Research Potential Causes of Gulf War Illness

Current RAND Policy Studies and Literature Reviews

Veterans of the 1991 Gulf War have reported a wide range of physical and psychological symptoms, some of which remain unexplained. In order to make every effort to understand and explain the illnesses, educate veterans and the public, and recommend changes in Department of Defense (DoD) policies and procedures to minimize these problems in the future, the Secretary of Defense appointed the Office of the Special Assistant for Gulf War Illnesses and its Special Assistant the Office of the Special Assistant for Gulf War Illnesses, OSAGWI) in 1996 to oversee all DoD activities related to Gulf War veterans' illnesses: Department of Veterans Affairs activities.

To supplement its research, OSAGWI commissioned the RAND National Defense Research Institute and the RAND Health Center for Military Health Policy Research to conduct a review of the scientific literature and other policy research on the health effects of eight disease-prone areas. It was hoped that the combined scientific studies of the Gulf War would provide a better understanding of Gulf War veterans' illnesses.

This research report summarizes RAND studies on the health effects of infectious diseases, pyridostigmine bromide (PB), immunization, war stress, chemical and biological warfare agents, oil shale fires, depleted uranium (DU), and pesticides.

Many of these studies were reviews of the scientific literature, typically involving data published or accepted for publication in peer-reviewed journals, books, government publications, and conference proceedings. Sometimes RAND used unpublished data, but only to develop hypotheses. In some cases, RAND commissioned independent studies on the nature or extent of possible causes of Gulf War illnesses.

Summary 

Shortly after the end of the 1991 Gulf War, veterans of that conflict began reporting a variety of physical and psychological symptoms, some of which remain unexplained. In response, the Secretary of Defense appointed a Special Assistant for Gulf War Illness (OSAGWI) in 1996 to oversee all Department of Defense activities related to Gulf War illness.

This research report summarizes RAND's assistance to OSAGWI in studying the health effects of eight potential pathogens: infectious diseases, pyridostigmine bromide, immunization, war stress, chemical and biological warfare agents, oil well fires, depleted uranium, and pesticides.

RAND Studies on Gulf War Illness

Diseases

• Compared to other wars, the incidence of infectious diseases among U.S. soldiers in the Gulf War was very low.
• Known infectious diseases were diagnosed and treated appropriately.

Possibe Cause:

• Commonly known infectious diseases were ruled out, but it is possible that an unknown infectious disease caused the undiagnosed illnesses.
• One theory still being explored involves the role of mycoplasma, an elusive bacterium that one researcher believes caused the disease in a published paper.

Pyridostigmine bromide

• PB was distributed to U.S. and allied troops as a pretreatment for the eventual use of the nerve agent soman in Iraq. PB is an acetylcholinesterase inhibitor.
• RAND has studied the known effects of PB on the central and peripheral nervous system and the validity of hypotheses regarding the possible effect of PB on disease.

Possible Cause:

• Based on the scientific evidence available to date, RAND could not rule out the possibility that PB may have contributed to some of the symptoms of Gulf War veterans.
• The report calls for further research on the safety and efficacy of PB administration to humans.

Stress

• The general scientific literature has shown that stress can cause a myriad of health effects.
• These effects can manifest as symptoms and conditions similar to those reported by Gulf War veterans.

Possible Cause:

• Although the scientific literature suggests that stress can cause symptoms similar to those observed in Gulf War veterans, there are currently no empirical studies to prove this.
• It is inappropriate both to consider stress as a tacit explanation for the many health problems reported by Gulf War veterans, when there is no evidence to support this view, and to assume that stress plays no role.

Chemical and biological warfare agents

• No evidence of exposure to militarily effective doses was found. Such exposures would have caused death or severe symptoms.
• Low-level exposures may have caused mild symptoms that could have been ignored.
  There are few studies on the effects of low exposures below the symptomatic dose.

Possible Cause:

• Acetylcholinesterase inhibitor neurotoxicity, acetylcholinesterase inhibitor neurotoxicity, Gulf War veterans.
• Exposure to military effective doses was not considered. Although the scientific literature provides no evidence of exposure, the possibility that exposure to low doses of certain chemical warfare agents may have contributed to the symptoms observed in Gulf War veterans cannot be ruled out. Further research is needed in this area.

Oil Spill Fires

• Contaminant levels in Kuwait and Saudi Arabia were well below U.S. recommended occupational health standards and comparable to ambient levels.
• Particulate matter concentrations were elevated, but they were primarily sand particles, the size of which does not affect the respiratory system of smokers, asthmatics, or other sensitive populations.

Possible Cause:

• A review of the scientific literature does not suggest that there are any health effects associated with the levels of pollutants measured in oil well fires.

Depleted uranium

• During the Gulf War, armor-piercing and anti-tank projectiles made from depleted uranium were widely used.
• Although there is very little direct literature on the health effects of DU exposure, much of the literature deals with the health effects of natural and enriched uranium. Toxicologically, DU is similar to natural uranium, but less radioactive.

Possible Cause:

• RAND has not found any health effects reported in the literature that could be attributed to exposure to natural uranium at concentrations above those that likely occurred during the Gulf War.
• The Gulf War veterans most exposed to DU-those with shrapnel embedded in them-did not show toxicological side effects from DU or health problems related to DU radiation.

Pesticides

• RAND reviewed the scientific literature on 12 of the 35 pesticides used during the Gulf War.
• RAND focused on known exposures and doses and associated health effects, with particular attention to the long-term chronic effects of organophosphate and carbamate pesticides that act as acetylcholinesterase inhibitors.

Possible Cause:

• Little evidence was found regarding the long-term effects of the four pesticides studied.
• Phosphoelectron pesticides and carbamates have been shown to cause similar symptoms in some Gulf War veterans. There is evidence that these pesticides may contribute to some of the undiagnosed illnesses in Gulf War veterans. However, no prospective studies have identified pesticides as causative agents.
  
  

Infectious Diseases

The RAND literature review focused on known or probable communicable diseases (excluding influenza or rhinitis) that had actually been diagnosed in Gulf War veterans or were known to be present in the Gulf region. The study found that the prevalence of infectious diseases among U.S. soldiers during the Gulf War was very low and that known infectious diseases were diagnosed and treated appropriately.

However, the study could not rule out the possibility that some previously unknown infectious diseases may have caused the undiagnosed illnesses of Gulf War veterans. Most of the known infectious diseases have been ruled out, but one theory that still deserves attention is the role of mycoplasma. This is an elusive bacterium that one researcher theorized in a paper would cause the illnesses of Gulf War veterans.

Pyridostigmine bromide

Pyridostigmine bromide was distributed to U.S. and allied troops as a preventive treatment to improve the effectiveness of post-exposure treatment in cases where Iraq used Soman neurotoxin during the Gulf War. RAND investigated the role of PB in the persistence of chronic health problems in Gulf War veterans. After examining the known effects of PB on the central and peripheral nervous system, the RAND research team could not deny the possible contribution of PB to the undiagnosed health problems of some veterans.

The RAND research team evaluated three possible mechanisms that could lead to increased susceptibility to PB in some people during the Gulf War. The researchers found evidence consistent with all of these mechanisms and concluded that additional research is needed to assess their potential role in Gulf War-related health problems. The researchers also evaluated four hypotheses about how PB may cause chronic disease.

They found enough evidence to rule out one hypothesis, but not enough to evaluate another. They also concluded that the last two closely related mechanisms are biologically plausible, but that additional research is needed to confirm or deny whether these mechanisms contributed to the health effects of Gulf War service. The report of this study calls for additional research to clarify the role of PB.

The use of drugs that have not yet been approved by the FDA for Gulf War defense purposes

In another study, RAND examined regulatory issues related to the use of drugs and vaccines “studied” by the Department of Defense to protect U.S. military personnel from chemical and biological weapons. The U.S. Food and Drug Administration (FDA) has authorized the administration of these drugs and vaccines to members of the armed forces in certain situations, although these substances have not been specifically tested for use in such situations.

RAND examined (1) the rule that authorizes the FDA commissioner to waive informed consent for these substances, (2) how this authority was used for PB and botulinum toxin vaccine during the Gulf War, and (3) the controversies surrounding the rule, its application, and its consequences.

Vaccines

Vaccination is one factor that has been widely considered as a possible cause of Gulf War veterans' illness. Military personnel receive a variety of vaccinations as part of their military service, and Gulf War veterans received a number of additional vaccinations, including anthrax and botulinum toxoid vaccines. RAND reviewed evidence from the scientific literature and other sources (including newspapers and the internet) regarding the possible link between these two vaccines and the chronic health problems reported by ill Gulf War veterans.

RAND also investigated whether multiple vaccination (i.e., administration of one or both vaccines in combination with other vaccines) is associated with symptoms experienced by Gulf War veterans. RAND also examined the efficacy of anthrax and botulinum toxoid vaccines and reviewed the history of anthrax vaccine production. The results of this review will be presented in an upcoming RAND report scheduled for publication in 2005.

Stress

U.S. soldiers who served in the Gulf theater during the Gulf War had a number of stressful experiences before, during, and after deployment, and these experiences may have contributed to the health problems they reported. The RAND report states that studies in the general scientific literature have shown that stress can cause a myriad of health effects and that these effects can manifest themselves in symptoms and illnesses similar to those reported by Gulf War veterans.

The RAND report also states that while empirical studies of Gulf War veterans suggest that stress plays a role in the onset or exacerbation of illnesses, current studies do not show a causal link between stress and unexplained illnesses in Gulf War veterans.

The second RAND study examined the psychological and psychosocial consequences of combat deployments and operations, with a particular focus on the Gulf War. The study found that the stress of combat or simple deployment can have direct and long-term physical and psychological consequences.

The study also concludes that, although it would be simplistic to claim that stress caused the Gulf War illnesses, stress affects many psychological and somatic symptoms, such as making soldiers more susceptible to environmental pathogens. Because stress is susceptible to multiple influences and many factors act synergistically, this report argues that it is unlikely that there is a single, independent cause of the illnesses seen in Gulf War veterans.

Chemical and Biological Warfare Agents

RAND reviewed the scientific literature on the effects of exposure to certain chemical or biological weapons. For battlefield veterans, RAND found that militarily effective doses of any of the agents studied would have caused serious health effects that would have required clinical treatment or resulted in death. However, no health effects were observed in battlefield veterans, so there is no evidence of exposure to militarily effective doses.

However, because low levels of exposure may have resulted in mild clinical signs that may have been overlooked or misinterpreted, the study cannot rule out the possibility that low levels of exposure may be a possible cause of some of the illnesses suffered by Gulf War veterans.

However, the study found it unlikely that an exposure affecting large numbers of people would have gone unnoticed clinically. The literature review also failed to confirm what veterans reported to be true for about half of the Gulf War-related health problems: clinical symptoms did not appear until years after their initial exposure to CW/BW doses.

Oil spill fires

A RAND literature review found that measurements in the battlefields of Kuwait and Saudi Arabia, where most troops were deployed during the Gulf War, showed that contaminant levels in these areas were an order of magnitude below U.S. recommended occupational exposure standards and comparable to ambient levels.

RAND's review of the scientific literature found nothing to suggest that the levels of pollutants measured during the oil spill fires had a health impact. Particulate matter concentrations were high, but this was largely due to the size of the sand particles, which are likely to affect the respiratory system of sensitive populations such as smokers or asthmatics.

Depleted uranium

Because of its density and metallurgical properties, depleted uranium was widely used during the Gulf War to improve armor and anti-tank munitions. The RAND report reviews the scientific literature on the potential health effects of DU exposure on U.S. soldiers. Although very little of the literature deals directly with depleted uranium, much of the literature deals with the health effects of natural and enriched uranium. Toxicologically, DU is similar to natural uranium, but because it is less radioactive, it is less radiologically dangerous.

The RAND literature review found no adverse health effects from exposure to natural uranium at levels above those to which military personnel were likely exposed during the Gulf War. This literature review pays particular attention to ongoing research on the group of Gulf War veterans most exposed to depleted uranium from shrapnel. Individuals with high levels of uranium, but a review of the literature did not indicate that kidney damage was due to hydroactivity or to adverse health effects associated with hydroactivity.

Pesticides

The RAND report summarizes the scientific literature on 12 of 35 pesticides that may have been used during the Gulf War. The report focuses on known pesticide exposures, doses, and health effects, with particular emphasis on the long-term chronic effects of organophosphates and carbamates.

Epidemiological studies and studies of genetic and biological differences between diseased and healthy individuals, as well as studies of the physiological mechanisms of organophosphate and carbamate pesticides, are desirable but inconclusive. Studies suggest that these pesticides may be a possible cause of some of the undiagnosed illnesses in Gulf War veterans. However, no prospective study has conclusively identified pesticides as the cause.

The second report presents the results of the RAND study of 2,500 Gulf War veterans. The study sought to determine the extent to which service personnel used pesticides before and during the conflict. While most personnel were exposed to pesticides, RAND found that pesticide use varied by service, rank, military rank, and lifestyle. RAND found no evidence of widespread pesticide misuse, but identified a few possible instances of misuse.

What do RAND's policy studies and literature reviews mean?

Although no definitive cause was found to explain the health problems reported by Gulf War veterans, the RAND study and studies by other researchers identified several areas that could not be ruled out as possible causes of the symptoms and therefore require further investigation. Based on the work published by RAND to date, these areas of additional research include pyridostigmine bromide and the health effects of pesticides.

RAND will soon publish a study on the possible role of vaccination. In addition, because battlefields are “messy” in the sense that troops are exposed to many occupational hazards and high levels of stress, RAND is calling for additional research on the effects of a combination of factors and on the susceptibility of individuals to these exposures. RAND's research also highlights the need for improved data collection and record keeping on the potential causes of Gulf War illnesses, which the Department of Defense has already begun to improve significantly.