Following the conclusion of the Gulf War, many veterans reported suffering from a variety of medical symptoms and illnesses. Of the approximately 697,000 men and women deployed to the Persian Gulf area during the war, most returned to productive lives in the military or in the civilian sector. Many veterans, however, complained of a variety of health problems potentially attributable to service in the Gulf War. Due to inadequate management of medical records and the lack of a statistically valid sampling of Gulf War veterans' health problems, it is impossible to state with any accuracy the number of veterans who have medical complaints due to Gulf War deployment.

In 1992, the VA created the Persian Gulf Registry Health Examination Program. In 1994, the DoD created the Comprehensive Clinical Evaluation Program (CCEP). Both these registries provide systematic medical evaluations for Gulf War veterans and collect information about the health of Gulf War veterans. The combined registries include the largest number of Gulf War veterans evaluated to date and the largest group given systematic medical examinations. Currently, more than 100,000 veterans have enrolled in one or both registry programs. The VA and DoD have each published analyses of the data collected in their respective registries.

The VA reported on the registry data of 52,835 veteran participants through September 1996. The most frequently diagnosed conditions among the International Classification of Diseases, Revision 9 (ICD-9-CM), categories were diseases of the musculo-skeletal and connective tissue (25.2 percent), mental disorders (15.1 percent), diseases of the respiratory system (14.3 percent), and diseases of the skin and subcutaneous tissue (13.5 percent). The most commonly reported symptoms were fatigue (20.5 percent), skin rash (18.4 percent), headache (18.0 percent), muscle and joint pain (16.8 percent), and cognitive problems (14.0 percent). Veterans who reported no symptoms, or who were deemed healthy by medical examination, comprised 12.3 percent of the total.

DoD reported on the medical evaluations of 20,000 veterans in the CCEP as of April 1, 1996. The most common ICD-9-CM classifications were "diseases of the musculo-skeletal system and connective tissue" (18.6 percent), "mental disorders" (18.3 percent), and "symptoms, signs, and ill-defined conditions" (17.8 percent). The latter category included 3,558 veterans with a variety of symptoms, including primarily fatigue, headache, memory problems, and sleep disorders. Nine percent of the CCEP participants were found to be healthy.

Both the CCEP and the VA Registry are "self-selected" databases (i.e., enrollment in the registries is voluntary and recruitment is non-specific). Therefore, the veterans enrolled in these registries are not necessarily representative of the entire U.S. Gulf War veterans' population. For example, Army veterans are over-represented in the CCEP enrollment by greater than 50 percent compared to the whole Gulf War population, and both the VA registry and CCEP registry have a higher percentage of females than among those veterans who were actually deployed. Thus, the measured prevalence of symptoms or diseases among veterans who participate in these registries is informative but may not accurately describe the Gulf War population as a whole. DoD acknowledged the limitations of the CCEP in one publication, stating: "... self-selection of patients, differential eligibility, recall bias, inability to validate self-reported exposures, and lack of an appropriate control group limit the generalization of these findings to other Gulf War veterans."¹

The VA Registry database was evaluated for five successive time periods, each representing a seven-month interval between August 1992 and July 1995. Self-reported "good" or "very good" health status declined over time for the 44,190 veterans in this analysis, and major symptoms (such as fatigue, skin rash, and headache) increased. Again, these trends may not represent the entire Gulf War veterans population. The Board knows of no other longitudinal analysis of Gulf War veterans' overall health.

Among the approximately 100,000 veterans evaluated to date from both the CCEP and the VA Registry, about 80,000 (80 percent) either report no adverse health conditions or have medical problems that are commonly recognized diseases or conditions. The approximately 20,000 remaining veterans (20 percent) have been found to have symptoms of undiagnosed illnesses. These undiagnosed illnesses have been the focus of concern among veterans groups, Congress, the media, and, indeed, DoD and the VA.

The symptoms of the Gulf War undiagnosed illnesses include chronic fatigue, skin rash, headache, muscle and joint pain, memory problems, shortness of breath, sleep disturbances, gastrointestinal symptoms, and chest pain. These symptoms are generally unaccompanied by objective physical signs or objective laboratory or radiological findings pointing to specific diagnoses. No consistent association of symptoms, potential toxic exposures, or troop deployment location has been found to identify a single cause of these symptoms or illnesses. The lack of uniformity of the symptoms and the paucity of existing evidence linking sick veterans to one or another environmental exposure suggest that the veterans' illnesses are not one disease, but are multiple diseases with multiple causes. Review panels from the National Institutes of Health, the National Academy of Sciences' Institute of Medicine, and the Presidential Advisory Committee on Gulf War Veterans' Illnesses have also reached this conclusion.

Although the Special Oversight Board was not tasked with identifying a cause of Gulf War undiagnosed illnesses, the Board reviewed every published study on Gulf War illnesses; heard testimony from numerous scientists, veterans, and DoD and VA officials; and held a large number of public hearings and open discussions on the issue of veterans' health problems. A complete review of these studies, discussions, and hearings is beyond the scope of this section. Rather, the following is a summary of Board conclusions and observations on Gulf War illnesses.

The symptoms most often reported by veterans suffering from undiagnosed illnesses following deployment to the Gulf War are nearly identical to the most common symptoms reported by patients in community outpatient medical clinics. Fatigue, headaches, muscle and joint pains, chest pain, abdominal pain, and skin rashes account for a large proportion of complaints causing patients to seek care from family practice physicians or general practitioners. The Board concludes, therefore, that some veterans would suffer these same symptoms had they not been deployed to the Gulf War. In other words, some portion of veterans suffering from undiagnosed illnesses would have these same complaints without having been exposed to any potential toxic substance during the war. Indeed, this conclusion is supported by studies comparing the complaints of deployed and non-deployed veterans. However, deployed veterans complain of the above symptoms at two or three times the rate of non-deployed veterans.

The symptoms of veterans' undiagnosed illnesses also bear a striking resemblance to those of patients suffering from chronic fatigue syndrome, fibromyalgia, or multiple chemical sensitivity. These three clinical entities have been the subject of much research over the past decades, yet there have been no definitive, scientifically accepted etiologies found for any of them. It is likely that some Gulf War veterans with the symptoms of undiagnosed illnesses are suffering from one of these three clinical problems. Similar conclusions were reached in studies of veterans from Canada and the United Kingdom as well as from the United States. In a recent study based on a random sample of veterans in the VA Registry, researchers found that approximately 16 percent met the diagnostic criteria for chronic fatigue syndrome, while approximately 13 percent met the criteria for multiple chemical sensitivity. A more specific study of VA Registry patients, using physical examinations as well as symptom questionnaires, found that of 53 veterans studied, 62 percent qualified for the diagnosis of chronic fatigue syndrome, 38 percent met the criteria for multiple chemical sensitivity, and approximately 6 percent qualified for the diagnosis of fibromyalgia. The Board concurs with the IOM conclusions that "some veterans with fatigue and chemical sensitivity fulfill case definitions for chronic fatigue syndrome, multiple chemical sensitivity and fibromyalgia."²

The symptoms of Gulf War undiagnosed illnesses are not unique to personnel deployed to the Persian Gulf. After every deployment of troops for war, similar symptoms have occurred in returning service personnel. This "post-war syndrome" has been attributed to the stresses of deployment. It has been described in various ways in every war since the Civil War. In the Civil War, soldiers suffering from headache, chest pain, shortness of breath, palpitations, and similar ailments were said to be suffering from an "irritable heart," later described as Da Costa's syndrome. No specific cause was identified for this problem, although most who had these symptoms had been subject to "hard field service and excessive marching." In the Boer War (1899-1902), a large number of British troops suffered from "debility, a chronic fatigue syndrome with no demonstrable organic cause."³ Fourteen percent of British troops in that war were awarded pensions for "functional disorders represented by unexplained symptoms." In World War I, "shell shock" was the term used to describe soldiers suffering from fatigue, muscle and joint pains, headache, and mental impairment. Again, no obvious cause or physical findings could explain these symptoms. Large numbers of both American and British troops were found to suffer from this syndrome. Similar findings pertain to World War II ("battle fatigue"), the Korean War, and the Vietnam War.

An exceptional example of this post-deployment syndrome from the Gulf War involves Canadian Naval personnel aboard HMCS Protecteur. This vessel, a 564-foot armed support ship with a crew of 370, deployed to the Persian Gulf during the Desert Shield buildup of troops. The crew aboard received no immunizations for anthrax or botulism; was not exposed to DU, oil well fires, or CW; and did not take PB tablets for prophylaxis against nerve agents. Prior to the onset of Operation Desert Storm, the complete crew re-deployed back to Canada, and a replacement crew was deployed aboard the vessel for the duration of the war. This replacement crew also had no exposure to DU or CW, but they were exposed to oil well fires; they did take PB tablets; and they were immunized against anthrax. Following the war, a survey of both crews for symptoms of illnesses was performed. Identical proportions of each crew were found to be suffering from the symptoms of undiagnosed illnesses. The only significant exposure factors shared by each crewmember were simply deployment to a war zone and routine pre-deployment immunizations. Thus, deployment itself was a likely explanation for the development of illness in at least some of the HMCS Protecteur crewmembers.

Peacekeeping deployments since the Gulf War have also been associated with these same symptoms of undiagnosed illnesses. Some British troops have complained of a "Balkan Syndrome" following their deployment to Bosnia and Kosovo. Although a few British troops felt that exposure to DU dust was the cause of their health problems, a U.K. governmental and scientific investigation into the issue found no link between the troops' symptoms and DU pathophysiology or exposure.

In another peacekeeping deployment, some of the nearly 9,000 Canadian troops returning from a 1993-95 United Nations operation in Croatia complained of a variety of symptoms similar to the undiagnosed illnesses discussed above. A number of these troops suspected that exposure to environmental contaminants in the "red dirt" of southern Croatia was the specific cause of the illnesses. A thorough Canadian governmental investigation revealed, however, that stress was the major cause of the ailments, stating: "Stress quickly emerged as an issue as the Board listened to soldiers recall the events of their missions. They recounted desperate efforts to build defensive structures ..., frequent shelling and small arms fires, the constant threats posed by landmines, the horrors of recovering the bodies of victims of ethnic cleansing, and weeks of living and operating in dire circumstances without a break ... in addition to the chronic stress due to frequent deployments, lengthy pre-deployment training, career courses between deployments, all amid an organization in the process of downsizing." The Canadian Board concluded "It is highly probable that at least some of these symptoms result from the very high level of chronic stress experienced during the operation."⁴

The Board concludes that it is highly likely that a proportion of Gulf War veterans suffering from the symptoms of undiagnosed illnesses fall into the generalized category of "post-war syndrome" or post-deployment illness. As with all previous wars, stressful deployments to a combat zone can create significant medical problems for returning troops. The fact that no specific cause or toxic exposure accounts for the signs or symptoms of post-deployment illness makes it no less debilitating for the troops involved. The Board recognizes that veterans suffering from these symptoms of post-deployment illness have real medical problems that can pose a significant disruption in their lives.

The remaining possible etiology of Gulf War undiagnosed illnesses is the potential exposure to toxic substances encountered by troops in the Gulf War and/or the exposure to medications and vaccines used by troops prior to and during deployment. This subject has been the primary focus of over $155 million in federally funded research into Gulf War illnesses, with 192 research projects either under way or proposed in both the private and federal sectors. The subject of toxic exposures will be reviewed in the following section. In addition, a separate section will discuss the possible role of stress in Gulf War illnesses.

The possible etiologies of the symptoms of Gulf War undiagnosed illnesses are summarized in the following diagram. The four etiologies discussed above are shown as layers in a pyramid. The pyramid depicted is used for graphical purposes and is not meant to represent the proportion of illness attributable to each factor. No data or research findings to date allow for definitive conclusions as to how many ill veterans can be accounted for by each of the possible etiologic categories.

The potential exposures for Gulf War illnesses, with one exception, are chemical and biological substances, both man-made and endogenous. They include:

• Biological warfare agents (BWA)
• Chemical warfare agents (CWA)
• Depleted uranium (DU)
• Indigenous infectious disease
• Oil well fires
• Pesticides
• Pyridostigmine bromide (PB)
• Sand
• Vaccines
• Stress (see Chapter 7 for a full discussion)

This section presents brief summaries of the published scientific literature concerning some of the possible environmental causes of Gulf War illnesses. It should be noted that none of the studies to date were designed to answer the question, "Is this exposure factor a cause of undiagnosed Gulf War illnesses?" In the few cases where there are studies of specific exposure factors, researchers have been concerned with the possible correlation of exposures with specific (defined or diagnosed) health outcomes-not with undiagnosed illnesses.

No study can determine with any certainty whether a measured association between exposures and health outcomes represents a cause and effect. Scientists and analysts have difficulty making statistically valid conclusions about causality because of the limited information characterizing exposures during the Gulf War. Few measurements of exposures were recorded during the war, and most survey data rely on veterans' memories of events, now nearly ten years later, or their judgment on whether they were exposed to a particular factor. The DoD has provided some estimates of exposures for the following substances: oil well fires emissions, depleted uranium, particulate matter, sand (not yet released), chemical warfare agents at Khamisiyah, CARC paint, and pesticides. The quality of these exposure estimates is generally unknown. DoD and the National Oceanic and Atmospheric Administration were able to partially validate modeled exposure estimates to oil well fire emissions by comparing the modeled results to ground level air measurements of sulfur dioxide concentrations. However, the Board has not seen any analysis of the quality of other exposure estimates by any method. We expect that the exposure estimates to some factors are poor (e.g., pesticide use, diesel fumes, and exhausts) because there do not appear to be reliable methods to estimate those exposures. The Board concurs with the Institute of Medicine's comments on exposure data: "Determining whether or not Gulf War veterans face an increased risk of illness because of their exposures during the Gulf War requires extensive information about each exposure (e.g., the actual agent(s), duration of exposure, route of entry, internal dose) and documentation of adverse reactions. Unfortunately, very little is known about most Gulf War exposures."⁵ Thus, nearly all studies on Gulf War exposures and potential associations with health effects contain elements of measurement uncertainty, recall bias, selection bias, and other potential confounding variables.

The CIA, DoD, and other agencies have found no evidence that Iraq used BWA during the Gulf War. There is no dispute, however, that the Iraqi military possessed bulk and weaponized biological warfare agents (e.g., anthrax and botulinum toxin). A review of Gulf War hospitalization records identified no cases of anthrax or botulism during the war. Furthermore, among the 225 non-battle-related deaths, only one person died of an infectious disease, meningococcosis.

The CIA, DoD, and other agencies found no evidence that Iraq used chemical weapons or chemical warfare agents during the Gulf War. The Board found that the only documented evidence about potential exposures to CWA in theater resulted from a large-scale postwar demolition of Iraqi munitions stockpiles at Khamisiyah. Modeling by DoD and the CIA suggests that the Khamisiyah release of the chemical warfare agents sarin and cyclosarin resulted in only low-level releases and only extremely low-dose potential exposures. These potential exposures did not result in any acute symptoms or any immediately reported adverse health outcomes associated with chemical nerve agent exposure. No chemical alarms sounded in the areas where troops might have been exposed. In fact, recent analysis of the Khamisiyah demolition reveals that no troops were situated in any area where sarin and cyclosarin potential exposures would have reached sufficient concentration to activate a chemical alarm. Furthermore, postwar hospitalization records do not indicate an increased prevalence of chronic disease among those veterans who were possibly exposed to low-dose CWA from the Khamisiyah demolitions.

OSAGWI's investigations into possible exposures to chemical warfare agents during and after Operations Desert Shield/Desert Storm (i.e., those incidents reported in seventeen case narratives) could not confirm any other CWA exposure. These investigations identified fewer than ten individuals who were associated with those incidents and who reported acute or chronic illnesses.

Based on the current body of evidence in the medical literature on studies of humans accidentally exposed to organophosphate nerve agents and on controlled animal exposures to organophosphate nerve agents at levels causing no acute signs or symptoms, low-level exposures do not produce chronic illnesses. However, gaps exist in the scientific literature regarding the potential long-term health consequences of exposure to low concentrations of nerve agents that are initially asymptomatic. VA, DoD, and DHHS have initiated research projects in this area. The Board concurs with the IOM's recommendations that research in this area focus on the "long-term effects of acute, short-term sarin [and cyclosarin] exposure at doses that do not cause overt ... effects" and also that research focus on "genetic factors that may alter susceptibility to sarin toxicity."⁶

Allied forces used DU in tank armor and in penetrators of various antitank munitions during the Gulf War. Although Iraq did not possess DU rounds, friendly-fire incidents caused more than 110 U.S. soldiers to be exposed to DU following impact of DU rounds to their own or others' vehicles or to damaged vehicles they inspected, recovered, or repaired.

The likely routes of exposure are primarily skin and muscle penetration of DU fragments and inhalation of DU dusts and aerosols. In general, DU penetrators pyrolyze (catch fire) upon impact and form insoluble uranium oxide dusts that may be inhaled. DU fragments in muscle tissue and insoluble DU oxides in the lung slowly release uranium to the bloodstream over many years. Soluble forms of uranium are excreted in the urine. The primary target organs for uranium toxicity are the kidneys, bones, and lungs, although other organ systems may be affected.

The VA and the Armed Forces Radiobiological Research Institute are both studying the long-term health effects of embedded DU in a small number of Gulf War veterans who were the victims of friendly-fire incidents. OSAGWI feels these veterans were exposed to the highest levels of DU during the war, since they not only have small masses of embedded DU penetrator fragments, but they were also exposed to inhalation of DU dusts and aerosols within their vehicle from the impact of the DU penetrator. The studies have found no evidence of significant adverse health effects from DU in these veterans. Renal function is unimpaired, even in those veterans with the highest levels of urine uranium excretion. On a few neurocognitive tests, veterans with higher urine uranium levels performed less well (on computerized cognitive tests, but not on pen-and-paper cognitive tests) than those with lower urine uranium levels. These neurocognitive tests were only given to a small number of veterans with DU fragments, and the study authors stated that the results from a few veterans with complex medical histories might have skewed the overall results. The clinical significance of these results is unknown.

Although semen levels of DU were elevated in veterans with embedded DU fragments (as would be expected, since dissolved DU will be found in nearly all tissue fluids), semen physiological characteristics (volume, concentration, morphology, and motility) were found to be the same in veterans with high urinary levels of DU as in veterans with low urinary levels of DU. More important, to date there have been no birth defects found in children fathered by veterans with embedded DU fragments.

To date there have been no studies assessing the effects of inhaled DU in Gulf War veterans. There have been mortality studies of miners exposed to uranium dusts that show higher-than-expected rates of death from lung cancer. However, these excess deaths may be attributed to other toxic inhalants present in the mines, such as radon, and they may not be a result of inhalation of uranium only. Also, in many of the uranium miner studies, use of tobacco was not evaluated and it could have contributed to some of the deaths. In studies of workers at uranium mills and uranium processing plants where there was no excessive exposure to radon, no increase in deaths was noted. The U.S. Army is currently conducting studies to estimate the possible extent of inhalation exposures to survivors of military vehicles hit by DU munitions and to personnel working in and around DU-contaminated vehicles.

The Board is aware that DoD, the Department of Energy, and the Nuclear Regulatory Commission (NRC) are investigating the levels of transuranic radionuclides (such as plutonium) that may have contaminated some of the lots of depleted uranium that were used to manufacture tank armor and penetrators used during the Gulf War. To date, no lots of DU used in tank armor or munitions have been found to contain levels of transuranics that appreciably increase the health risk from exposure to the DU, nor has the NRC yet required DoD to obtain additional licensing to maintain DU munitions.

The Board concludes that DU is unlikely to be the cause of either the unexplained illnesses among Gulf War veterans or the diagnosed illnesses found during CCEP and VA Registry evaluations. The Board concurs with the Institute of Medicine recommendations for: (1) "...additional studies in experimental animals to investigate the specific effects of depleted uranium"; and (2) "long-term follow-up of veterans exposed [and potentially exposed] to depleted uranium, including ... [those] involved in cleanup operations or radiation control units."⁷

During World War II, infectious diseases such as cutaneous leishmaniasis, hepatitis, sandfly fever, schistosomiasis, typhus, and typhoid fever had a significant impact on military operations in the Middle East. However, during the Gulf War there were few reported cases of infectious diseases and only one mortality attributable to an infectious disease. A review of DoD hospital records showed no reported cases of cholera, typhoid fever, amoebic dysentery, giardiasis, schistosomiasis, echinococcosis, brucellosis, sandfly fever, anthrax, or botulism. Only a few cases were identified of each of the following: cutaneous leishmaniasis (19 cases), visceral leishmaniasis (12 cases), Coxiella burnetii infection (i.e., Q Fever, 3 cases), malaria (7 cases), meningococcosis (2 cases), and West Nile fever (1 case).

The only endemic infectious diseases demonstrated to cause chronic illness among Gulf War veterans were cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). The mode of transmission of leishmaniasis is through bites from infected sand flies; person-to-person transmission does not occur. Unlike CL, which causes a characteristic ulcerative or nodular skin rash that can persist for more than a year without treatment, VL presents nonspecific effects like those of Gulf War illnesses (arthralgia, fever, malaise, abdominal pain, diarrhea, nausea, chronic fatigue, rigors, weight loss, coryza, nonproductive cough, and headache). However, there were very few confirmed cases of VL among sick Gulf War veterans who sought treatment in theater, in stateside DoD medical treatment facilities upon their return from the Gulf, or in VA facilities.

Mycoplasma infection has been proposed as a cause of veterans' undiagnosed illnesses, with many of the symptoms experienced by the Gulf War veterans explained by aggressive pathogenic intracellular mycoplasmal infections (i.e., Mycoplasma fermentans incognitus or Mycoplasma penetrans produces chronic symptoms long after the initial, and brief, exposure). Some experts disagree with this proposition and claim that, with the exception of mycoplasma pneumonia, forty years of research have failed to prove a clear connection between mycoplasmas and serious human diseases. Researchers favoring the mycoplasma theory also claim that a majority of chronic fatigue or fibromyalgia patients whom they studied had multiple mycoplasma infections (30.8 percent with double infections, 22 percent with triple infections) in their blood samples, compared with none in a healthy control group. Infections with multiple mycoplasma species also appeared to be associated with increased duration of illness. Researchers studying symptomatic and asymptomatic deployed and non-deployed Gulf War-era veterans, however, did not observe greater prevalence of Mycoplasma fermentans antibodies in the blood of sick Gulf War veterans.

Those researchers favoring the mycoplasma theory believe that symptoms arising from mycoplasmal infections could be treated by a long-term course of antibiotics (specifically, doxycycline, one of the tetracycline class of antibiotics). In early 2000, the Departments of Veterans Affairs and Defense began a treatment trial of deployed Gulf War veterans who presented symptoms of Gulf War illness and tested positive on a controversial laboratory test for Mycoplasma species. The purpose of the study was to see whether a daily regimen of 200 milligrams doxycycline for twelve months could improve the functional status of the veterans compared to veterans given a placebo. Secondary objectives of the study were to determine whether the treatment regimen reduces symptoms (such as pain, fatigue, and neurocognitive concerns), whether it converts mycoplasma-positive patients to mycoplasma-negative status, and whether benefits of the treatment persist after the treatment is ended. The doxycycline treatment trial is being conducted nationwide at twenty-six VA Medical Centers and two DoD research facilities. Recent analysis of laboratory results, however, has called into serious question the validity of the laboratory tests used to diagnose the presence of mycoplasma species. If the test is found to be invalid, then a large number of veterans are being exposed to a long-term course of antibiotics without evidence of an infection. The ethics of this experiment are thus in question. A decision by DoD and VA to continue the treatment trial is currently under review.

Some Gulf War illness veterans and advocates claim that Gulf War illnesses are contagious, capable of infecting family, co-workers, friends, and even pets. However, there exist neither epidemiological evidence nor laboratory-based infectious disease studies to support the hypothesis that contagious Mycoplasma sp. or another microorganism is a cause of Gulf War illnesses.

The U.S. Army Center for Health Promotion and Preventive Medicine (CHPPM) estimated troop exposures to oil well fires emissions during and after the Gulf War. CHPPM concluded that the only component of the pollution from oil well fires that was at levels of health concern was particulate matter. However, the Board noted that CHPPM did not fully evaluate the risks from oil fire emissions and recommended to CHPPM that it reconsider its risk evaluations and include in its estimates exposures to raining oil or oil mists. CHPPM agreed to reconsider its oil well fire exposure and risk assessments.

The RAND Corporation conducted toxicological evaluations of air concentration data of those substances that CHPPM measured in the Persian Gulf between May and December 1991, after many of the oil well fires had been extinguished. RAND concluded that particulate matter may be a cause of respiratory problems, especially among those veterans who were predisposed to asthma, but other pollutants were not at levels of health concern.

Some researchers have noted that self-reported levels of asthma or other respiratory illness are higher in veterans exposed to oil fire emissions compared to veterans who were not exposed. Other researchers observed a poor agreement between self-reported exposure to oil well fire smoke and modeled exposure estimates; still other researchers observed good agreement between self-reported and modeled exposure estimates. None of the studies of respiratory illnesses in Gulf War veterans and exposure to oil well fire emissions have yet been published in peer-reviewed journals. The Board concludes that there are insufficient data to state whether oil well fires are or are not a factor in the undiagnosed illnesses of Gulf War veterans.

Some of the pesticides used in the Gulf War are similar to nerve agents. Studies have demonstrated that many of these pesticides are toxic to humans above threshold exposure levels that vary with each pesticide. The Board is not aware of any published estimates of pesticide exposure to Gulf War veterans or of any published peer-reviewed studies looking at the relationship between pesticide use (or exposure) and Gulf War illnesses.

OSAGWI is planning to publish an environmental exposure report on pesticide use during the Gulf War, and the RAND Corporation will provide DoD two reports on pesticides use during the Gulf War. DoD, DHHS, and VA have funded university-based studies on the health effects of pesticides, with and without concurrent exposures to stress and other chemicals. Finally, the Institute of Medicine will publish an analysis of the potential role of pesticides in Gulf War illnesses.

During the Gulf War, the United States and some allied and coalition forces were provided PB tablets as prophylaxis against possible exposure to the nerve agent Soman. This was necessary since PB is the only possible prophylaxis for this toxin. Based on the number of tablets delivered but not returned in the system, an estimated 250,000 to 300,000 U.S. personnel received some PB during deployment.

PB is a reversible inhibitor of acetylcholinesterase (AchE), a critical enzyme used to deactivate the neurotransmitter acetylcholine. Repeated exposure to PB has been suggested as a potential cause of the persistent fatigue reported among Gulf War veterans due to pathological changes in neurons affecting skeletal muscles. Such nerve degeneration from PB loading has been studied in animals but not in humans. Other research indicates that the abnormal physiologic changes in nerve endings exposed to PB are reversible upon cessation of exposure (in vitro), and therefore PB exposure could not explain the chronic fatigue reported by some Gulf War veterans.

Gulf War deployed veterans were exposed to a variety of organophosphate pesticides (e.g., chlopyrifos, malathion) to protect against insects carrying diseases. There has been some suggestion that besides being neurotoxic itself, PB may lead to neurotoxicity following concurrent exposures to organophosphate compounds by interfering with the enzymatic degradation of the organophosphates, allowing them to enter the central nervous system. However, when using handgrip strength as an instrument for measuring muscle strength in humans, it was demonstrated that postwar handgrip strength was not associated with PB intake or exposure to pesticides. As with other exposures, military records from the Gulf War are inadequate to validate PB ingestion with or without concurrent pesticide exposures.

The Board concurs with both the RAND study on PB and the Institute of Medicine analysis that "available evidence is of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of an association [of PB use with adverse health effects] in humans."⁸ Further study is clearly needed in this area, since PB remains the only viable prophylactic agent for Soman exposure, and DoD intends to continue its use in future conflicts (although such use without informed consent will require a specific directive from the President).

Some researchers have suggested that inhalation of exceptionally fine-grain sand from the Arabian Peninsula can lead to a silicon-based immune system failure, possibly accompanied by concomitant opportunistic infections or toxemia from silicon dust (and other metals found in sand) in the bloodstream. The authors termed this illness "Al Eskan" disease after observing that the prevalence of respiratory illness among Gulf War veterans residing in Al Eskan Village, Saudi Arabia, was as high as 43 percent and that the fine sand at Al Eskan was commingled with large amounts of pigeon droppings. The authors suggested that the inhabitants of the desert have acclimated to the environment but that the immune depression from inhalation of sand made many service members susceptible to infectious agents and environmental toxicants, such as oil well fires pollution, depleted uranium, and chemical warfare agents. The authors have not published any studies of sick Gulf War veterans. No other researchers have published studies concerned with the possible link between inhalation of sand and Gulf War illnesses. However, CHPPM is currently modeling inhalation exposures to sand during the Gulf War. The Board concludes that there is insufficient information to state whether there is or is not an association of exposure to sand with the symptoms of Gulf War undiagnosed illnesses.

There are no reproducible scientific studies or existing data that show that routine vaccinations have significant detrimental effects on military personnel. All military vaccines are approved by the Food and Drug Administration (FDA), and DoD has a permanent position on the Advisory Committee on Immunization Practices (ACIP), coordinated by the U.S. Centers for Disease Control and Prevention (CDC). In addition, DoD is an active participant in the national Vaccine Adverse Event Reporting System (VAERS).

Military personnel receive routine vaccinations during their initial entry into the armed forces. They receive routine revaccinations and booster immunizations throughout their careers in accordance with the appropriate schedules specified by DoD vaccination directives.

During the Gulf War, two additional vaccinations were provided to select personnel. Approximately 8,000 service members were immunized in theater with the botulinum toxoid, an investigational new drug vaccine. In addition, about 150,000 service members and a proportion of forward-deployed operational forces were immunized in theater with the FDA-approved anthrax vaccine. The absence of accurate immunization records (and record keeping) has been highlighted in multiple reports.

The FDA's approval of the anthrax vaccine relied heavily on a 1962 study indicating the vaccine was safe and had an effectiveness of 92.5 percent (with a lower confidence limit of 65 percent). The incidence of individual reactions to the vaccine was relatively low: 2.8 percent of recipients had an edema-producing local reaction, and 0.2 percent had systemic reactions. These adverse event rates were comparable to other vaccines commonly in use. However, in its recent report on Gulf War health issues, the Institute of Medicine, after reviewing all available data, stated: "The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between anthrax vaccination and long-term adverse health effects."⁹

Some researchers have speculated that multiple vaccines given over a short period of time could adversely affect the immune system, potentially leading to adverse chronic health problems. A recent study in the United Kingdom found that personnel receiving the most vaccines prior to deployment had a slightly higher (but statistically significant) incidence of symptoms of undiagnosed illnesses. The Institute of Medicine, in evaluating this issue, found that, "The U.K. Gulf War studies provide some limited evidence of an association between multiple vaccinations and long-term multisymptom outcomes, particularly for vaccinations given during deployment. There are some limitations and confounding factors in these studies, and further research is needed."¹⁰ Another U.K. study showed that those who received their immunizations prior to deployment were less symptomatic than those who received their immunizations in theater, regardless of the number of immunizations received.

Some Gulf War veterans expressed concern that squalene, an endogenous hydrocarbon used by the body in the biochemical synthesis of cholesterol, may have been added to some Gulf War vaccines to enhance the antibody response of the immunization. In particular, these veterans have focused on the anthrax vaccine. These concerns were bolstered by a study by Dr. Asa and colleagues purportedly showing that Gulf War veterans with multisymptom illnesses had antibodies to squalene, whereas veterans who were healthy had no squalene antibodies. DoD has steadfastly maintained that no squalene was added to the anthrax immunizations. Dr. Asa has repeatedly rebuffed invitations from this Board to discuss the results of the study.

The IOM had the following comments concerning Dr. Asa's study: "This study has several shortcomings. The subjects were self-selected, rather than being chosen at random from a larger sample, which can introduce substantial selection bias and does not allow inferences to the broader population of Gulf War veterans. Sample sizes were small, and the study may suffer from misclassification errors since the group of Gulf War veterans categorized as healthy (n=12) was not devoid of individuals with serious symptoms. ... Further, the report provides inadequate evidence that the assay is able to accurately detect antibodies to squalene ... [and] the authors did not show that the assay was specific to squalene. ... The committee does not regard this study as providing evidence that the investigators have successfully measured antibodies to squalene."

In March 2000 the FDA, in a letter to Representative Jack Metcalf (R-Washington), stated that "neither the licensed vaccines known to be used in the Gulf War, nor the one investigational product known to have been used, contained squalene as an adjuvant in the formulations on file with the FDA."¹¹ The FDA tested select lots of anthrax and other bacterial vaccines (e.g., diphtheria and tetanus) for the presence of squalene. They found extremely small amounts (parts per billion) of squalene in all of the bacterial vaccines tested -- both anthrax and the common diphtheria and tetanus vaccines. The Board concludes that squalene is a highly unlikely cause of the multisymptom illness of some Gulf War veterans. If the extremely small levels of squalene in the anthrax vaccine (which was not administered to all deployed troops) were capable of causing symptoms in a small fraction of Gulf War veterans, one would logically expect that a very large number of military personnel, and civilians as well, to include school-age children, would have these symptoms, since all troops and a very large portion of the civilian population have received diphtheria and tetanus immunizations. The absence of such a "syndrome" in both groups clearly mediates against a role for squalene in Gulf War illnesses.

No person or agency has studied the health of all 697,000 deployed U.S. Gulf War veterans. However, the VA is currently conducting a study (the VA National Survey) of more than 15,000 U.S. Gulf War veterans to see how their health compares with that of 15,000 non-deployed Gulf War-era veterans. This study is the first and only study that is randomized over (very nearly) the entire U.S. Gulf War veterans population. Although the study employs a self-report survey questionnaire to measure veterans' health symptoms and potential or suspected exposures, it also includes a review of medical records and medical examinations of a sample of the larger study group.

Several studies of smaller numbers of Gulf War veterans have provided information regarding veterans' health problems. The limitation of these studies is that the participating veterans were not selected at random over the entire Gulf War veterans' population; the findings are therefore not necessarily representative of the entire deployed Gulf War veterans population. Also, they used self-report surveys and may represent only the individual's perception of illnesses, not specifically diagnosed physical illnesses. Some of the studies included a medical follow-up to validate survey data while others did not.

The natural course of Gulf War veterans' illnesses over time remains generally unknown because no fully random, longitudinal studies of symptom experience (i.e., repeat monitoring of the same group of veterans over time) have been conducted and reported in the medical literature. However, the VA has published one report where some veterans' medical records were reviewed at multiple points in time over two and a half years. Another study presents the change between two points in time in the number of self-reported symptoms by selected veterans from New England and New Orleans. These studies provide insight into how some veterans' health changed over time, but they are not necessarily indicative of how the health of Gulf War veterans as a whole has changed.

Clinical, toxicological, and epidemiological investigations into the health of veterans who took part in the Gulf War have resulted in widely varying views in the scientific community regarding the causes of Gulf War illnesses. To date, no specific cause of these illnesses has been scientifically validated. Nevertheless, some veterans remain convinced that their adverse health conditions are a consequence of wartime exposure to a host of potentially hazardous substances, either singly or in combination. In addition, some veterans believe that they have an illness that has or will cause birth defects in their children or that their illnesses will be contagious to their families. To date, however, there is little or no evidence in the peer-reviewed scientific literature supporting this concern.

The following section summarizes some of the major studies that have sought to characterize Gulf War veterans' symptoms. This summary will include the VA National Survey (introduced above) that is randomized over the entire U.S. Gulf War veterans population, several studies of smaller groups of U.S. Gulf War veterans, and studies from the United Kingdom.

The National Health Survey of Persian Gulf Veterans, Department of Veterans Affairs

Gulf War veterans reported a higher prevalence of all forty-eight symptoms on the questionnaire than did non-Gulf War veterans. The most frequently reported severe symptoms were back pain, runny nose, joint pain, headaches, anxiety, and difficulty sleeping. The most frequently reported chronic medical conditions (in decreasing order) were sinusitis, gastritis, dermatitis, arthritis, and frequent diarrhea. Gulf War veterans were three times more likely to report that their health status was poor compared with non-deployed Gulf War veterans; they also reported a substantially lower prevalence of excellent health than did non-deployed veterans. Gulf War veterans reported a 200 percent higher rate of functional impairment and an almost 50 percent higher rate of limitation of employment, and they sought more medical care than non-deployed veterans. The largest rate differences between Gulf War veterans and non-Gulf War veterans were consistently observed among National Guard members, followed by reserve unit members and active unit members. National Guard members also reported higher rates of exposure in nineteen out of twenty-three exposure categories compared with other deployed veterans. Leading exposures included diesel, kerosene, and/or other petrochemical fumes (including tent heater or vehicle exhaust); eating local food; and wearing chemical protective gear (other than during training) or hearing chemical alarms sounding. A substantial number of veterans reported exposure to nerve gas (9.6 percent) and mustard gas (4.8 percent). However, Gulf-deployed veterans reported the incidence of many diseases (e.g., diabetes, coronary heart disease, stroke, and asthma) at about the same rates as their non-deployed counterparts. This study began in 1995. Data evaluation and medical follow-up of a portion of the study participants is ongoing.

The University of Iowa conducted a study of 3,695 randomly selected veterans who listed the State of Iowa as their home of record. Researchers surveyed the veterans concerning their health and analyzed the results using factor analysis.

Approximately one half of the deployed veterans (n=1,896 from 889 units) and 14 percent of the non-deployed controls (n=1,799 from 893 units) reported health problems they attributed to military service during 1990-91. Compared with the non-deployed controls, the deployed veterans reported significantly greater frequency of 123 of 137 symptoms. The greatest differences in reported symptoms between the deployed veterans and non-deployed controls included polyarthralgia (multiple joint pain), fatigue, joint stiffness, headaches, and memory problems.

The factor analysis conducted by these researchers identified three replicable patterns (symptom factors) in both the deployed and the non-deployed veterans. The symptom patterns were as follows: somatic distress (joint stiffness, myalgia, numbness or tingling, headaches, and nausea), psychological distress (feeling nervous, worrying, feeling distant or cut off, and depression), and panic (anxiety attacks, a racing or skipping heart, attacks of chest pain, and attacks of sweating). These patterns were found in similar proportions in both the deployed and non-deployed veterans' groups.

The factor analysis results indicate that the health complaints of Gulf War veterans are comparable to those of the general military population and are not consistent with the existence of a unique Gulf War syndrome. However, these results do not explain the large disparity between the proportion of deployed veterans who reported health problems compared to non-deployed veterans, and they may not be applicable beyond the military population of Iowa.

In 1994, medical epidemiologists from the U.S. Centers for Disease Control and Prevention (CDC) conducted interviews and examinations of fifty-nine Gulf War veterans at a VA medical center in Pennsylvania to investigate veterans' unexplained illnesses. The most frequently reported "moderate" or "severe" symptoms were fatigue (61 percent), joint pain (51 percent), nasal or sinus congestion (51 percent), diarrhea (44 percent), and joint stiffness (44 percent). However, standardized physical examinations and review of VA laboratory tests did not reveal consistent abnormalities.

In the second phase of this investigation, the researchers surveyed more than 3,900 veterans and active duty Air Force personnel from four units with questions describing the frequency, duration, and severity of thirty-five symptoms most commonly mentioned during the phase 1 investigation. In all units, the prevalence of thirteen chronic symptoms was significantly greater among deployed Gulf War veterans than among those not deployed.

The researchers then developed multisymptom-illness case descriptions from clinical observations and factor analysis. Analysis of the data showed that Gulf War veterans were significantly more likely to meet criteria for severe and mild-to-moderate illness than were non-deployed personnel. The prevalence of chronic symptoms was highest among severe cases. However, the finding that 15 percent of non-deployed personnel also met the illness criteria adopted in this analysis indicates that the illness is not unique to Gulf War service. Deployment to the Gulf was the most significant risk factor for both severe and mild-to-moderate illnesses.

A U.K. study used a cross-sectional survey of a random sample of U.K. Gulf War veterans (deployed and not deployed to the Gulf) and Bosnia-conflict veterans. The survey included questions about deployment, exposures, symptoms, and illnesses. The Gulf War-deployed veterans reported symptoms significantly more frequently than both non-Gulf-deployed veterans and Bosnia-deployed veterans. Also, Gulf War-deployed veterans reported potentially harmful exposures more often than the other two groups. The authors suggest that, since ill health was associated with exposures in all three groups, the illnesses may not be unique to Gulf War-deployed veterans. The authors noted that the differences in the reported exposures among the three groups were not substantial. However, the excess reporting of ill health among Gulf-deployed veterans over Bosnia-deployed veterans suggests that adverse health effects associated with service in the Gulf were due to something "over and above" deployment to an unfamiliar hostile environment, and may be due to "different experiences of hazardous exposures" in the Gulf compared to other environments. The authors noted that multiple vaccinations were associated with poorer health, regardless of deployment. The U.K. researchers conducted a factor analysis on their data and found, much like in the Iowa study, that the symptom patterns were similar across all three of their study populations, suggesting that the illnesses among Gulf War veterans are not unique.

Summary

The results of the Iowa, Pennsylvania Air National Guard, and United Kingdom studies above suggest the following:

1. The symptoms reported by veterans appear to be consistent across the studies, with minor variations in rank order and percent of the veterans reporting them.
2. The pattern of illnesses is not markedly different between the deployed Gulf War veterans and control groups, although the proportion of veterans reporting symptoms is significantly greater among deployed veterans.

These studies do not address causality of Gulf War illnesses. Rather, they show that Gulf War veterans report various symptoms at a higher rate than non-deployed veterans of the same era and at a higher rate than veterans deployed to sites other than the Persian Gulf. Whether this higher prevalence of symptoms is due to exposure factors unique to the Gulf War, to the sensitivity of Gulf War veterans to potential illnesses secondary to their deployment, or to other factors cannot be determined from the available data.

1. A substantial number of Gulf War veterans suffered significant illness, impairment, and disability following their deployment to the Persian Gulf.

2. Studies published to date have not identified a cause of undiagnosed Gulf War illnesses.

3. The symptoms of Gulf War undiagnosed illnesses are similar to those found in the general population and are similar to those of veterans returning from combat duty in previous wars and from contemporary peacekeeping duties.

4. The symptoms of Gulf War undiagnosed illnesses are similar to those of patients suffering from chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity.

5. Deployment stress is a likely causal or potentiating factor in at least some Gulf War veterans' illnesses.
6. Epidemiological studies of Gulf War veterans are compromised because exposure estimates for many factors are of poor quality or are nonexistent. Self-reported exposures, which are subject to recall bias, misinformation, or other confounding variables, are often the only exposure data available.
7. Further research is necessary to evaluate the potential relationship between toxic exposures and symptoms of undiagnosed Gulf War illnesses.

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