier. 2001. Chemical composition of aerosols from kerosene heaters burning jet fuels. Aerosol Science and Technology 35(6):949- 957. Costa, L., W. Li, R. Richter, D. Shih, A. Lusis, and C. Furlong. 1999. The role of paraoxonase (PON1) in the detoxification of organophosphates and its human polymorphism. Chemico- Biological Interactions 119-120:429-438. Department of Veterans Affairs. 1998. Consolidation and Combined Analysis of the Databases of the Department of Veterans Affairs Persian Gulf Health Registry and the Department of Defense Comprehensive Clinical Evaluation Program. Washington, DC: Environmental Epidemiology Service, Department of Veterans Affairs. DoD (Department of Defense). 2001. Environmental Exposure Report: Pesticides, Final Report. Falls Church, VA: Department of Defense. Gunby, P. 1991. Physicians provide continuum of care for Desert Storm fighting forces. Journal of the American Medical Association 265(5):557-559.

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INTRODUCTION 21 Hyams, K. C., K. Hanson, F. S. Wignall, J. Escamilla, and E. C. Oldfield, 3rd. 1995. The impact of infectious diseases on the health of U.S. troops deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. Clinical Infectious Diseases 20(6):1497-1504. IOM (Institute of Medicine). 1995. Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action. Washington, DC: National Academy Press. IOM. 1996. Health Consequences of Service During the Persian Gulf War: Recommendations for Research and Information Systems. Washington, DC: National Academy Press. IOM. 1999. Gulf War Veterans: Measuring Health. Washington, DC: National Academy Press. IOM. 2000. Gulf War and Health, Volume 1: Depleted Uranium Sarin, Pyridostigmine Bromide, Vaccines. Washington, DC: National Academy Press. IOM. 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. IOM. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. IOM. 2005. Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. IOM. 2006a. Amyotrophic Lateral Sclerosis in Veterans: Review of the Scientific Literature. Washington, DC: The National Academies Press. IOM. 2006b. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. IOM. 2007. Gulf War and Health, Volume 5: Infectious Diseases. Washington, DC: The National Academies Press. IOM. 2008. Gulf War and Health, Volume 6: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress. Washington, DC: The National Academies Press. IOM. 2009. Gulf War and Health, Volume 7: Long-Term Consequences of Traumatic Brain Injury. Washington, DC: The National Academies Press. Joellenbeck, L. M., P. J. Landrigan, and E. L. Larson. 1998. Gulf War veterans’ illnesses: A case study in causal inference. Environmental Research 79(2):71-81. Joseph, S. C. 1997. A comprehensive clinical evaluation of 20,000 Persian Gulf War veterans. Military Medicine 162(3):149-155. Lawler, M. K., D. E. Flori, R. J. Volk, and A. B. Davis. 1997. Family health status of National Guard personnel deployed during the Persian Gulf War. Families, Systems, and Health 15(1):65-73. NIH Technology Assessment Workshop Panel. 1994. The Persian Gulf experience and health. JAMA 272(2):391-395. PAC (Presidential Advisory Committee). 1996. Presidential Advisory Committee on Gulf War Veteran’ Illnesses: Final Report. Washington, DC: US Government Printing Office. PAC. 1997. Presidential Advisory Committee on Gulf War Veterans' Illnesses: Special Report. Washington, DC: Presidential Advisory Committee on Gulf War Veterans’ Illnesses.

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22 GULF WAR AND HEALTH Persian Gulf Veterans Coordinating Board. 1995. Unexplained illnesses among Desert Storm veterans: A search for causes, treatment, and cooperation. Archives of Internal Medicine 155(3):262-268. RAND. 2000. Review of the scientific literature as it pertains to Gulf War illnesses. Volume 8: Pesticides. Santa Monica, CA: RAND Corporation. Ursano, R. J., and A. E. Norwood. 1996. Emotional Aftermath of the Persian Gulf War: Veterans, Families, Communities, and Nations. Washington, DC: American Psychiatric Publishing.