Veteran Services Transparency

I. Primary Medical Problems of Gulf War II Veterans Match Gulf War Illness:

Infectious and Parasitic Diseases

Malignant Neoplasm

Benign Neoplasm

Diseases of Endocrine/Nutritional/Metabolic Systems

Diseases of Blood and Blood Forming Organs

Mental Disorders

Diseases of Nervous System/ Sense Organs

Diseases of Circulatory System

Disease of Respiratory System

Disease of Digestive System

Diseases of Genitourinary

Diseases of Skin

Diseases of Musculoskeletal System/Connective System

Symptoms, Signs and Ill Defined Conditions

Injury/Poisonings

Post Traumatic Stress Disorder (PTSD)

Depressive

Neurotic Disorders

Affective Psychoses

Nondependent Abuse of Drugs

Alcohol Dependence Syndrome

Special Symptoms, Not Elsewhere Classified

Sexual Deviations and Disorders

Specific Non-psychotic Mental Disorder due to Organic Brain Damage

Drug Dependence

(Source; Analysis of VA Health Care Utilization Among US Global War on Terrorism (GWOT) Veterans, January 2009, pages 13, 14)

II. 1,094,502 OEF and OIF veterans who have left active duty and become eligible for VA health care since FY 2002. 508,152 (46%) have obtained VA health care since FY 2002 (cumulative total):

52% (573,404) Are Former Active Duty Troops

47% (271,988) have sought VA health care since FY 2002 (cumulative total)

48% (521,098) Are Reserve and National Guard Troops

45% (236,164) have sought VA health care since FY 2002 (cumulative total)

48% (243,685) of those veterans who sought VA health care received a diagnosis of a possible mental disorder.

(Source; Analysis of VA Health Care Utilization Among US Global War on Terrorism (GWOT) Veterans, February, 2010, pages 4, 7, 8 & 14)

III. Demographic Characteristics of Gulf War Veterans (Gulf War II – OEF, OIF) Utilizing VA Health Care:

* Due to the effects of rounding, the total percentage is greater than 100 percent.

Cumulative through 4^th Quarter FY 2009

(Source; Analysis of VA Health Care Utilization Among US Global War on Terrorism (GWOT) Veterans, January 2009, pages 4, 7, 8 & 14)

IV. Gulf War Illness and the Health of Gulf War Veteran:

Scientific Findings and Recommendations – Research Advisory Committee on Gulf War Veterans’ Illnesses – November 2008

(It is important to note that this report relates only to veterans of Gulf War I, 2000-2001). However, many of the same conditions exist today that existed in 2000-2001. Consequently the illnesses of Gulf War II veterans closely track those of Gulf War I.

Findings in Brief

Gulf War illness, the multisymptom condition resulting from service in the 1990-1991 Gulf War, is the most prominent health issue affecting Gulf War veterans, but not the only one. The Congressionally mandated Research Advisory Committee on Gulf War Veterans’ Illnesses has reviewed the extensive evidence now available, including important findings from scientific research and government investigations not considered by earlier panels, to determine what is known about the health consequences of military service in the Gulf War. This evidence identifies the foremost causes of Gulf War illness, describes biological characteristics of this condition, and provides direction for future research urgently needed to improve the health of Gulf War veterans.

Gulf War illness is a serious condition that affects at least one fourth of the 697,000 U.S. veterans who served in the 1990-1991 Gulf War. – This complex of multiple concurrent symptoms typically includes persistent memory and concentration problems, chronic headaches, widespread pain, gastrointestinal problems, and other chronic abnormalities not explained by well-established diagnoses. No effective treatments have been identified for Gulf War illness and studies indicate that few veterans have recovered over time.

Gulf War illness fundamentally differs from trauma and stress-related syndromes described after other wars. – Studies consistently indicate that Gulf War illness is not the result of combat or other stressors and that Gulf War veterans have lower rates of posttraumatic stress disorder than veterans of other wars. No similar widespread, unexplained symptomatic illness has been identified in veterans who have served in war zones since the Gulf War, including current Middle East deployments.

Evidence strongly and consistently indicates that two Gulf War neurotoxic exposures are causally associated with Gulf War illness: 1) use of pyridostigmine bromide (PB) pills, given to protect troops from effects of nerve agents, and 2) pesticide use during deployment. – Evidence includes the consistent association of Gulf War illness with PB and pesticides across studies of Gulf War veterans, identified dose-response effects, and research findings in other populations and in animal models.

For several Gulf War exposures, an association with Gulf War illness cannot be ruled out. These include low-level exposure to nerve agents, close proximity to oil well fires, receipt of multiple vaccines, and effects of combinations of Gulf War exposures. – There is some evidence supporting a possible association between these exposures and Gulf War illness, but that evidence is inconsistent or limited in important ways.

Other wartime exposures are not likely to have caused Gulf War illness for the majority of ill veterans. – For remaining exposures, there is little evidence supporting an association with Gulf War illness or a major role is unlikely based on what is known about exposure patterns during the Gulf War and more recent deployments. These include depleted uranium, anthrax vaccine, fuels, solvents, sand and particulates, infectious diseases, and chemical agent resistant coating (CARC).

Gulf War illness is associated with diverse biological alterations that most prominently affect the brain and nervous system. – Research findings in veterans with Gulf War illness include significant differences in brain structure and function, autonomic nervous system function, neuroendocrine and immune measures, and measures associated with vulnerability to neurotoxic chemicals. There is little evidence of peripheral neuropathies in Gulf War veterans.

Gulf War illness has both similarities and differences with multisymptom conditions in the general population. – Symptom-defined conditions like chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity occur at elevated rates in Gulf War veterans, but account for only a small proportion of veterans with Gulf War illness.

Studies indicate that Gulf War veterans have significantly higher rates of amyotrophic lateral sclerosis (ALS) than other veterans, and that Gulf War veterans potentially exposed to nerve agents have died from brain cancer at elevated rates. – Although these conditions have affected relatively few veterans, they are cause for concern and require continued monitoring.

Important questions remain about other Gulf War health issues. – These include questions about rates of other neurological diseases, cancers, and diagnosed conditions in Gulf War veterans, current information on overall and disease-specific mortality rates in Gulf War veterans, and unanswered questions concerning the health of veterans’ children.

Federal Gulf War research programs have not been effective, historically, in addressing priority issues related to Gulf War illness and the health of Gulf War veterans. – Substantial federal Gulf War research funding has been used for studies that have little or no relevance to the health of Gulf War veterans, and for research on stress and psychiatric illness. Recent Congressional actions have brought about promising new program developments at the Departments of Defense and Veterans Affairs, but overall federal funding for Gulf War research has declined dramatically since 2001.

A renewed federal research commitment is needed to identify effective treatments for Gulf War illness and address other priority Gulf War health issues. –Adequate funding is required to achieve the critical objectives of improving the health of Gulf War veterans and preventing similar problems in future deployments. This is a national obligation, made especially urgent by the many years that Gulf War veterans have waited for answers and assistance.

(Source Findings in Brief – pages 1&2 of Nov. 2008 Gulf War Illness and Health of Gulf War Veterans from the Research Advisory Committee on Gulf War Veterans’ Illnesses)

Executive Summary

More than seventeen years have passed since the United States and its international allies liberated Kuwait from the grip of Saddam Hussein’s Iraqi military forces in the 1990-1991 Gulf War. Despite the swift and decisive victory achieved in Operation Desert Storm, at least one fourth of the nearly 700,000 U.S. military personnel who served in the war have experienced a complex of difficult and persistent health problems since their return home. Illness profiles typically include some combination of chronic headaches, cognitive difficulties, widespread pain, unexplained fatigue, chronic diarrhea, skin rashes, respiratory problems, and other abnormalities. This symptom complex, now commonly referred to as Gulf War illness, is not explained by routine medical evaluations or by psychiatric diagnoses, and has persisted, for many veterans, for 17 years. While specific symptoms can vary between individuals, a remarkably consistent illness profile has emerged from hundreds of reports and studies of different Gulf War veteran populations from different regions of the U.S., and from allied countries.

For many years, diverse views about the cause or causes of Gulf war illness have been put forward and vigorously debated. Hundreds of burning oil well fires that turned the Kuwaiti sky black with smoke, dramatic reports of uranium-tipped munitions, sandstorms, secret vaccines, and frequent chemical alarms, along with the government’s acknowledgment of nerve agent releases in theater, led many to believe that veterans were suffering from effects of hazardous exposures that occurred during their deployment. Government officials and special committee reports maintained that there was little evidence that this was the case, and noted that veterans returning from other wars have often experienced chronic health problems related to the stressful circumstances of serving in a war zone. All sides called for research to better understand the problem. Multiple official investigations were launched and hundreds of research studies funded.

In 1998, the U.S. Congress mandated the appointment of a public advisory panel of independent scientists and veterans to advise on federal research studies and programs to address the health consequences of the Gulf War. The Research Advisory Committee on Gulf War Veterans’ Illnesses was appointed by the Secretary of Veterans Affairs in 2002 and directed to evaluate the effectiveness of government research in addressing central questions on the nature, causes, and treatments of Gulf War-related illnesses. According to its charter, the guiding principle for the Committee’s work is the premise that the fundamental goal of all Gulf War-related government research is to improve the health of Gulf War veterans, and the choice and success of federal Gulf War research should be judged accordingly.

The Committee has convened public meetings on a regular basis to consider the broad spectrum of scientific research, investigative reports, and government research activities related to the health of Gulf War veterans. In addition to annual reports on Committee meetings and activities, it has periodically issued formal scientific recommendations and reports. The Committee’s last extended report, Scientific Progress in Understanding Gulf War Veterans’ Illnesses, issued in 2004, provided findings and recommendations on topics the Committee had considered up to that time. The present report provides a comprehensive review of information and evidence on topics reviewed by the Committee since that time, as well as additional information on topics considered in the 2004 report.

The central focus of this report is Gulf War illness, the multi-symptom condition that affects veterans of the 1990-1991 Gulf War at significantly elevated rates. Despite considerable government, scientific, and media attention, little was clearly understood about Gulf War illness for many years. Now, 17 years after the war, the extensive body of scientific research and government investigations that is currently available provides the basis for an evidence-based assessment of the nature and causes of Gulf War illness. As described throughout the report, scientific evidence leaves no question that Gulf War illness is a real condition with real causes and serious consequences for affected veterans. Research has also shown that this pattern of illness does not occur after every war and cannot be attributed to psychological stressors during the Gulf War.

Although Gulf War illness is the most prominent and widespread issue related to the health of Gulf War veterans, it is not the only one. Additional issues of importance include diagnosed medical and psychiatric conditions affecting Gulf War veterans, and questions related to the health of veterans’ family members. Section 1 of this report provides an overview of information related to the prevalence and characteristics of Gulf War illness, and other health issues, from the large body of Gulf War epidemiologic research. Section 2 addresses evidence related to the causes of Gulf War illness, including what has been learned about effects of psychological stressors, oil well fires, depleted uranium, and other exposures of possible concern, and compares the weight of evidence related to each exposure as a cause or contributor to Gulf War illness. Section 3 addresses the nature of Gulf War illness, reviewing research on biological findings associated with Gulf War illness and its relationship with multi-symptom conditions found in the general population. Section 4 reviews research programs sponsored by federal agencies to address Gulf War-related health issues. Research recommendations provided in relation to topics considered in each section are summarized and prioritized in Section 5 of the report.

Gulf War research has posed a complex scientific challenge for researchers. Most obviously, Gulf War illness does not fit neatly into well-established categories of disease. The underlying path physiology of Gulf War illness is not apparent from routine clinical tests, and the illness appears not to be the result of a single cause producing a well-known effect. There are relatively few sources of objectively measured data for studying Gulf War illness or its association with events and exposures in the Gulf War. Some observers have suggested that these complexities pose too difficult a challenge, and that it is unlikely that the nature and causes of Gulf War illness can ever be known. On the contrary, the Committee has found that the extensive scientific research and other diverse sources of information related to the health of Gulf War veterans paint a cohesive picture that yields important answers to basic questions about both the nature and causes of Gulf War illness. These, in turn, provide direction for future research that is urgently needed to improve the health of Gulf War veterans.

Epidemiologic Research: What is Gulf War Illness and How Many Veterans Are Affected?

Gulf War illness refers to the complex of symptoms that affects veterans of the 1990-1991 Gulf War at significantly excess rates. It is characterized by multiple diverse symptoms not explained by established medical diagnoses or standard laboratory tests, symptoms that typically include a combination of memory and concentration problems, persistent headache, unexplained fatigue, and widespread pain, and can also include chronic digestive difficulties, respiratory symptoms, and skin rashes. A similar profile of excess symptoms has been described in every study of U.S. Gulf War veterans from different regions and units, and in Gulf War veterans from the United Kingdom and other allied countries.

Gulf War illness is not the only health condition related to Gulf War service, but it is by far the most common. Gulf War illness prevalence estimates vary with the specific case definition used. Studies consistently indicate, however, that an excess of 25 to 32 percent of veterans who served in the 1990-1991 Gulf War are affected by a complex of multiple symptoms, variously defined, over and above rates in contemporary military personnel who did not deploy to the Gulf War. That means that between 175,000 and 210,000 of the nearly 700,000 U.S. veterans who served in the 1990-1991 Gulf War suffer from this persistent pattern of symptoms as a result of their wartime service.

Research has not supported early speculation that Gulf War illness is a stress-related condition. Large population-based studies of Gulf War veterans consistently indicate that Gulf War illness is not the result of combat or other deployment stressors, and that rates of posttraumatic stress disorder (PTSD) and other psychiatric conditions are relatively low in Gulf War veterans. Gulf War illness differs fundamentally from trauma and stress-related syndromes that have been described after other wars. No Gulf War illness-type problem, that is, no widespread symptomatic illness not explained by medical or psychiatric diagnoses, has been reported in veterans who served in Bosnia in the 1990s or in current conflicts in Iraq and Afghanistan.

Epidemiologic studies indicate that rates of Gulf War illness vary in different subgroups of Gulf War veterans. Gulf War illness affects veterans who served in the Army and Marines at higher rates than those in the Navy and Air Force, and enlisted personnel more than officers. Studies also indicate that Gulf War illness rates differ according to where veterans were located during deployment, with highest rates among troops who served in forward areas. More specifically, studies consistently show that the rate of Gulf War illness is associated with particular exposures that veterans encountered during deployment.

Identified links between veteran-reported exposures and Gulf War illness have raised a great deal of interest, but have also been the source of considerable confusion. The use of self-reported exposure information raises a number of concerns, most obviously in relation to recall bias. These concerns emphasize the importance of assessing findings across a broad spectrum of studies, rather than relying on results from individual studies, and of evaluating the impact of recall and other information bias on study results where possible.

The Committee identified an additional problem that has had a profound effect on epidemiologic study results and their interpretation. Exposures assessed in Gulf War studies are highly correlated, that is, veterans who had one type of exposure also usually had many others. In analyzing the effects of any single exposure during the war, it is essential that effects of other exposures be considered and adjusted for, to avoid the well-known problem of “confounding,” or confusing the effects of multiple exposures with one another. Many Gulf War epidemiologic studies failed to control for confounding effects, yielding illogical results that made it appear as if all, or nearly all, wartime exposures caused Gulf War illness. In contrast, adjusted results—that is, those that controlled for effects of other exposures in theater—consistently identified a very limited number of significant risk factors for Gulf War illness.

The Urgent Need for Effective Treatments for Gulf War Illness

Gulf War illness has persisted for a very long time for most ill veterans—over seventeen years for many. Studies indicate that few veterans with Gulf War illness have recovered over time and only a small minority has substantially improved. The federal Gulf War research effort has yet to provide tangible results in achieving its ultimate objective, that is, to improve the health of Gulf War veterans. Few treatments have been studied and none have been shown to provide significant benefit for a substantial number of ill veterans.

Treatments that are effective in improving the health of veterans with Gulf War illness are urgently needed. In recent years, Congressional actions have led to promising initiatives in this effort at both the Department of Defense (DOD) and the Department of Veterans Affairs (VA). At DOD, the Office of Congressionally Directed Medical Research Programs has developed an innovative program aimed at identifying treatments and diagnostic tests for Gulf War illness. The program funded a limited number of new treatment studies in 2007 and has invited proposals for additional studies to be funded in 2009. In addition, VA has sponsored a center of excellence for Gulf War research at the University of Texas Southwestern, focused on identifying specific biological abnormalities that underlie Gulf War illness that can be targeted for treatment. Research to identify effective treatments for Gulf War illness has been given highest priority by the Committee and requires expanded federal support.

Other Health Issues Affecting Gulf War Veterans

Although Gulf War illness has been the most prominent health issue associated with military service in the 1990-1991 Gulf War, a number of other health issues are extremely important. Studies have indicated that veterans of the 1990-1991 Gulf War have developed amyotrophic lateral sclerosis (ALS) at twice the rate of nondeployed veterans of the same era. Gulf War veterans who were downwind from nerve agent releases resulting from weapons demolitions at Khamisiyah, Iraq, in March of 1991, have also been found to have twice the rate of death due to brain cancer as other veterans in theater. Recent studies have suggested that excess cases of ALS have declined in recent years, but the seriousness of both ALS and brain cancer are clear causes for concern and require continued monitoring for the foreseeable future. These findings also highlight the need for information on rates of other diagnosed diseases, particularly neurological diseases and cancers, which have only minimally been assessed in Gulf War veterans. Multiple studies have reported that rates of PTSD and other psychiatric disorders are higher in Gulf War veterans than in nondeployed era veterans but are, overall, substantially lower than in veterans of other wars.

Hospitalization and mortality studies have identified only limited differences between Gulf War and nondeployed era veterans. Early U.S. mortality studies indicated that Gulf War veterans had higher death rates due to accidents, and somewhat lower disease-related mortality rates. Although identified differences appeared to diminish in the years after the war, the most recent year for which comprehensive mortality information has been reported for U.S. Gulf War veterans is 1997. Given concerns about diseases of longer latency, it is extremely important that current disease-specific mortality rates for U.S. Gulf War veterans be made publicly available, and reported on a regular basis.

For many years, concerns have been raised about rates of birth defects in Gulf War veterans’ children and anomalous health problems in their family members. Large population-based studies in the U.S. and the U.K. have provided some evidence of excess rates of several types of birth defects among children born to Gulf War veterans, in comparison to nondeployed era veterans. The specific types of birth defects identified have differed in different studies, however, and rates, overall, have been in the normal range expected in the general population. Phase III of VA’s large U.S. National Survey of Gulf War Era Veterans and their Families included clinical evaluations of veterans’ spouses and children. On clinical evaluation, no notable differences were identified between spouses of Gulf War and nondeployed veterans. Findings from clinical evaluations of veterans’ children have not been reported from this study, however. Further, no studies have provided comprehensive information on the health of Gulf War veterans’ children, including rates of diagnosed conditions, symptomatic illness, and learning and behavioral disorders.

What Caused Gulf War Illness? Review of Evidence Relating Gulf War Illness to Experiences and Exposures During Deployment

In addition to the many physical and psychological challenges common to other wartime deployments, military personnel who served in the 1990-1991 Gulf War were exposed to a long list of potentially hazardous substances. Many possible “causes” of Gulf War illness have been suggested and even promoted in different quarters since the war. Understanding the causes of Gulf War illness has been particularly challenging because of the lack of hard data on individual exposures in theater. Efforts by early government and scientific panels to address this issue were also limited by the scarcity of scientific research information on the health of Gulf War veterans for the first 10 years after the war.

This is no longer the case today, as a result of the extensive number of government investigations and scientific studies conducted to better understand events of the Gulf War and their association with Gulf War illness. Government reports have provided important insights into the types and patterns of exposures encountered by Gulf War military personnel. The large number of epidemiologic and clinical studies of Gulf War veterans also allows assessment of associations between Gulf War experiences and chronic health problems across a broad spectrum of veteran groups and research designs. In addition, toxicological studies conducted in recent years have provided extensive information on biological effects of Gulf War-related exposures that were previously unknown. The Committee found that epidemiologic research on Gulf War veterans, assessed across diverse study designs and populations, provided clearer and more consistent findings than had previously been assumed. When combined with what has been learned about patterns of exposures in theater and findings from toxicological research, a coherent picture emerges about the most likely causes of Gulf War illness.

The Committee used a standardized approach for evaluating available evidence related to psychological stressors in theater and each of the other deployment-related hazards of possible concern. Three major categories of evidence were considered. First, the Committee reviewed what is known about the extent and patterns of veterans’ exposure to each potential hazard. Second, the Committee reviewed the broad spectrum of available scientific research to determine what is known, in general, about health effects of each exposure. This included consideration of epidemiologic and clinical studies of human populations, and laboratory studies conducted in animal models. Third, the Committee reviewed, in detail, results from the many studies of Gulf War veterans that assessed associations between symptom complexes and the exposure in question.

Individually, single studies or types of information might suggest that a specific exposure could have caused Gulf War illness. But it is important to consider evidence of all types and studies from all sources to determine what the evidence most clearly indicates did cause Gulf War illness. Of the many experiences and exposures associated with Gulf War service, studies of Gulf War veterans consistently implicate only two wartime exposures as significant risk factors for Gulf War illness: use of pyridostigmine bromide (PB) pills as a nerve agent protective measure, and use of pesticides during deployment. This is consistent with what is known about the extent and patterns of these exposures in theater, and with general information from other human and animal studies. Studies of Gulf War veterans have also consistently indicated that psychological stressors during deployment are not significantly associated with Gulf War illness. For several other deployment exposures an association with Gulf War illness cannot be ruled out, due to inconsistencies or limitations of available information. Remaining exposures appear unlikely, from available evidence, to have caused Gulf War illness for the majority of affected veterans.

Psychological stress. Studies of Gulf War veterans consistently indicate that serving in combat and other psychological stressors during the war are not significantly associated with Gulf War illness, after adjusting for effects of other wartime exposures. Time-limited biological effects of psychological stressors have long been described in human studies, and more extreme psychological stressors and trauma can lead to chronic psychiatric disorders such as PTSD. Combat and extreme psychological stressors were less widespread and less sustained in the Gulf War than in other wars, including current Middle East deployments, and PTSD rates are lower in Gulf War veterans than in veterans of other wars. Population-based studies generally indicate that between three and six percent of Gulf War veterans are diagnosed with PTSD and that the large majority of veterans with Gulf War illness have no psychiatric disorders. Serving in combat and other wartime stressors are associated with higher rates of PTSD in Gulf War veterans, but not with higher rates of Gulf War illness.

Kuwaiti oil well fires. Widespread exposure to smoke from the Kuwaiti oil well fires was unique to military service in the 1991 Gulf War, and most prominently affected ground troops in forward locations. Epidemiologic findings relating oil well fire smoke exposure to Gulf War illness have been mixed, although a dose-response effect has been identified by several studies. There is little information from human or animal research to indicate whether intense exposure to petroleum smoke or vapors can lead to persistent multisymptom illness. Although studies of Gulf War veterans do not provide consistent evidence that exposure to oil fire smoke is a risk factor for Gulf War illness for most veterans, questions remain about effects for personnel located in close proximity to the burning wells for an extended period. Limited findings from epidemiologic studies indicate that higher-level exposures to smoke from the Kuwaiti oil well fires may be associated with increased rates of asthma in Gulf War veterans, and that an association with Gulf War illness cannot be ruled out.

Depleted uranium (DU). Low-level exposure to spent DU munitions and dust is thought to have been widespread during the Gulf War and was most prominent among ground troops in forward locations. Recent animal studies have demonstrated acute effects of soluble forms of DU on the brain and behavior, but persistent effects of short term, low-dose exposures like those encountered by the majority of Gulf War veterans have only minimally been assessed. There is little information from Gulf War or other human studies concerning chronic symptomatic illness in relation to DU or uranium exposure. Exposure to DU in post-Gulf War deployments, including current conflicts in the Middle East, has not been associated with widespread multisymptom illness. This suggests that exposure to DU munitions is not likely a primary cause of Gulf War illness. Questions remain about long-term health effects of higherdose exposures to DU, however, particularly in relation to other health outcomes.

Vaccines. Receipt of multiple vaccines over a brief time period is a common feature of overseas military deployments. About 150,000 Gulf War veterans are believed to have received one or two anthrax shots, most commonly troops who were in fixed support locations during the war. Although recent studies have demonstrated that the anthrax vaccine is highly reactogenic, there is no clear evidence from Gulf War studies that links the anthrax vaccine to Gulf War illness. Taken together, limited findings from Gulf War epidemiologic studies, the preferred administration to troops in support locations, and the lack of widespread multisymptom illness resulting from current deployments, combine to indicate that the anthrax vaccine is not a likely cause of Gulf War illness for most ill veterans. However, limited evidence from both animal research and Gulf War epidemiologic studies indicates that an association between Gulf War illness and receipt of a large number of vaccines cannot be ruled out.

Pyridostigmine bromide (PB). Widespread use of PB as a protective measure in the event of nerve gas exposure was unique to the 1990-1991 Gulf War. Pyridostigmine bromide is one of only two exposures consistently identified by Gulf War epidemiologic studies to be significantly associated with Gulf War illness. About half of Gulf War personnel are believed to have taken PB tablets during deployment, with greatest use among ground troops and those in forward locations. Several studies have identified dose-response effects, indicating that veterans who took PB for longer periods of time have higher illness rates than veterans who took less PB. In addition, clinical studies have identified significant associations between PB use during the Gulf War and neurocognitive and neuroendocrine alterations identified many years after the war. Taken together, these diverse types and sources of evidence provide a consistent and persuasive case that use of PB during the Gulf War is causally associated with Gulf War illness.

Pesticides. The widespread use of multiple types of pesticides and insect repellants in the Gulf War theater is credited with keeping rates of pest-borne diseases low. Pesticide use, assessed in different ways, is one of only two exposures consistently identified by Gulf War epidemiologic studies to be significantly associated with Gulf War illness. Multisymptom illness profiles similar to Gulf War illness have also been associated with low-level pesticide exposures in other human populations. In addition, Gulf War studies have identified dose-response effects, indicating that greater pesticide use is more strongly associated with Gulf War illness than more limited use. Pesticide use during the Gulf War has also been associated with neurocognitive deficits and neuroendocrine alterations in Gulf War veterans in clinical studies conducted many years after the war. Taken together, all available sources of evidence combine to support a consistent and compelling case that pesticide use during the Gulf War is causally associated with Gulf War illness.

Nerve agents. There have been no reports that U.S. forces encountered large-scale, high-dose exposures to chemical weapons during the Gulf War, but concerns have emerged related to possible longterm effects of low-dose nerve agent exposures. Recent animal studies have identified brain, autonomic, behavioral, neuroendocrine, and immune effects of low-level sarin exposure that were previously unknown. Studies of individuals exposed to symptomatic but sublethal doses of sarin in Japanese terrorist incidents in the 1990s have identified central nervous system effects that have persisted for many years. The extent of low-level exposure to nerve agents during the Gulf War, however, is unclear. Monitoring equipment used by U.S. forces had little capacity to detect nerve agents at levels that did not cause immediate symptoms. The Department of Defense estimates that about 100,000 U.S. troops may have been exposed to low levels of nerve agents following weapons demolitions in March of 1991 at Khamisiyah, Iraq, but questions have been raised about the models used to determine who was exposed, and at what levels. It is also unclear whether additional low-level exposures may have occurred in other locations. Veterans’ self-reported experiences concerning low-level nerve agent exposure in the Gulf War are particularly uncertain, and findings from epidemiologic studies linking chemical agents with Gulf War illness are inconsistent. Studies of Gulf War veterans have identified increased rates of brain cancer

and measurable differences in brain structure and function that relate, in a dose-response manner, to modeled nerve agent exposure levels resulting from the Khamisiyah demolitions. Findings from Gulf War clinical studies, and from other human and animal research, suggest that an association between Gulf War illness and low-level nerve agent exposure cannot be ruled out, for whatever subgroups of veterans were exposed.

Infectious disease. A substantial proportion of Gulf War military personnel contracted acute gastrointestinal and respiratory infections during deployment, but there is little information concerning patterns of infection in theater and no evidence of widespread chronic illness resulting from those infections. Atypical leishmania infections were identified in a limited number of veterans who served in the 1990-1991 Gulf War, and a much larger number of leishmaniasis cases have been reported in personnel serving in the current Iraq War. Several studies have identified DNA indicators of mycoplasma infection in about 40 percent of symptomatic Gulf War veterans, but questions about testing methods have not been adequately addressed. Taken together, there is little clear evidence implicating infectious diseases as prominent causes of Gulf War illness. Questions remain, however, concerning the possibility that some individuals with Gulf War illness have undetected chronic leishmania and mycoplasma infections.

Other exposures in theater. A number of other potentially hazardous exposures in theater have been suggested as causing or contributing to Gulf War illness. These include fine sand and airborneparticulates, exhaust from tent heaters, other fuel exposures, solvents, and freshly-applied CARC(chemical agent resistant coating) paint. For most, there is limited evidence of the types considered for other exposures. Available information, however, suggests that these exposures are not likely to have caused Gulf War illness for most affected veterans. Epidemiologic studies have provided little clear information linking any of these exposures to Gulf War illness and most were not most prevalent among ground troops who were forward deployed. Some, like sand, solvents, and fuel exposures, have also been widely encountered by personnel in current Middle East deployments. Information from human and animal studies indicates that fuel and solvent exposures can have neurological effects compatible with symptoms of Gulf War illness, but neither has been associated with Gulf War illness in studies of Gulf War veterans.

Combinations of exposures. Compared to the diverse types of evidence available related to effects of individual exposures, research on effects of combinations of Gulf War-related exposures is limited. Gulf War studies consistently indicate that exposures in theater were highly correlated—that is, that personnel most often experienced individual exposures in connection with multiple other exposures. This includes correlations between use of PB and pesticides and among different types of pesticides. Animal studies have identified significant effects of exposure to combinations of PB, pesticides and insect repellants, sarin, and stress, at dosage levels comparable to those experienced by veterans during the Gulf War. Diverse findings have been reported in relation to chemical absorption, metabolism, and biological effects of mixtures of neurotoxicants, which differ from those of individual exposures. There is little information from human studies, however, including the many epidemiologic studies of Gulf War veterans, concerning combined effects of Gulf War exposures.

A persuasive theoretical case can be made that exposure to mixtures of neurotoxic compounds in theater are likely contributors to Gulf War illness. Such a case would draw on the consistency of evidence from all sources indicating that both PB and pesticides are significantly associated with Gulf War illness, the high correlation between troops’ use of PB and pesticides during deployment, and synergistic effects between these exposures demonstrated by animal studies. Many of the pesticides used in the Gulf War, as well as PB and nerve agents, exert toxic effects on the brain and nervous system by altering levels of acetylcholine, an important nerve signaling chemical. Although such a case is compelling, little evidence is available from studies of Gulf War veterans to indicate whether or not Gulf War illness is associated with combinations of these exposures. This important possibility can and should be fully evaluated in Gulf War studies. Pending such assessments, it is not possible to definitively determine the extent to which mixtures of cholinergic and other neurotoxicant exposures during deployment contributed to Gulf War illness. Based on evidence from toxicological research in animals and what is known about patterns of exposures during the Gulf War, an association between Gulf War illness and combined effects of neurotoxicant exposures cannot be ruled out.

There is almost no research to indicate if other wartime exposures interact synergistically with these neurotoxic compounds or with one another. That is, the biological effects of different combinations of PB, multiple pesticides, low-level nerve agents, oil and dense smoke from burning wells, DU dust, fuel vapors, exhaust from tent heaters, CARC paint, airborne particulates, infectious agents, and receipt of multiple vaccines, experienced concurrently or over a brief time period, are unknown. Many have suggested that unknown and difficult-to-characterize effects may have been precipitated by an “exposure cocktail” or “toxic soup” effect during Gulf War deployment. While such a theory is intriguing, there is currently little evidence to indicate whether or not such effects actually occurred, and the extent to which they may have contributed to Gulf War illness.

What the Weight of Evidence Tells Us About the Causes of Gulf War Illness

Seventeen years after the Gulf War, answers to the question of what caused Gulf War illness remain vitally important. An extensive amount of available information now permits an evidence-based assessment of the relationship of Gulf War illness to the many experiences and exposures encountered by military personnel during the Gulf War. The strongest and most consistent evidence from Gulf War epidemiologic studies indicates that use of pyridostigmine bromide (PB) pills and pesticides are significant risk factors for Gulf War illness. The consistency of epidemiologic evidence linking these exposures to Gulf War illness, identified dose-response effects, findings from Gulf War clinical studies, additional research supporting biological plausibility, and the compatibility of these findings with known patterns of exposure during deployment, combine to provide a persuasive case that use of PB pills and pesticides during the 1990-1991 Gulf War are causally associated with Gulf War illness. Gulf War studies also consistently indicate that psychological stressors during deployment are not significantly associated with Gulf War illness.

Evidence related to other deployment-related exposures is not as abundant or consistent as evidence related to PB, pesticides, and psychological stressors. For several wartime exposures, there is some evidence supporting a possible association with Gulf War illness, but that evidence is inconsistent or limited in important ways. Clinical studies of Gulf War veterans, studies of other populations exposed to sarin, and findings from animal studies all suggest that low-level nerve agent exposure can produce persistent neurological effects that may be compatible with symptoms of Gulf War illness. Therefore, an association between Gulf War illness and low-level nerve agents cannot be ruled out for those veterans who were exposed. However, inconsistencies in epidemiologic studies and unreliable exposure information preclude a clear evaluation of the extent to which such exposures occurred and may have contributed to Gulf War illness. Limited evidence from several sources also suggests that an association with Gulf War illness cannot be ruled out in relation to combined effects of neurotoxicant exposures, receipt of multiple vaccines, and exposure to the Kuwaiti oil fires, particularly for personnel in close proximity to the burning wells for an extended period.

There is little reliable information from Gulf War studies concerning an association of DU or anthrax vaccine to Gulf War illness. The prominence of both exposures in more recent deployments, in the absence of widespread unexplained illness, suggests these exposures are unlikely to have been major causes of Gulf War illness for the majority of affected veterans. Fine blowing sand, solvents, and fuel exposures were also widely encountered in both the 1990-1991 Gulf War and in the current Iraq War and results from studies of Gulf War veterans have not supported an association between these exposures and Gulf War illness. All of the exposures described can be hazardous in some circumstances, however, and some veterans may have experienced adverse effects on a more limited basis.

The Nature of Gulf War Illness: Biological and Clinical Findings in Gulf War Veterans

Although veterans’ symptoms are the most obvious and consistent indicators of Gulf War illness, dozens of research studies conducted by multiple investigators have identified objective measures that significantly distinguish veterans with Gulf War illness from healthy controls. Identified differences relate to structure and function of the brain, function of the autonomic nervous system, neuroendocrine and immune alterations, and variability in enzymes that protect the body from neurotoxic chemicals. These findings provide indicators of diverse biological differences associated with Gulf War illness, but have not, as yet, provided measures that can be used as diagnostic tests. While scientific progress has been made in understanding the biological nature of Gulf War illness, important work remains in characterizing the specific pathophysiological processes that underlie veterans’ symptoms. The Committee reviewed the broad spectrum of studies that have evaluated biological and clinical parameters in Gulf War veterans, focusing most specifically on Gulf War illness.

Identified effects on the brain and central nervous system. Multiple lines of research have supported early indications that service in the Gulf War, for some veterans, resulted in long term effects on the central nervous system. Population-based studies of Gulf War veterans have consistently identified significantly excess rates of symptom complexes suggestive of central nervous system abnormalities. Studies have also indicated that Gulf War veterans developed amyotrophic lateral sclerosis (ALS) at twice the rate of nondeployed era veterans, and that veterans downwind from the Khamisiyah munitions demolitions have died from brain cancer at twice the rate of other Gulf War veterans. Earlier reports suggesting that Gulf War illness is not associated with neurological abnormalities generally referred to the lack of significant findings identified with standard clinical evaluations and peripheral nerve function testing. It is important to distinguish the lack of findings in these areas from the diverse central nervous system effects identified using specialized brain imaging scans, neuropsychological testing, and measures of balance and audiovestibular function.

Neuroimaging studies. Three research teams have identified significant differences between veterans with Gulf War illness and controls using proton magnetic resonance spectroscopy (MRS) scans of the brain. Findings indicate that symptomatic veterans have significantly reduced functioning brain cell mass in the brainstem, basal ganglia, and hippocampus. Reduced neuronal function in the left basal ganglia was correlated with increased central dopamine activity in one study. Symptomatic Gulf War veterans have also been reported to exhibit alterations in overall and regional cerebral blood flow, using specialized SPECT scan analyses. In addition, a significant correlation has been reported between reduced white matter volume in Gulf War veterans and levels of nerve agent exposures resulting from the Khamisiyah weapons demolitions. Preliminary results from three unpublished federal Gulf War research projects are also of great interest, and will be reviewed in final form as they become available. These include early results from a larger MRS study that appear not to support earlier findings of reduced neuronal function in the brainstem and basal ganglia of symptomatic Gulf War veterans. Preliminary findings from an additional SPECT study suggest that symptomatic Gulf War veterans differ from healthy controls in cerebral blood flow responses to cholinergic challenge. Early results from a third study indicate that symptomatic Gulf War veterans have significantly reduced total white matter volume compared to healthy controls. In contrast to the diverse findings reported from studies using specialized brain imaging methods, few abnormalities have been identified in symptomatic veterans using electroencephalograms (EEG), computed tomography (CT) scans, or standard magnetic resonance imaging (MRI) of the brain.

Overall, of the seven identified Gulf War research projects that evaluated brain structure and function using proton MRS, specialized SPECT scans, and specialized MRI assessments, six have identified significant differences between veterans with Gulf War illness and healthy controls, and one identified no case/control differences. An additional study has identified significant brain volume differences in Gulf War veterans in relation to modeled nerve agent exposures during the Gulf War. These findings have been important in documenting brain alterations in Gulf War veterans, but have often come from relatively small studies that assessed different types of abnormalities in different areas. Additional research is needed to determine if these findings can be replicated and/or further extended in larger samples.

Neuropsychological studies. Neuropsychological studies provide objective measures of brain function and have been used for many years to quantify neurocognitive deficits resulting from chemical exposures. They constitute the largest body of research on central nervous system function in Gulf War veterans. A wide variety of specialized tests are used to assess cognitive domains that include attention, executive system functioning, motor skills, visuospatial functioning, memory, and mood. Changes in affect and emotional functioning can be symptoms of brain injury, and so are important to measure in neuropsychological tests. But PTSD and other psychiatric conditions can themselves affect neurocognitive function, and so must be appropriately controlled for when analyzing test outcomes.

Research studies have consistently identified significant differences in neurocognitive function between symptomatic Gulf War veterans and healthy controls. These include differences on tests of attention and executive system functioning, memory, visuospatial skills, psychomotor skills, and mood and emotional functioning. Some studies indicate that symptomatic veterans display a slowing of response speed that affects their mental flexibility across multiple cognitive domains. Identified differences have generally been modest, but have consistently been significant and remained significant after adjustments for emotional functioning and psychiatric disorders. Studies also indicate that many symptomatic veterans who report cognitive difficulties do not have objectively measurable neurocognitive deficits. Two studies have identified subgroups of symptomatic Gulf War veterans with more marked neurocognitive impairment on measures of memory, attention, and response time, suggesting this subgroup should be the focus of additional study.

Studies have also evaluated veterans’ neurocognitive function in relation to exposures during the Gulf War. Significantly poorer performance on tests of memory, attention, and mood has been identified in relation to self-reported exposure to pesticides, PB, and chemical weapons. Neurocognitive effects have also been identified in relation to modeled nerve agent exposures resulting from the Khamisiyah weapons demolitions. Department of Defense-modeled nerve agent exposure levels were significantly correlated with slower performance on psychomotor and visuospatial tasks in a dose-response pattern—that is, greater exposure was associated with worse neurocognitive performance.

Autonomic nervous system dysfunction. The autonomic nervous system (ANS) is the part of the nervous system that regulates involuntary, or “automatic” physiological activities. Autonomic pathology can be associated with diverse symptoms such as dizziness, weakness, digestive abnormalities, and sexual dysfunction. Autonomic function is often assessed by determining effects of physiological challenges on ANS regulation of heart rate and blood pressure. The Committee reviewed results from seven published studies and two additional federal projects that assessed ANS function in symptomatic Gulf War veterans. Eight of nine projects identified significant ANS differences between veterans with Gulf War illness and healthy controls. Several studies demonstrated blunted autonomic responsivity to physiological challenges, for example, reduced cardiovascular compensation in response to orthostatic challenge on tilt table testing. Studies have also identified a general reduction in heart rate variability in the high frequency range among veterans with Gulf War illness, observed over a 24-hour period in one study and during nighttime hours in another. Although ANS differences have consistently been reported in veterans with Gulf War illness, specific ANS alterations identified by different studies have varied, as a result of differences in study characteristics and testing methods. Additional comprehensive research is needed to provide a clear characterization of Gulf War illness-related autonomic dysfunction.

Neuromuscular and sensory findings. Symptoms reported by Gulf War veterans frequently include muscle pain and weakness, or numbness and tingling sensations in the extremities. Such symptoms potentially indicate abnormalities in peripheral nerve function related to sensation and motor function. Nine studies have assessed peripheral sensory and neuromuscular function in Gulf War veterans. Overall, based on standard clinical examination, electromyography, and nerve conduction tests, these studies have provided little indication that veterans with Gulf War illness are affected by generalized polyneuropathies or abnormal neuromuscular transmission. Three of four studies that evaluated sensory threshold measures identified significantly higher (that is, less sensitive) thresholds in symptomatic compared to healthy veterans, however. Two identified higher cold sensory thresholds, and one reported a higher threshold for detecting light touch, suggesting that some Gulf War veterans may have subtle small sensory fiber neuropathies. Consistent findings that Gulf War veterans are not affected by more generalized polyneuropathies or neuromuscular abnormalities indicate that veterans’ neuromuscular symptoms are not attributable to overt muscle damage or peripheral nerve pathology.

Neuroendocrine alterations. A series of recent studies have provided detailed evaluation of hypothalamic-pituitary-adrenal (HPA) axis functioning in Gulf War veterans. Studies indicated that Gulf War veterans are similar to nondeployed veterans on baseline measures of cortisol and ACTH (adrenocorticotropic hormone), but had significantly greater suppression of both hormones in response to dexamethasone challenge. These responses were significantly associated with veterans’ symptoms, most prominently their musculoskeletal symptoms, but were unrelated to combat exposure or whether veterans had PTSD. Cortisol suppression was most pronounced in veterans who reported using PB during deployment. In addition, 24-hour ACTH levels were significantly reduced among Gulf War veterans who did not have PTSD, and were associated with veterans’ use of pesticides and PB. No HPA alterations were associated with combat stress, with other self-reported exposures during deployment, or with PTSD in Gulf War veterans. Overall, these studies suggest that Gulf War service and symptoms of Gulf War illness are associated with a unique profile of HPA alterations many years after the war, effects that differ from HPA findings associated with other conditions, including PTSD. Identified effects were independent of combat stress, but significantly associated with veterans’ use of PB and/or pesticides.

Vulnerability to neurotoxicants. A question often asked about Gulf War illness is why some Gulf War military personnel developed chronic symptoms during and after deployment, while others who served along side them remained well. It is well established that some people are more vulnerable to adverse effects of certain chemicals than others, due to variability in biological processes that neutralize those chemicals, and clear them from the body. The enzyme paraoxonase (PON1) circulates in the blood and hydrolyzes organophosphate compounds such as pesticides and nerve agents, converting them to relatively harmless chemicals that are then excreted. Individuals who produce different types and amounts of PON1 differ, sometimes dramatically, in their ability to neutralize different organophosphate compounds. The Committee reviewed results from four published studies and two additional federal projects that have assessed PON1 measures in Gulf War veterans. Five of the six projects identified significant PON1 differences that were associated with Gulf War illness or, more generally, with Gulf War service. Specific findings from these studies varied, however, reflecting different types of data that addressed different research questions. Additional research is needed to better characterize the precise nature of the PON1-Gulf War illness relationship. It is unknown if Gulf War illness is linked to biological variability in other enzymes that protect the body from neurotoxic exposures. Limited and preliminary information from three studies suggest a possible link between Gulf War illness and butyrylcholinesterase (BChE) that may involve the subset of veterans who have very low BChE activity and also experienced specific exposures during the war.

Immune parameters. There has been little indication that Gulf War service, overall, is associated with increased rates of diagnosable immune conditions, including autoimmune diseases and allergies, or with increased susceptibility to infectious disease. A well-known hypothesis, suggesting that Gulf War illness is related to a systemic shift favoring Th-2 type immunity, has not been supported by studies of Gulf War veterans. Veterans with Gulf War illness have been shown to differ from healthy controls on a number of immune parameters, however. A variety of specific differences have been identified by individual studies, and a number of consistent findings have emerged. Results from two studies, using different methods in different groups of symptomatic veterans, indicate that Gulf War illness is associated with a low-level, persistent immune activation, reflected in elevated levels of the cytokines IL-2, IFN-γ and IL-10. Several studies have also reported that NK cell numbers and/or cytotoxic activity are significantly reduced in veterans with Gulf War illness. A fuller understanding of immune function in ill Gulf War veterans is needed, particularly in veteran subgroups with different clinical characteristics and exposure histories.

Additional research and clinical findings in Gulf War veterans. Additional information pertaining to biological and clinical characteristics of symptomatic Gulf War veterans is available from a variety of clinical reports and studies. Individual clinical studies have provided several findings of interest, such as increased sensitivity to pain and elevated rates of fibromyalgia in veterans with musculoskeletal symptoms, dyspepsia and persistent diarrhea similar to irritable bowel syndrome in veterans with gastrointestinal symptoms, abnormal pulmonary function in a subset of veterans with respiratory symptoms, and verification of rashes and other skin anomalies in veterans with dermatological symptoms. But overall, objective indicators of disease are often not identified in symptomatic Gulf War veterans who are referred for specialty evaluations. Clinical reports have also not provided explanations for identified problems, such as the causes of veterans’ persistent diarrhea or rashes. One study evaluated Gulf War veteran males and their sexual partners who experienced a painful burning reaction to the veterans’ seminal fluid, a problem reported by about seven percent of Gulf War veterans. Evaluations indicated that about 40 percent of the women had a hypersensitivity reaction to the veterans’ seminal fluid, but provided no explanation for the phenomenon, overall. In general, very limited information is available on health problems specific to women veterans. Single studies have reported that Gulf War veteran women report elevated rates of yeast and bladder infections and breast lumps or cysts, but no results are available from medical evaluations.

Single studies have identified additional significant differences between symptomatic veterans and controls on a number of specific laboratory tests. These include elevated rates of coagulation abnormalities in symptomatic veterans, an elevated proportion of symptomatic veterans with insertion/deletion polymorphisms in the gene encoding for angiotensin-converting enzyme, and identification of atypical circulating polyribonucleotides potentially indicative of chromosome alterations.

Future directions in identifying physiological mechanisms that underlie Gulf War illness. To advance efforts to identify effective treatments and diagnostic tests for Gulf War illness, the Committee has recently expanded its work to review areas of research that may contribute to a better understanding of the specific pathophysiological mechanisms that underlie veterans’ symptoms. This has included preliminary discussions in several areas, including biological processes associated with neuroplasticity, disordered sensory processing and neuroendocrine dysregulation, and mitochondrial insufficiency. The Committee has also reviewed, in greater detail, diverse scientific findings that suggest a potential role for central nervous system inflammatory processes in the pathophysiology of Gulf War illness, and has identified this as a promising area for future research. The research considered indicates that neurotoxic Gulf War exposures may activate inflammatory processes in the brain and that increased brain levels of proinflammatory cytokines can produce a complex of multiple symptoms similar to Gulf War illness. Additional research suggests that these processes can become dysregulated by mechanisms that include repeated cycles of brain cell injury and glial activation, as well as autonomic and neuroendocrine disruption. Research in this area is especially warranted because of its possible clinical implications. Imaging methods are available that can potentially identify these processes in the brain and a variety of therapeutic agents are being studied for their effectiveness in treating dysregulated central inflammatory processes.

Gulf War Illness in Relation to Other Multisymptom Conditions. Parallels are commonly drawn between Gulf War illness and symptom-defined conditions such as chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivity (MCS) found in the general population. The prevalence of CFS in Gulf War veterans is unique, and dramatically higher than CFS rates found in nondeployed veterans and in the general population. Rates of FM and MCS are also elevated in Gulf War veterans, but to a lesser degree. It is clear from multiple studies, however, that case definitions for CFS, FM, and MCS do not adequately describe the chronic symptom complex that affects Gulf War veterans at excess rates, and that only a fraction of veterans with Gulf War illness can be diagnosed with any of these conditions. Overall, research studies have identified both similarities and differences between Gulf War illness and other multisymptom conditions. General similarities are reflected in indicators of autonomic dysregulation and neurocognitive impairment in Gulf War illness, FM, and CFS, and by indications that Gulf War illness and MCS are linked to PON1 variability. In contrast, the epidemiologic profile of Gulf War illness significantly differs from multisymptom conditions in the general population. Studies have also identified immune parameters and a number of other measures that differ in veterans with Gulf War illness, compared to patients with CFS or FM. Many objective measures associated with these conditions have not been evaluated in veterans with Gulf War illness, however. Additional research in these areas can potentially provide useful insights into biological mechanisms that underlie Gulf War illness and contribute to identifying beneficial treatments.

Federal Gulf War Research Programs. In addition to scientific studies and government reports, the Committee is charged with reviewing federal research programs established to address health consequences of the 1991 Gulf War. Since 1994, the U.S. government has reported expenditures of $340 million, over $440 million if indirect costs are considered, for hundreds of studies identified as Gulf War research in interagency reports to Congress. This research has been funded primarily by the Department of Defense (DOD) and the Department of Veterans Affairs (VA). Many federally-funded studies have provided valuable insights regarding the health of Gulf War veterans, as detailed throughout this report. But much of the federally funded research has not advanced understanding of Gulf War illness or other Gulf War-related health problems. Consequently, federal Gulf War research programs have not, as yet, succeeded in achieving the primary objective of Gulf War research, that is, to improve the health of Gulf War veterans.

The Committee identified major problems related to the historical use of research funds identified as “Gulf War research” expenditures by federal agencies. Historically, the large majority of Gulf War research funding was provided by DOD. In recent years, DOD has dramatically cut funding for projects identified as Gulf War research from nearly $30 million annually in 2001 to under $5 million in 2006. More troubling, many studies identified as “Gulf War research” at DOD over that period had little or no relevance to Gulf War illness or the health of Gulf War veterans. The DOD “Gulf War” portfolio consisted largely of costly projects that addressed broad questions related to current deployments and other health issues unrelated to the Gulf War. By 2006, less than 10 percent of the $4.7 million identified as DOD funding for “Gulf War research” supported studies that related to Gulf War illness or other health problems associated with Gulf War service.

The Department of Veterans Affairs had historically funded a smaller proportion of federal Gulf War research, but increased funding in recent years from a low of $4 million annually in 2002 to nearly $13 million in 2006. VA also historically identified a large number of studies as “Gulf War research” that had little relevance to Gulf War health issues. Until 2004, this included substantial funding for research on stress and psychiatric illness. By 2006, a larger number of studies had been funded that were related to Gulf War illness and effects of Gulf War exposures. Still, the largest amount of funding in VA’s Gulf War research portfolio, nearly 40 percent of the $13 million in 2006, supported projects focused on amyotrophic lateral sclerosis (ALS), few of which included Gulf War veterans or research issues related to the development of ALS in Gulf War veterans.

A number of important changes have taken place in federal Gulf War research programs in recent years. Beginning in 2006, Congressional actions brought about major changes in Gulf War research at both VA and DOD. Congress allocated an additional $15 million annually for Gulf War research at VA, and directed that it be used to support a center of excellence for Gulf War research at the University of Texas Southwestern (UTSW) in Dallas. The VA/UTSW program is focused on identifying biological abnormalities associated with Gulf War illness that can be targeted to develop diagnostic tests and treatments. Congress also appropriated $5 million in 2006 and $10 million in 2008 to support an innovative Gulf War research program managed by DOD’s Office of Congressionally Directed Medical Research Programs. The new DOD Gulf War research program is focused on identifying treatments for Gulf War illness and objective measures that distinguish ill from healthy veterans. Early indications suggest that developments at both VA and DOD represent promising new directions in the federal Gulf War research effort. The overall federal funding commitment for Gulf War research, however, remains substantially below historical funding levels and far below that warranted by the scope of the problem.

Research Priorities and Recommendations

The Committee is charged with determining what has been learned about the nature, causes, and treatments for Gulf War illness and advising on federal research, with the primary goal of improving the health of Gulf War veterans. In reviewing information on the broad variety of topics related to the health of Gulf War veterans, the Committee identified many scientific issues for which additional research was needed. Specific research recommendations have been provided in relation to each topic considered, and are compiled and prioritized in the final section of the report.

The Committee recommends that highest priority be given to research directed at identifying beneficial treatments for Gulf War illness. This includes clinical studies that systematically evaluate the effectiveness of currently available treatments, as well as research to identify specific path physiological mechanisms associated with Gulf War illness that can be targeted for treatment. The Committee also gives high priority to research aimed at identifying objective biological markers associated with Gulf War illness, especially those that advance efforts to improve diagnostic testing. Recommended research includes studies that expand on existing biological findings in Gulf War veterans—comprehensive research on brain structure and function, autonomic function, neuroendocrine and immune alterations, and processes associated with biological vulnerability to neurotoxicants—as well as studies that investigate neuroinflammatory processes and utilize genomic and related technologies to identify biological characteristics of Gulf War illness. Additional research priority areas include studies that characterize effects of neurotoxic exposures associated with Gulf War illness, and epidemiologic studies to assess rates of neurological diseases in Gulf War veterans.

The Committee identified additional areas of research needed to address other important Gulf War health issues. These include epidemiologic studies to identify mortality and cancer rates in Gulf War veterans, evaluation of health problems in veterans’ children, and improved characterization of Gulf War-related health problems in relation to exposures in theater. Recommendations are also provided for improving clinical and epidemiologic research on Gulf War veterans, and emphasize the importance of evaluating outcomes in subgroups of Gulf War veterans identified by illness characteristics and exposures in theater.

The Committee recognizes the vital importance of Congressional support, agency commitment and leadership, and adequate federal funding for achieving critical scientific objectives related to the health of Gulf War veterans and preventing similar problems in future deployments. It therefore recommends that the Administration request and that Congress allocate not less than $60 million annually in the federal budget for Gulf War research, an amount commensurate with the scope of the problem, and compatible with funding levels between 1999 and 2001. The Committee also recommends that this funding be specifically directed to research most capable of improving the health of Gulf War veterans, as outlined in this report.

Conclusions

Veterans of the 1990-1991 Gulf War had the distinction of serving their country in a military operation that was a tremendous success, achieved in short order. But many had the misfortune of developing lasting health consequences that were poorly understood and, for too long, denied or trivialized. The extensive body of scientific research now available consistently indicates that Gulf War illness is real, that it is the result of neurotoxic exposures during Gulf War deployment, and that few veterans have recovered or substantially improved with time. Addressing the serious and persistent health problems affecting 175,000 Gulf War veterans remains the obligation of the federal government and all who are indebted to the military men and women who risked their lives in Iraq, Kuwait, and Saudi Arabia 17 years ago. This obligation is made more urgent by the length of time Gulf War veterans have waited for answers and assistance.

NOTE: The 454 page full report of the “Gulf War Illness and the Health of Gulf War Veterans – Scientific Findings and Recommendations – Research Advisory Committee on Gulf War Veterans’ Illnesses – November 2008” can be downloaded from the VA website: www.va.gov/RAC-GWVI

The above extract is the entire Executive Summary of the November 2008 report.