Gulf War Illness and the Health

of Gulf War Veterans

Scientific Findings and Recommendations

Research Advisory Committee on

Gulf War Veterans’ Illnesses

Gulf War Illness and the Health

of Gulf War Veterans

Scientific Findings and Recommendations

Research Advisory Committee on

Gulf War Veterans’ Illnesses
Research Advisory Committee on Gulf War Veterans’ Illnesses

Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations

Washington, D.C.: U.S. Government Printing Office, November 2008
Research Advisory Committee on Gulf War Veterans’ Illnesses

James H. Binns, Committee Chair

Carrolee Barlow, M.D., Ph.D.

Floyd E. Bloom, M.D.

Daniel J. Clauw, M.D.

Beatrice A. Golomb, M.D., Ph.D.

Joel C. Graves, D.Min.

Anthony Hardie

LTC Marguerite L. Knox, M.N., N.P.

William J. Meggs, M.D., Ph.D.

Mary Dekker Nettleman, M.D., M.S.

James P. O’Callaghan, Ph.D.

Steve Smithson

Lea Steele, Ph.D.

Roberta F. White, Ph.D.

Consultant to the Committee:

Jack Melling, Ph.D.
Research Advisory Committee on Gulf War Veterans’ Illnesses

U.S. Department of Veterans Affairs

Washington, D.C.

website: www.va.gov/RAC-GWVI

Committee Staff Office:

Research Advisory Committee on Gulf War Veterans’ Illnesses

Boston University School of Public Health

715 Albany Street (T-4W)

Boston, MA 02118

email: RAC@bu.edu
Table of Contents  i

Gulf War Illness and the Health of Gulf War Veterans

Table of Contents

Findings in Brief................................................................................................................................ 1

Executive Summary.......................................................................................................................... 3

Introduction...................................................................................................................................... 19

1| Gulf War Illness and the Health of Gulf War Veterans................................................... 23

Characteristics and impact of Gulf War illness: Epidemiologic research ........................................

– How many Gulf War veterans have Gulf War illness?.........................................................................

– Characteristics of Gulf War illness.......................................................................................

– Which veterans are most affected by Gulf War illness?......................................................................

– Evaluating causal factors in Gulf War illness ........................................................................

25

25

27

31

32

Gulf War illness prognosis and the need for treatments .....................................................................

– Are veterans with Gulf War illness getting better or worse with time?.............................................

– The urgent need for effective treatments for Gulf War illness.................................................

36

36

36

Is there a unique Gulf War Syndrome?........................................................................................................ 41

Other Gulf War health issues ...................................................................................................

– Diagnosed diseases affecting Gulf War veterans...................................................................

– Mortality rates among Gulf War veterans..............................................................................

– Hospitalization rates among Gulf War veterans.....................................................................

– Birth defects and the health of Gulf War veterans’ family members.........................................

43

43

47

48

49

Special committee and government reports on the health of Gulf War veterans............................... 53

Recommendations................................................................................................................... 56

2| What Caused Gulf War Illness? Effects of Gulf War Experiences and Exposures.. 59

Psychological stressors and the health of Gulf War veterans..............................................................

– Traumatic experiences and psychological stressors in the Gulf War........................................

– Health effects of psychological stressors.............................................................................

– Research on the health of Gulf War veterans in relation to psychological stressors...................

– Recommendation.................................................................................................................

61

62

63

66

74

Kuwaiti oil well fires and the health of Gulf War veterans.............................................................

– Exposure to oil well fires and smoke during Gulf War deployment..........................................

– Health effects of Kuwaiti oil fire-related exposures...............................................................

– Studies evaluating the health of Gulf War veterans in relation to the Kuwaiti oil fires................

– Recommendations............................................................................................................

75

75

79

80

84

Depleted uranium and the health of Gulf War veterans.........................................................................

– Depleted uranium exposure in the Gulf War..........................................................................

– Health effects of DU exposure.............................................................................................

– Research on the health of Gulf War veterans in relation to DU exposure..................................

– Recommendations.............................................................................................................

85

86

87

95

100
ii  Table of Contents

Table of Contents

2| What Caused Gulf War Illness? Effects of Gulf War Experiences and Exposures (cont.)

Vaccines and Gulf War illness...................................................................................................

– Vaccines given to Gulf War military personnel......................................................................

– Health effects of vaccines given to Gulf War troops...............................................................

Anthrax vaccine...........................................................................................................

Other vaccines given to Gulf War troops.........................................................................

Vaccine adjuvants........................................................................................................

Health effects of receiving multiple vaccines..................................................................

– Studies evaluating the health of Gulf War veterans in relation to vaccines................................

– Recommendations.............................................................................................................

101

101

105

106

114

115

120

122

127

Cholinergic and related neurotoxicants: Pyridostigmine bromide, pesticides, and nerve agents......

– Exposure to cholinergic and related neurotoxicants during the Gulf War..................................

Pyridostigmine bromide use in the Gulf War....................................................................

Pesticide use and exposure in the Gulf War.....................................................................

Exposure to chemical weapons in the Gulf War................................................................

– Health effects of cholinergic and related neurotoxicants.........................................................

Health effects of pyridostigmine bromide........................................................................

Health effects of pesticides and insect repellants used in the Gulf War...............................

Health effects of low-level sarin exposure........................................................................

– Effects of combinations of Gulf War neurotoxicant exposures.................................................

– Research on the health of Gulf War veterans in relation to cholinergic and related

neurotoxicants...................................................................................................................

The health of Gulf War veterans in relation to pyridostigmine bromide ...............................

The health of Gulf War veterans in relation to pesticides....................................................

The health of Gulf War veterans in relation to chemical agents...........................................

– Recommendations.............................................................................................................

128

129

130

131

134

147

147

151

157

166

177

178

180

181

186

Infectious diseases in Gulf War veterans....................................................................................

– Infectious disease in the Gulf War.......................................................................................

– Evaluation of infectious diseases in Gulf War veterans since the war.......................................

– Antibiotic treatment of Gulf War illness................................................................................

– Biological warfare agents in the Gulf War.............................................................................

– Recommendations.............................................................................................................

187

187

191

196

197

200

Other exposures in theater.............................................................................................................

– Sand and particulate exposures in the Gulf War....................................................................

– Exposure to combustion products from tent heaters..............................................................

– Organic solvents in the Gulf War ........................................................................................

– Jet fuel in relation to Gulf War illness...................................................................................

– CARC paint: Exposure to chemical agent resistant coating in the Gulf War..............................

– Contaminated food and water in the Gulf War........................................................................

– Other potential hazards encountered by military personnel in the Gulf War...............................

– Recommendations.............................................................................................................

201

201

203

204

205

208

210

212

214

Synthesis: What the weight of evidence tells us about the causes of Gulf War illness.....................

– General patterns of exposure in the Gulf War........................................................................

– General information on health effects of exposures...............................................................

– Evidence from studies of Gulf War veterans..........................................................................

– Overview of the evidence linking Gulf War illness with experiences and exposures during

Gulf War deployment.........................................................................................................

– Summary...............................................................................................................................................

215

216

218

220

224

227
Table of Contents  iii

Table of Contents

3| The Nature of Gulf War Illness........................................................................................... 229

Biological and clinical characteristics of Gulf War illness....................................................................

– Brain and central nervous system alterations........................................................................

Neuroimaging findings in Gulf War veterans...................................................................

Neurocognitive findings in Gulf War veterans..................................................................

– Autonomic nervous system alterations in Gulf War veterans...................................................

– Neuromuscular and sensory findings in Gulf War veterans.....................................................

– Neuroendocrine alterations.................................................................................................

– Vulnerability to neurotoxicants: variation in genotype and activity of protective enzymes..........

– Immune parameters in Gulf War veterans.............................................................................

– Additional clinical and research findings associated with Gulf War illness...............................

– Future directions in identifying physiological mechanisms underlying Gulf War illness..............

– Recommendations.............................................................................................................

230

232

233

237

243

246

249

250

257

262

267

273

Gulf War illness in relation to multisymptom conditions in the general population...........................

– Fatigue and chronic fatigue syndrome in Gulf War veterans...................................................

– Chronic pain and fibromyalgia in Gulf War veterans...............................................................

– Sensitivity to chemicals and multiple chemical sensitivity in Gulf War veterans........................

– Is Gulf War illness the same as multisymptom conditions found in the general population?.......

– Recommendations.............................................................................................................

274

275

276

278

280

288

4| Federal Research on Gulf War Illness and the Health of Gulf War Veterans............ 289

Historical funding and management of federal Gulf War research.................................................. 290

Gulf War research at the Department of Veterans Affairs.............................................................. 295

Gulf War research at the Department of Defense......................................................................... 300

Gulf War research at the Centers for Disease Control and Prevention ............................................ 303

Additional VA programs relevant to Gulf War research................................................................. 303

Recommendations................................................................................................................... 309

5| Research Priorities and Recommendations.................................................................... 311

Highest priority Gulf War research............................................................................................. 311

Other research areas of importance for addressing Gulf War health issues.................................... 314

Guidelines for clinical and epidemiologic research on Gulf War veterans....................................... 315

Acknowledgements ......................................................................................................................... 317

References...................................................................................................................................... 323
iv  Table of Contents

Table of Contents

Appendices

Appendix A| Association of Gulf War Experiences and Exposures with Chronic Symptoms

and Multisymptom Illness: Results from Studies of Gulf War Veterans................ 395

A-1. CARC paint................................................................................................................ 397

A-2. Chemical agents.......................................................................................................... 399

A-3. Contaminated food and water....................................................................................... 403

A-4. Depleted uranium............................................................................................................. 405

A-5. Fuel exposures................................................................................................................ 407

A-6. Oil well fires............................................................................................................... 411

A-7. Pesticides and insect repellants................................................................................... 413

A-8. Psychological stressors.............................................................................................. 417

A-9. Pyridostigmine bromide.................................................................................................... 423

A-10. Sand............................................................................................................................... 427

A-11. Solvents.................................................................................................................... 429

A-12a. Vaccines: Individual types................................................................................................ 431

A-12b. Vaccines: Number received........................................................................................ 435

Appendix B| Charter of the Research Advisory Committee on Gulf War Veterans’ Illnesses...... 437

Appendix C| Members of the Research Advisory Committee on Gulf War Veterans’

Illnesses..................................................................................................................

441

Abbreviations and Acronyms..................................................................................................... 447
Findings in Brief  1

| Gulf War Illness and the Health

of Gulf War Veterans

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 Congressionallymandated 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).
2  Gulf War Illness and the Health of Gulf War Veterans

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.
Executive Summary  3

| 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 multisymptom 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
4  Gulf War Illness and the Health of Gulf War Veterans

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 multisymptom 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 pathophysiology 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
Executive Summary  5

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 have 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.
6  Gulf War Illness and the Health of Gulf War Veterans

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 sparsity 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
Executive Summary  7

exposures encountered by Gulf War military personnel. The large number of epidemiologic and clinical

studies of Gulf War veterans also allow 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
8  Gulf War Illness and the Health of Gulf War Veterans

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.
Executive Summary  9

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 airborne

particulates, 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
10  Gulf War Illness and the Health of Gulf War Veterans

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
Executive Summary  11

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
12  Gulf War Illness and the Health of Gulf War Veterans

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 have 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.
Executive Summary  13

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
14  Gulf War Illness and the Health of Gulf War Veterans

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 IL10. 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.
Executive Summary  15

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.
16  Gulf War Illness and 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 pathophysiological

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
Executive Summary  17

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.
18  Gulf War Illness and the Health of Gulf War Veterans
Introduction  19

| Introduction

More than 17 years have passed since the Gulf War. The events and successes of Operation Desert Storm

are becoming a distant memory for some, with international attention now focused on current military

operations in Iraq and Afghanistan. But for too many who served in the Persian Gulf theater in 1990 and

1991, the Gulf War has had lasting consequences—health consequences beyond the well-recognized

effects of bullets and bombs and the psychological impact of war. This report describes what has been

learned in the last 17 years about the health effects of military service in the Gulf War and identifies

priority research issues that remain to be addressed. Although the report covers the broad spectrum of

health concerns related to Gulf War service, its primary focus is the multisymptom condition that has

come to be known as Gulf War illness. Over the years, this condition has been the foremost Gulf Warrelated health issue and the focus of intense political and scientific interest. It is also the condition for

which the largest numbers of Gulf War veterans are still seeking clear answers and effective treatments.

The Gulf War was unlike any war fought before or since. In the days following Iraq’s invasion of Kuwait

in August 1990, an international effort was swiftly mounted to stand up to the aggression of Saddam

Hussein’s forces. During Operation Desert Shield, hundreds of thousands of American troops, along with

military forces from the United Kingdom and dozens of other allied countries, established a strong

foothold in the region over the course of a few months. By mid-January, 1991, Operation Desert Storm

began with a massive air campaign. Six weeks later, on February 24, 1991, the ground offensive was

launched as U.S. and allied troops moved into Southern Iraq and Kuwait. In just three days the allies

achieved their primary objective, retaking Kuwait City as the Iraqis fled. The next day, just 100 hours

after the ground war had begun, a cease fire was established. Kuwait was free and the U.S. and its allies

had achieved a great victory in the desert.

The 1990-1991 Gulf War was an overwhelmingly successful campaign. Following the six-week air war

and four-day ground war, victorious troops were welcomed home and hailed as heroes in parades and

ceremonies across the nation. Just under 150 combat-related deaths occurred among the 700,000

Americans who deployed to the region, far fewer than had been anticipated before the war.1633,1813 The

military medical system established for the war had also performed impressively. Even with the quick

mobilization and harsh, unfamiliar desert environment, a record low number of troops required medical

attention during deployment.664,1595,1607 The Gulf War was unquestionably a unique war—for its brevity,

for the success with which it was executed, and for the decisive nature of the victory.

Yet, despite the successful staging and outcome of the Gulf War, military personnel who served in theater

reported persistent, baffling symptoms during deployment and in the months and years that followed their

return home. Reports indicated that Gulf War veterans who had served in different units, from all parts of

the U.S. and from allied countries were affected by similar types of symptoms. Illness profiles typically

included a complex of multiple symptoms not explained by conventional medical or psychiatric

diagnoses—cognitive difficulties, persistent and widespread pain, fatigue, headaches, chronic diarrhea

and other digestive abnormalities, and skin rashes. Just what these problems were and what had caused

them was unknown.

Over the years, Gulf War illness has posed diverse and difficult challenges for veterans who are ill and for

healthcare providers and research scientists working to address this condition. From the earliest time

veterans’ symptoms became known, they have been surrounded by controversy and

conjecture.31,210,283,409,536,1350 And for most of the decade that followed the Gulf War, relatively little was

understood about the nature and causes of Gulf War illness. Since the middle 1990s, Gulf War-related
20  Gulf War Illness and the Health of Gulf War Veterans

health problems have been the subject of numerous expert panel reports, U.S. and international

government investigations, and hundreds of scientific studies. As a result, an enormous amount of

information is now available on events and circumstances of the Gulf War and the health of Gulf War

veterans. These resources, when considered in aggregate, provide long-needed answers to questions

concerning Gulf War illness and provide a focus for the scientific research needed to effectively address

it.

The Research Advisory Committee on Gulf War Veterans’ Illnesses. In 1998, with many

questions remaining about veterans’ unexplained health problems, Congress mandated the appointment of

an independent panel of scientists and veterans to review all federal research programs and available

evidence relating to the health of Gulf War veterans. In response to Section 104 of Public Law 105-

368,1243 the Research Advisory Committee on Gulf War Veterans’ Illnesses was appointed in 2002 by

then Secretary of Veterans Affairs Anthony J. Principi. The Committee was charged with assessing the

effectiveness of the federal research effort in answering “central questions on the nature, causes, and

treatments for Gulf War-associated illnesses” (Appendix B) and with providing scientific

recommendations on federal research programs and studies.

Over the past six years, the Committee has had the privilege and responsibility of reviewing diverse types

of information on the many topics pertinent to the health of Gulf War veterans. A challenge common to

earlier government and expert panels was the sparsity of scientific information on which to base findings

and recommendations. In contrast, the Committee found that the quantity of currently available

information created a different kind of challenge, requiring a comprehensive review and cohesive

synthesis of a voluminous number of reports and studies. A complete picture of what is currently known

about the Gulf War and the health of Gulf War veterans was needed in order to make meaningful research

recommendations on the best way forward.

Since its inception, the Committee has conducted its work in public meetings, convened three times per

year. Due to the breadth of information to be considered, a systematic approach has been used in

reviewing each area of interest. For each topic considered, relevant materials have been reviewed by the

Committee, and scientists and government representatives with diverse expertise and perspectives have

been invited to present results of their investigations. The information presented typically addressed what

has been learned about particular exposures and events in theater and/or results of scientific studies

concerning health effects of those exposures. Committee meetings have functioned in large part as

symposia, providing opportunities for Committee members, visiting scientists, and government officials

to review and discuss available information on each topic, as well as opportunities for comments and

questions from members of the public.

In addition to annual reports on its activities and ongoing discourse with federal research officials, the

Committee has periodically issued recommendations and formal reports concerning topics it has

considered. An early “Interim Report” was issued in June, 2002, that provided the Committee’s

preliminary impressions and recommendations based on an initial overview of available research

information.1267 The Committee’s first extensive report was issued in the fall of 2004, providing detailed

information on topics considered to that time.1268 These included the scope of Gulf War illness and the

need for treatment research, evidence concerning effects of Gulf War-related neurotoxic exposures,

studies of birth defects in veterans’ children, and programmatic and funding issues related to federal

research on the health of Gulf War veterans. In January, 2006, the Committee provided updated

recommendations that outlined priority research objectives and topics to VA’s Office of Research and

Development.1270 Additional recommendations were provided to the Secretary in February, 2007,

concerning the need for updating Gulf War illness-related research and educational materials for VA

clinicians.1271 In 2008, the Committee reported its findings and recommendations concerning initial plans

and research activities at the VA-funded Gulf War Illness and Chemical Exposure Research Program at
Introduction  21

the University of Texas Southwestern.1272 Committee members have also testified before Congress on

issues related to Gulf War illness research, including the need to identify effective treatments.

The present report summarizes information reviewed by the Committee since its last major report in 2004

and synthesizes all information considered by the Committee thus far. This synthesis forms the basis for

the scientific recommendations made in each area, and for identification of research priorities. In the

current report, as in all its activities, the Committee has been mindful of the guiding principle designated

for its work, as described in the Committee’s charter. It states that “the fundamental goal of Gulf Warrelated government research, either basic or applied, is to ultimately improve the health of ill Gulf War

veterans, and that the choice and success of research efforts shall be judged accordingly”(Appendix B).

The current report differs from earlier Gulf War panel and committee reports in several important

respects. First, the central focus of this report is Gulf War illness. The Committee reviewed available

information on all health issues associated with Gulf War service, but prioritized information relating to

the nature and causes of the undiagnosed, multisymptom illness affecting Gulf War veterans. Despite the

prominence of this condition in the lives of ill veterans and the amount of government and media

attention given to this problem, Gulf War illness has received surprisingly little in-depth consideration by

previous scientific panels. The present report is also distinct from earlier Gulf War reports because it

comes at a time when an unprecedented amount of information is available to inform the work and

conclusions of the Committee, information that was not available to earlier review panels and scientific

committees.

Lastly, this report is unique because of the specific charge and scope of activities assigned to the

Committee. This has enabled a single panel to consider the extensive range of topics related to the health

of Gulf War veterans. It has also required full consideration of the many types of scientific studies and

government reports relevant to veterans’ health and effects of veterans’ experiences and exposures during

the war. As a result, the Committee has had the opportunity to engage these complex issues in a more

comprehensive manner than previously has been possible. Most importantly, it has permitted the

Committee to synthesize diverse information from diverse sources in order to identify patterns and

inconsistencies across a broad spectrum. In effect, the Committee was given the opportunity to assemble

and evaluate all available pieces from a complex puzzle, and to determine what, collectively, they tell us

about the nature and causes of Gulf War illness.

It is regrettable that, 17 years after the war, so little clear information has emerged from scientific

committees that specifically addresses the nature and causes of Gulf War illness. It is perhaps

understandable, in light of the many complexities related to research in this area, as will be described

throughout this report. Most obviously, Gulf War illness does not fit neatly into our current concepts of

disease. The underlying pathobiology 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. Researchers and

clinicians are generally not familiar with methods required to evaluate and address health problems

identified entirely by veterans’ symptoms. This might explain why Gulf War researchers and committees

have often focused their attention on problems that are more routinely assessed and measured. It has

become clear over the years, however, that the important questions surrounding Gulf War illness do not

have simple answers. Addressing these questions requires that complex issues be engaged in a complex

and comprehensive manner. Overly simplistic and compartmentalized approaches have provided little

progress.

The present report is divided into several sections that reflect different aspects of available information on

Gulf War-related health issues. The first section provides an overview of what has been learned from

population studies, the large body of epidemiologic research on Gulf War veterans. The second section

addresses the cause of Gulf War illness, reviewing what has been learned about the many Gulf Warrelated experiences and exposures that potentially contributed to veterans’ ill health—from the
22  Gulf War Illness and the Health of Gulf War Veterans

psychological stress of war to the effects of oil well fires, nerve agents, vaccines, and depleted uranium.

The third section addresses the nature of Gulf War illness, reviewing research on biological abnormalities

associated with veterans’ symptoms, the relationship of Gulf War illness with multisymptom conditions

in civilian populations, and topics the Committee has considered in exploring physiological mechanisms

that may underlie veterans’ symptoms. The fourth section summarizes the current status of federal

research programs related to the health of Gulf War veterans. Each of the first four sections includes

research recommendations related to the specific topics considered. The fifth section summarizes and

prioritizes these recommendations.

As is described throughout the report, there is no question that Gulf War illness is a real condition with

real causes and serious consequences for affected veterans. Study after study has consistently

documented this multisymptom condition in large numbers of Gulf War 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. Because research studies have so compellingly demonstrated that Gulf

War illness cannot be explained simply as the expected result of wartime stress, it remains the

responsibility of the federal government to fully elaborate the source and nature of this condition, to care

for affected veterans, and to prevent similar problems from happening in the future.

Some have suggested that the many scientific and political challenges that have impeded understanding of

Gulf War illness are too complex, that the events of the war are too remote, and that answers to the many

questions surrounding Gulf War illness might never be known.870,1765 On the contrary, the Committee has

found that the diverse sources of information and research data associated with Gulf War service 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 most capable of improving the

health of Gulf War veterans. Completing this mission, that is, finding answers and treatments for ill Gulf

War veterans, requires continued dedicated effort and cooperation between government officials,

scientists, clinicians, and veterans. As will be evident from the information and recommendations that

follow, the Committee believes that this is a challenge that can be met. It is also, unquestionably, an

obligation that must be met.
Gulf War Illness and the Health of Gulf War Veterans  23

1| Gulf War Illness

and the Health of Gulf War Veterans

I arrived in Theater on January 6, 1991 ... During official visits to strategic military cities there

were frequent SCUD attacks during which I heard chemical alarms sound. When I asked if

these alarms meant chemicals had been detected, I was told that the chemical alarms had

malfunctioned. I became ill and was treated for nausea, headaches, vomiting, diarrhea, and

high temperature. Rashes I had over my body I thought were normal and expected since I

spent most days in the sand, wind, and sun with all the attendant fleas, flies, and desert

parasites. Headaches I attributed to fatigue and lack of sleep. The symptoms...continued

after I returned home and got progressively worse.

--COL GR, Gulf War veteran1684

Unexplained illness in the wake of Desert Storm. In the years immediately following Desert

Storm, widespread reports indicated that Gulf War veterans were suffering from a complex of symptoms

that included memory problems, profound fatigue, chronic pain, persistent diarrhea, and unusual skin

lesions. Similar symptom complexes were widely reported by veterans from different units in different

parts of the U.S., and also by veterans from allied countries. Medical evaluations provided limited

insights, since veterans’ symptoms were typically not associated with abnormalities on laboratory tests or

other diagnostic measures. No clear explanation was apparent for this unexplained symptom complex,

labeled “Gulf War Syndrome” by the media.

Veterans and other observers soon raised questions about whether hazardous exposures encountered

during the Gulf War had made troops sick. Suggested causes included the billowing clouds of thick black

smoke produced by the Kuwaiti oil wells that were set afire by retreating Iraqi soldiers in the closing days

of the war. There were also widespread reports that alarms designed to detect chemical agents repeatedly

sounded in some areas of theater after Coalition air bombing began in January of 1991. Additional

concerns were raised about the use of measures that had never before been fielded by the military on a

widespread basis. These included use of munitions and armoring containing depleted uranium, use of an

anti-nerve agent prophylaxis regimen that included regular doses of the drug pyridostigmine bromide, and

administration of the anthrax and botulinum toxoid vaccines.

Since the mid-1990s, the federal government has funded hundreds of research studies to investigate the

health problems affecting Gulf War veterans.340 Multiple large epidemiologic studies and impressive data

collections have been conducted in diverse populations of Gulf War veterans. These studies have

provided extensive documentation of the symptoms and symptom complexes associated with Gulf War

service, rates of psychiatric conditions in Gulf War veterans, and limited data on the extent to which Gulf

War veterans have been affected by diagnosed medical diseases. Without exception, studies of Gulf War

veterans have found that the most prevalent health problem associated with Gulf War service is the

complex of multiple symptoms not explained by familiar medical or psychiatric diagnoses.

The condition once labeled “Gulf War Syndrome” by the media is now commonly referred to as Gulf

War veterans’ illnesses or Gulf War illness. The Committee has adopted the term Gulf War illness for

simplicity’s sake. It is used as an umbrella term to represent varying definitions and descriptions of the

complex of multiple symptoms found at significantly excess rates in Gulf War veterans. As with other

conditions, the specific symptoms affecting veterans with Gulf War illness can vary somewhat from

person to person. The overall consistency of the types of health problems described in Gulf War veterans,

however, indicates that it is most useful to consider this excess symptomatology as a cohesive “entity” to
24  Gulf War Illness and the Health of Gulf War Veterans

be studied as a “multisymptom illness” as opposed to considering symptoms individually. This is the

approach adopted by most epidemiologic studies of Gulf War veterans. Use of the specific term, Gulf

War illness, also allows this multisymptom condition to be clearly distinguished from other, more

familiar, diagnosed conditions that affect individual veterans.

Although Gulf War illness is the most prominent condition affecting Gulf War veterans, it is just one

health issue to be addressed in the larger context of the health of Gulf War veterans. Other Gulf Warrelated health issues of importance include rates of diagnosable medical conditions and post-war mortality

among Gulf War veterans, and questions related to the risk of birth defects and other health problems in

veterans’ family members.
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  25

Characteristics and Impact of Gulf War Illness:

Epidemiologic Research

My symptoms began in the Gulf with severe abdominal cramping and severe diarrhea. I also

had terrible headaches and bouts of dizziness and tingling. Once I returned to the base in

Germany, the headaches persisted, and I experienced the cramps and diarrhea on a cyclic

basis. I also went through periods of night sweats. And there were periods when I would

sleep a lot because I was so fatigued. My joints were stiff, and my knees would swell after I

ran. It was harder for me to do things without feeling short of breath. These symptoms

became worse as time passed...

Ever since my return from the Gulf, I’ve been plagued by multiple rashes and lesions on my

face, neck, arms, and back. They come and go.

--SSgt BJ, Army Gulf War veteran716

Significant scientific progress has been made in characterizing the health of Gulf War veterans, as

described in the Committee’s 2004 report.1268 This progress has relied, in large part, on the many Gulf

War epidemiologic studies conducted in the past decade. Epidemiologic research uses established

methods to study patterns of disease and related factors in populations. Among the strengths of this

research approach is its capacity for providing “big picture” information about the health of populations

and statistical assessment of the relationship of health problems with demographic characteristics,

biological and chemical exposures, and other factors that can affect health. It is, in fact, the only

scientific approach capable of evaluating health problems in relation to the actual complex conditions of

the Gulf War. Consequently, epidemiologic research has been a particularly important resource for

understanding Gulf War illness and the health of Gulf War veterans.

The extensive body of Gulf War epidemiologic research has provided a consistent picture of the general

characteristics of Gulf War illness and the patterns in which it affects diverse groups of Gulf War

veterans. This research is not without limitations, however. It is important that findings from individual

population studies of Gulf War veterans be evaluated in the context of identified limitations, and also

considered in the context of the larger body of studies addressing similar questions and issues.

How many Gulf War veterans have Gulf War illness?

The prevalence of Gulf War illness reported by different studies has varied with how Gulf War illness or

“chronic multisymptom illness” (CMI) cases are defined. Because no specific Gulf War illness case

definition has been widely accepted, the Committee reviewed prevalence estimates from all studies

reporting rates of multisymptom illness, by any case definition, in both Gulf War veterans and

nondeployed Gulf War-era veterans. The burden of multisymptom illness attributable to service in the

Gulf War was determined by comparing rates found in Gulf War veterans to those in nondeployed era

veterans. The excess rate in Gulf War veterans, that is, the rate over and above that in veterans who did

not serve in the Gulf War, reflects the proportion of veterans whose multisymptom condition can be

attributed to participation in the Gulf War.

As shown in Table 1, nearly all epidemiologic studies have reported that, regardless of the case definition

used, an excess of 25 - 32 percent of Gulf War veterans have multisymptom illness related to service in

the Gulf War. The only exception comes from results reported from Phase III of the U.S. National

Survey of Gulf War Era Veterans and Their Families, which found only a 13 percent excess rate of

multisymptom illness in Gulf War veterans.142 It is not clear why the rate of excess illness from this study

was lower, by about half, than all other studies, including a later follow-up of veterans from the same U.S.
26  Gulf War Illness and the Health of Gulf War Veterans

Table 1. Prevalence of Multisymptom Illness in Gulf War Veterans

and Nondeployed Era Veterans

Veterans Studied

Number of Gulf

War Veterans

Assessed

Year(s) of

Assessment

Case Definition

Used

Prevalence In

Nondeployed

Veterans

Prevalence in

Gulf War

veterans

Excess Illness

in Gulf War

Veterans

Air Force veterans464 1,155 1995 CMI 15% 45% 30%

New England Army

veterans1238

180 1994-1996 CMI (modified) 33% 65% 32%

U.K. male veterans1698 4,428 1998 CMI (modified) 36% 62% 26%

U.K. female veterans1699 226 1998 CMI (modified) 35% 64% 29%

Kansas veterans1476 1,548 1998 GWI (KS)

CMI

8%

20%

34%

47%

26%

27%

U.S. national study,

Phase III142

1,035 1999-2001 CMI (modified) 16% 29% 13%

U.S. national study,

longitudinal sample745,748

5,767 2005 Multisymptom

illness*

10% 35% 25%

Abbreviations: CMI = chronic multisymptom illness as defined by Fukuda,464 Gulf War illness = Gulf War illness, KS = Kansas case definition1476

Notes: *Multisymptom illness defined as multiple types of symptoms occurring together, not explained by medical or psychiatric diagnoses

national study. Like other studies, the Phase III study relied on veterans’ self-reported symptoms to

assess rates of multisymptom illness.142 The difference potentially relates to modifications made in the

CMI definition, as adapted for the Phase III study. Those modifications, for example, limited the number

of Gulf War veterans identified as being fatigued, a central criterion of the CMI case definition, to about

half the expected total.142,751 The excess rate of 13 percent identified in the Phase III study is particularly

unexpected in light of a later study of a larger sample taken from the same population. The later study

found an excess of 25 percent of Gulf War veterans affected by multisymptom illness, similar to rates

reported by all other studies.745,748

A similar degree of excess ill health related to Gulf War service is suggested by studies that have assessed

veterans’ health using more general indicators. For example, half of Iowa Gulf War veterans, but only 14

percent of nondeployed era veterans, indicated they had health problems that they attributed to their

military service in 1990-1991, an excess of 36 percent in Gulf War veterans.350 Similarly, an excess of 35

percent of Kansas Gulf War veterans reported having health problems attributable to military service in

1990-1991.1476 A 2002 British study determined that 53 percent of Gulf War veterans fell into one of

four clusters defined by patterns of elevated symptom scores, compared to 28 percent of nondeployed era

veterans, an excess of 25 percent in Gulf War veterans.421 A more recent British study reported that 61

percent of Gulf War veterans, and 37 percent of nondeployed era veterans reported new health problems

since the Gulf War, an excess of 24 percent in Gulf War veterans.1411 Overall, these studies provide a

consistent indication that excess subjective ill health attributable to service in the Gulf War affects

between 24 and 36 percent of those who served.

Due to the consistency of estimates of the excess prevalence of multisymptom illness from diverse

studies, the Committee concludes that approximately 25 to 30 percent of veterans who served in the Gulf

War have been affected by Gulf War illness. That is, studies indicate that between 175,000 and 210,000

of the 700,000 American veterans of the 1990-1991 Gulf War are affected by a complex of multiple

symptoms attributable to their service in the war.
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  27

Characteristics of Gulf War Illness

Gulf War illness has been widely described in government testimony, media reports, and scientific

studies. The condition is typically characterized as a combination of diverse symptoms such as memory

problems, chronic headaches, widespread pain, unexplained fatigue, mood changes, persistent diarrhea,

respiratory problems and skin rashes. One of the major challenges of identifying, treating, and

understanding Gulf War illness is that ill veterans often have no abnormal findings on clinical diagnostic

tests. As a result, Gulf War illness is characterized on the basis of veterans’ symptoms that are, by

definition, self-reported. While this presents a number of difficulties in clinical practice, it is not an

impediment to assessing Gulf War illness in epidemiologic studies of large groups of veterans, where

general patterns of symptoms can be assessed and compared.

In research studies, Gulf War illness is routinely defined by the presence of multiple symptoms affecting

different systems. The majority of these symptoms fall into general categories, or domains, that have

often been characterized statistically in large studies. Symptom domains identified in broadly

representative populations of Gulf War veterans are summarized in Table 2. Despite the diverse methods

used to characterize symptoms, the categories of symptoms that affect Gulf War veterans at excess rates

are remarkably consistent across studies. The two symptom groups most commonly identified include

those indicative of neurological/cognitive problems (e.g., chronic headache, cognitive difficulties, mood

disturbances, vision and balance abnormalities) and symptoms of persistent, widespread pain in joints and

muscles. Symptoms related to persistent fatigue (e.g. extreme tiredness, sleep abnormalities) are reported

just as frequently, classified in different studies either as a specific symptom domain, or as part of the

neurological domain.

Two additional symptom groups are also consistently found at excess rates in Gulf War veterans, but are

typically reported by fewer veterans than neurological, pain, and fatigue symptoms. These include

respiratory symptoms (e.g. wheezing, coughing) and gastrointestinal problems (e.g. chronic diarrhea,

abdominal cramping). Skin symptoms (unexplained rashes and lesions) are also routinely reported, but

have usually not been assessed by multiple variables, as required for identifying symptom “groups.”

Factor analysis of symptoms. A number of Gulf War studies have defined symptom domains that

affect Gulf War veterans using factor analysis. This statistical technique is generally used as a data

reduction method in developing psychometric instruments or defining patient subgroups in studies of

identified medical or psychiatric conditions. Factor analysis identifies “latent” constructs, or factors, that

may underlie sets of highly correlated variables. When applied to general health symptoms in diverse

populations, the factor constructs typically reflect the correlation between symptoms resulting from

problems affecting particular organs or biological processes. These correlations tend to be independent of

the specific diseases causing those symptoms. For example, symptoms of coughing, wheezing, and

shortness of breath are highly correlated in any population, regardless of whether different individuals in

that population have pneumonia, emphysema, or colds.

With limited exception,752 the types of symptom domains identified in Gulf War studies by factor

analysis also occur in nondeployed veterans, and in diverse, nonveteran populations.1127,1341,1786,1830 This

would generally be expected, since factor-identified symptom “groupings,” in studies that assess general

health symptoms in heterogeneous populations, simply reflect the high correlation between symptoms

resulting from distress in a particular organ or biological process, regardless of the underlying disease.1082

What is unique to Gulf War veterans is that persistent symptoms occur concurrently in multiple domains

at excess rates, and with greater severity, than in nondeployed veterans.240,464,698,752,1395,1476 As described

in the Committee’s 2004 report, individual Gulf War veterans experience chronic symptoms in multiple

domains at the same time. If a unique pattern of Gulf War symptoms were to be identified using factor

analysis, it would likely require consideration of higher-order factors, that is, second or third-level factors

that reflect “groupings” of the symptom factors identified in both Gulf War and nondeployed veterans.1082
28  Gulf War Illness and the Health of Gulf War Veterans

Table 2. Symptom Domains Affecting Gulf War Veterans at Excess Rates

Symptom Domains Described

Gulf War Veterans Studied

Method Used to

Identify Domains

Neuro/

Cognition/

Mood

Muscle/

Joint Pain

Respiratory

Gastrointestinal Fatigue

U.S. Veterans, All Branches

10,423 veterans in national survey752 Factor analysis + + + + +

1,548 Kansas veterans1476 Correlation

analyses + + + + +

1,161 veterans from 7 states*570 Factor analysis + + + + ±

867 veterans in Washington, Oregon*160 Factor analysis + + + ± ±

1,896 Iowa veterans350 Factor analysis ± + ±

Other Countries

9,588 U.K. veterans240 Factor analysis + + + + ±

3,454 U.K. veterans698,1125 Factor analysis + na + + ±

1,322 Australian veterans448 Factor analysis + + ± + ±

Notes: + multiple symptoms of this type were significantly correlated in a defined domain

± multiple symptoms of this type were significantly elevated, but correlated with another defined domain

na the study did not assess multiple symptoms in this category

* symptom domains assessed in Gulf War veterans only (no nondeployed comparison group)

Higher order analyses might indicate if symptoms in different domains are correlated with one another in

ways not typical of the general population.566,1082 Gulf War studies have thus far not compared higherorder factors of this type in Gulf War and nondeployed veterans. A unique pattern of symptom

expression in Gulf War veterans has been described in one study using a parallel approach, however. A

study of over 2,000 Kansas Gulf War era veterans characterized six different symptom domains that

affected Gulf War veterans at higher rates than nondeployed era veterans. A similar number of Gulf War

(30%) and nondeployed era veterans (29%) had symptoms in just one or two of the defined domains. In

contrast, a significantly higher proportion of Gulf War veterans (34%) than nondeployed era veterans

(8%) was affected by more severe symptomatology concurrently in three or more symptom domains.1476

Similarities between the types of symptoms that fall into factor-defined domains in Gulf War and

nondeployed veterans are sometimes cited as an indication that there is no “unique Gulf War

syndrome”.350,686,698,821 But a certain level of symptoms, ill health, and disease occur in any

population.840,1712 Symptom factors identified in diverse populations, including Gulf War veterans,

generally describe the symptoms expressed when problems affect particular biological systems, regardless

of their causes. Many investigators have pointed out that factor analysis has limited, if any, value in

determining whether there is or is not a unique Gulf War syndrome.429,668,821,1082,1395,1477 The Committee

found no examples in the scientific literature where factor analysis of health symptoms in a general

population sample, as typically used in Gulf War studies, has ever identified either a well-known chronic

disease, like diabetes, or a completely new syndrome.
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  29

Defining Gulf War illness. Several research teams have developed case definitions for use in their

investigations of the prevalence of and risk factors for Gulf War-related multisymptom illness. Generally,

case definitions that are nonspecific, that is, those based on a small number of common symptoms,

identify a relatively large number of “cases” among both Gulf War and nondeployed era veterans. More

restrictive case definitions, in terms of the types and severity of symptoms required, identify fewer cases.

Case definitions used to describe Gulf War illness and the methods for arriving at them have varied

between studies, as summarized below.

Haley syndromes. In 1997, Dr. Robert Haley and colleagues at the University of Texas Southwestern

Medical School defined three syndromes based on factor analysis of an extensive, detailed battery of

dichotomous and scaled symptoms in 249 members of the 24th Reserve Naval Mobile Construction

Battalion.565 Syndrome 1, labeled “impaired cognition,” included problems with attention, memory,

depression, and sleep abnormalities. Syndrome 2, labeled “confusion-ataxia,” was characterized by

problems with thinking and balance and was the most severe of the three syndromes. Syndrome 3,

labeled “arthro-myo-neuropathy” was associated with joint and muscle pain. Twenty percent of the

veterans in the study had one of more of the three defined syndromes.

Chronic multisymptom illness (CMI). In 1998, Dr. Keiji Fukuda and investigators from the U.S.

Centers for Disease Control and Prevention (CDC) defined a complex of symptoms, termed “chronic

multisymptom illness” in a population of 3,723 deployed and nondeployed Air Force Gulf War era

veterans.464 The symptom complex was defined using two parallel methods: one assessed symptoms that

affected more than 25 percent of Gulf War veterans, and the other used factor analyses of dichotomous

symptoms reported by both Gulf War and nondeployed veterans assessed together. The resulting CMI

definition required cases to report one or more symptoms lasting six months or longer in at least two of

three categories: fatigue, mood-cognition (feeling depressed, difficulty remembering or concentrating,

feeling moody, feeling anxious, trouble finding words, difficulty sleeping) and musculoskeletal pain (joint

pain, joint stiffness, muscle pain). Severe CMI cases rated each defining symptom as severe, other cases

were labeled “mild-to-moderate” CMI. As defined, the CMI symptom complex affected 45 percent of

Gulf War veterans in the Air Force sample, and 15 percent of nondeployed era veterans.

Oregon-defined Gulf War unexplained illness. In 1998, Dr. Peter Spencer and colleagues from the

Oregon Health Sciences University defined cases of Gulf War-related unexplained illness (GWUI) for

inclusion in a case control study.1465 GWUI cases were veterans who had at least one defining symptom

from any of three categories, but no diagnostic explanation for that symptom. The three categories

included unexplained symptoms associated with fatigue, cognitive/psychological problems, and

musculoskeletal complaints.

Kansas-defined Gulf War illness. In 2000, Dr. Lea Steele reported a case definition for Gulf War

illness, identified empirically as the pattern of symptoms that significantly distinguished 1,548 Gulf War

veterans from 482 nondeployed era veterans in the Kansas Gulf Veterans Health Study.1476 Kansasdefined Gulf War illness criteria excluded veterans diagnosed with specified medical or psychiatric

conditions that might explain their symptoms. Symptom criteria required that veterans report multiple or

moderately severe symptoms in at least three of six defined categories: fatigue/sleep problems, pain

symptoms, neurological/cognitive/mood symptoms, gastrointestinal symptoms, respiratory symptoms,

and skin symptoms. Gulf War illness, as defined in the Kansas study, affected 34 percent of Gulf War

veterans, and eight percent of nondeployed veterans.

U.S. National Survey-defined Gulf War syndrome. VA investigators identified a complex of four

neurological symptoms that constituted a unique factor in Gulf War veterans but not in nondeployed era

veterans in a large U.S. national sample.752 These symptoms included blurred vision, loss of balance,

tremors/shaking, and speech difficulty. Investigators reported that 277 (2%) of the over 10,000 Gulf War

veterans in the study were “cases” who endorsed all four symptoms. Cases were also significantly more
30  Gulf War Illness and the Health of Gulf War Veterans

likely to report a number of other symptoms and diagnosed conditions including migraines, seizures, and

diarrhea.

Other studies have distinguished ill from healthy veterans in ways that did not require veterans to report

specific symptoms. The 2002 Navy Seabee Health Study defined Gulf War illness “cases” as veterans

who reported being diagnosed with at least one of four conditions (chronic fatigue syndrome,

posttraumatic stress disorder, multiple chemical sensitivity, irritable bowel syndrome) and/or veterans

who reported having at least 12 health problems.527 Researchers evaluating a cohort of Army veterans

who returned from theater through Fort Devens, Massachusetts, have used several methods to classify

symptomatic veterans. In some studies of this cohort, veterans who reported having five or more frequent

symptoms from the Health System Checklist were identified as “high symptom” cases, and compared to

veterans with fewer symptoms.1802 An alternate approach relied on comparison of scores in nine defined

“body system” groups.1239 A separate study of veterans enrolled in VA’s Gulf War Registry also

distinguished “high symptom” and “low symptom” veteran subgroups, with categories defined

statistically using results of factor and cluster analyses.570 Studies have also used the chronic fatigue

syndrome case definition465 to distinguish symptomatic Gulf War veterans from controls.321,435,1090

Seventeen years after the Gulf War, no case definition has been widely accepted as the preferred standard

for defining the complex of multiple symptoms affecting Gulf War veterans, nor have there been

published efforts to optimize or validate a Gulf War illness case definition. The Fukuda CMI case

definition has been modified for use in several surveys and for two Gulf War illness clinical trials. That

definition is generally considered overly broad, that is, nonspecific for the health problems affecting Gulf

War veterans. The only case definition developed by characterizing a pattern of multiple symptom types

that differed between Gulf War and nondeployed era veterans is the Kansas case definition. In a random

sample of over 2,000 Kansas Gulf War era veterans, the Kansas definition more specifically distinguished

symptomatic Gulf War from nondeployed era veterans than the CMI case definition.1476

The severity and functional impact of Gulf War illness. Although not well characterized by any

research studies, anecdotal reports indicate that the severity of Gulf War illness is highly variable. Some

veterans are mildly or moderately affected by their symptoms, but still able to maintain many of their

usual activities. Others veterans have more severe, even disabling, illness. Different studies have shown

that between 13 and 50 percent who meet CMI criteria for Gulf War illness can be classified as “severe”

cases.142,464,1804 Illness severity is also said to vary for individuals, with symptoms waxing and waning

over time.

Several studies have evaluated the degree to which Gulf War illness has affected veterans’ functional

status, including their ability to work. The Medical Outcomes Study Short Form Survey (SF36),1753 and a

special SF36 developed for veteran populations,779 have been widely used in Gulf War studies. The SF36

evaluates functional status in eight defined areas (e.g., physical functioning, social functioning, general

health), providing a quantitative measure of health-related quality of life. Studies consistently report that

veterans meeting any case definition of Gulf War illness have significantly lower scores on all SF36

indicators than population norms and than healthy veterans.87,142,160,449,464,567,1542,1726 Veterans seen at

VA’s specialty referral clinics for multisymptom illness, the War Related Injury and Illness Study

Centers, exhibit considerable functional impairment. Those veterans’ mean score of 30 on the SF36

physical component scale (PCS) is substantially below the national average score of 50.907 In Gulf War

studies, SF36 scores vary with the case definition used and the domains assessed. The highly

symptomatic Gulf War veterans who meet defining criteria for the Haley syndromes had lower SF36

domain scores, indicating worse functional status, than scores for conditions such as congestive heart

failure and chronic obstructive pulmonary disease.567 In contrast, veterans meeting the CMI case

definition in the U.S. national survey were considerably less functionally impaired, with a mean SF36

PCS score of 43.142
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  31

In general, studies indicate that most veterans with Gulf War illness continue to work, although this varies

with illness severity. A relatively high rate of unemployment (29%) was reported in Gulf War veterans

seeking treatment at a VA Gulf War illness clinic in Seattle.1281 More representative figures come from a

population-based study in the Pacific Northwest, where 21 percent of Gulf War veterans with two or more

unexplained health problems were unemployed, compared to 13 percent of veterans without symptoms.

Employed-but-symptomatic veterans were also more likely to miss at least seven days of work due to

illness over a one-year period (29%) than healthy veterans (4%).160

Which Veterans are Most Affected by Gulf War Illness?

Epidemiologic studies traditionally describe patterns of disease in populations. Insights about the causes

of a condition can often be drawn from identifying subgroups that are affected at higher and lower rates.

Studies of Gulf War illness have reported patterns of this type, identifying different rates of illness in

relation to the characteristics of veterans’ military service and deployment to the Gulf War theater.

Differences related to branch of service and military rank. Epidemiologic studies have

consistently indicated that Gulf War veterans who served in the Army and Marines have higher rates of

multisymptom illness than those in the Navy and Air Force.753,1466,1476 Similarly, Army veterans are

disproportionately represented in VA and DOD Gulf War Registry programs. That is, Army personnel

constituted just 50 percent of the deployed force, but account for 77 percent of Gulf War veterans enrolled

in registries. Conversely, Air Force and Navy veterans are significantly underrepresented in U.S. Gulf

War registries.1651

Studies also consistently report that enlisted personnel have higher rates of Gulf War illness than

officers.241,511,697,753,1124,1466,1476 Comparisons between reservists and active duty personnel have produced

mixed results, with some studies finding similar Gulf War illness rates in the two groups, and others

reporting somewhat higher rates in either active duty or reserve veterans.692,697,753,1466,1476,1804

Demographic characteristics. Rates of Gulf War illness have generally not differed markedly with

veterans’ demographic characteristics such as gender, age, and race. Gulf War illness affects women at

about the same, or slightly higher rates than men,142,160,240,464,753,1476,1699,1804 and younger veterans at about

the same rates as older veterans.511,753,1124,1476,1804 Whites and nonwhites are also affected at similar

rates.142,160,240,464,753,1466,1476,1699,1804

Location in theater. Several studies have reported that Gulf War illness rates differ with the locations

where veterans served during the war. That is, veterans who served in some areas of theater have higher

rates of Gulf War illness than veterans who were in other locations. The study of Kansas veterans

indicated that veterans who entered Iraq or Kuwait, countries where all battles took place, had

significantly higher rates of Gulf War illness (42%) than veterans who served exclusively in support areas

on land (32%) or on board ship during deployment (21%).1476 Similarly, U.S. and Canadian ground

troops had higher rates of multisymptom illness than those who served on board ship511,753 and Iowa

veterans who had been in Iraq, Kuwait, or Saudi Arabia had more health conditions than those located

elsewhere in theater.692

Two studies have reported increased illness risk in more narrowly defined locations. Navy Seabees

located in a specific sector of northeastern Saudi Arabia on the third day of the air war had over four

times the rate of Gulf War illness as veterans in other areas, suggesting a link with a particular event or

exposure in that location.564 A more recent report, using troop location data and geographical information

system (GIS) methods, identified several localized spatial clusters where veterans with severe Gulf War

illness were more likely to have been located at certain time periods.1236 Taken together, these studies
32  Gulf War Illness and the Health of Gulf War Veterans

indicate that Gulf War illness did not randomly affect all Gulf War veterans who deployed to the region,

but occurred as a result of events, experiences, or exposures that differed by location.

In fact, epidemiologic studies have consistently found that Gulf War illness rates do vary significantly

according to veteran-reported experiences and exposures during the war. Observed associations between

Gulf War illness and veterans’ exposures have raised a great deal of interest, but have also been the

source of considerable confusion. Research related to illness-exposure associations will be considered

throughout this report, and analyzed in detail in Section 2. It is important that it be considered in the

larger context of limitations inherent in the use of self-reported data, as well as other methodological

issues affecting studies of Gulf War veterans.

Evaluating Causal Factors in Gulf War Illness

Limitations and shortcomings of Gulf War epidemiologic research. A great deal has been

learned from the many epidemiologic studies conducted in different populations of Gulf War veterans.

But like all areas of scientific investigation, epidemiologic research has limitations, some of which are

especially problematic in Gulf War studies. In addition to issues that are specific to Gulf War research,

broader issues such as shortcomings in how research questions have been posed or how studies have been

designed and executed have also greatly affected the degree to which Gulf War epidemiologic studies

have been useful and informative. Therefore, it is essential that research limitations be identified and

carefully considered when interpreting results of Gulf War epidemiologic studies.

Research on the health of Gulf War veterans is unusually complex and challenging for a number of

reasons. Relatively little objectively measured information is available on either the primary health

outcome of interest—Gulf War illness—or on potential causal factors assessed in epidemiologic studies.

Gulf War illness is generally identified on the basis of veterans’ symptoms which are, by definition, selfreported. In addition, wartime events and exposures have most often been assessed using veterans’ own

reports of what they experienced during deployment. Although not generally an optimal data resource, it

is the only option available for many Gulf War exposures of interest.

To add to these complexities, both the primary health outcome of interest—Gulf War illness—and the

etiologic factors being investigated are multifactorial. That is, Gulf War illness encompasses multiple

symptoms that co-occur in different ways. Likewise, the Gulf War experience included a wide array of

potentially hazardous and stressful exposures. Even under the best circumstances, understanding

relationships between multifaceted exposures and multifaceted health outcomes can be a complex

challenge.

Such issues, particular to studies of Gulf War illness, must also be considered in the context of limitations

and problems more generally associated with epidemiologic research. Typical issues relate to biases that

can result from the size and characteristics of the study sample, the response rate, identification of suitable

comparison groups, the content and wording of questions, methods used to assess outcomes, and

statistical problems stemming from multiple comparisons. These issues are well recognized and have

been discussed at length in reviews and committee reports on the health of Gulf War veterans.104,646,686

An additional concern that has received less attention, but one that can have serious consequences, relates

to methods used in analyzing and reporting the data collected in Gulf War studies. The present discussion

focuses on sources of error in epidemiologic studies that have had the greatest impact on research

findings, and interpretation of findings, in studies of Gulf War veterans.

Some reports have suggested that, given the limitations associated with studies of Gulf War veterans and

the lack of data on measured exposures in theater, little useful information can be obtained from

epidemiologic studies for understanding Gulf War illness and its relationship to exposures.79,667,686
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  33

But after reviewing results from the many Gulf War epidemiologic studies and carefully considering the

impact of identifiable limitations, the Committee has concluded that data from these studies are

interpretable and informative. In its analysis of Gulf War epidemiologic research, the Committee has

emphasized patterns of illness and associations that are consistent across multiple studies. It has also

given more credence to findings from studies that have used preferred methods in sampling, data

collection, and data analysis.

A key methodological issue raised in the Committee’s 2004 report is the importance of evaluating health

outcomes in identifiable subgroups of Gulf War veterans, as opposed to assessing all deployed veterans as

a single group. This requires assessing the health status of veterans who served in particular locations,

those in particular units, or those known to have had specific exposures.79,210,593,1477 Combining all Gulf

War veterans into a single group may obscure or completely mask health effects due to events or

exposures that did not affect all deployed personnel. For example, studies have reported selected health

outcomes in veteran subgroups identified by modeled exposure to oil well fire smoke as well as nerve

agents in relation to the Khamisiyah demolitions. Several have provided stark examples of links between

exposures and disease or biological abnormalities that were not apparent when all deployed veterans were

evaluated as a single group.190,192,599,1237

Confounding and risk factors for Gulf War illness. A major challenge in understanding results

from Gulf War epidemiologic studies relates to the complex exposure scenario present in the Gulf War

theater. Studies have typically evaluated effects of 20 or more experiences and exposures in theater—

everything from combat experiences and other sources of stress, to oil well fires, vaccines, pesticides, and

chemical alarms. Studies have consistently found that Gulf War exposures are highly

correlated.161,241,458,1466 That is, veterans who reported some specific exposures during deployment were

significantly more likely to also report other specific types of exposures. Those familiar with

epidemiologic methods will quickly recognize the serious potential this raises for confounding, that is,

confusing the effects of one deployment-related exposure with effects of multiple other exposures. 811

In less complex settings, confounding can be a major source of error that gives rise to incorrect—even

nonsensical—findings, misleading both investigators and those who read their studies.734 In a uniquely

complex exposure scenario such as the Gulf War, the impact of confounding can be profound.

Fortunately, familiar analytic methods are available that can both identify which exposures are related to

which other ones, and “tease out” effects of individual exposures. This allows epidemiologic studies to

identify “independent” associations between illness and each exposure in a complex setting. In scenarios

like the Gulf War, where many veterans encountered multiple varied exposures, use of such methods is

essential to determine which Gulf War experiences are truly linked to ill health and which only appear to

be, as a result of confounding.

Many Gulf War epidemiologic studies were careful to control for possible confounding by demographic

factors such as age and gender, or military characteristics such as rank and branch of service. As detailed

in Appendix A, adjustment for demographic factors typically had little effect on study results. In contrast,

consistent, sometimes dramatic, confounding effects were demonstrated by studies that adjusted

preliminary results for effects of multiple deployment-related exposures, as shown in Table 3. Invariably,

unadjusted, or “crude” analyses suggested that most exposures and experiences in theater—from bagging

sand to hearing chemical alarms—were significant risk factors for Gulf War illness. But relatively few

significant risk factors were identified after adjustments were made for the effects of multiple exposures,

as demonstrated in Table 3 and detailed in Appendix A.

The Committee was concerned and somewhat surprised to find that many Gulf War epidemiologic studies

had not accounted for the high degree of confounding introduced by the complex Gulf War exposure

scenario. As a result, some studies involving impressive population samples and data collections actually

reported that nearly all of the exposures in the Gulf War appeared to be significant risk factors for chronic
34  Gulf War Illness and the Health of Gulf War Veterans

Table 3. Effects of Confounding by Multiple Exposures in Theater:

Examples from Studies of Gulf War Veterans

Association of Gulf War Illness

with Experiences and Exposures in Theater

Gulf War

Veterans Studied

Number of

Veterans

Health

Outcome

Experience or

Exposure Assessed

No Adjustment for

Confounding by

Multiple Exposures

Adjusted for Effects of

Confounding by

Multiple Exposures

U.S. Air Force

veterans1124

1,155 Severe CMI Bagging/digging sand

Came under attack

Took pyridostigmine

sign* (OR = 3.1)

sign* (OR = 2.4)

sign* (OR = 3.0)

no association

no association

sign* (OR = 2.9)

U.S. Navy

Seabees527

3,831 Gulf War

Illness

Anthrax vaccine

Saw dead bodies

Pesticides

sign* (OR = 3.7)

sign* (OR = 2.6)

sign* (OR = 3.5)

no association

no association

sign* (OR = 1.9)

Army veterans in

Northeastern

U.S.1804

1,290 CMI 10+ chemical alerts

Diesel fuel

Oil fire smoke

sign* (OR = 2.7)

sign* (OR = 2.7)

sign* (OR = 2.9)

no association

no association

sign* (OR = 2.4)

Abbreviations: CMI = chronic multisymptom illness,

464 sign* = statistically significant association, OR = odds ratio

ill health in Gulf War veterans.104,692,1698 Such a conclusion is, of course, illogical. Nonsensical findings

of this type were sometimes dismissed by investigators as the result of veterans’ over-reporting of

exposures. But such results are actually an expected result of confounding introduced by multiple highly

correlated exposures during deployment.

Seven Gulf War population-based studies systematically evaluated exposure/illness relationships using

analyses that adjusted for effects of multiple exposures in theater. These included the CDC study of Air

Force veterans,1124 two studies of Army veterans from the northeastern U.S. who returned from the war

through Fort Devens, Massachusetts,1239,1804 large studies of British Gulf War veterans241 and U.S. Navy

Seabees,527 and studies that assessed neurological and gastrointestinal symptoms in Danish veterans.695,1507

In addition, two studies evaluated a limited number of individual exposures while adjusting for effects of

one or two other selected exposures, as opposed to controlling for confounding in a more comprehensive

way. These included a large study of Gulf War veterans from the states of Washington and Oregon1466

and the study of Navy Seabees from the 24th Naval Mobile Construction Battalion.564 Studies that

assessed illness-exposure relationships using statistical methods that accounted for effects of multiple

exposures were generally considered the most informative by the Committee. Moreover, the limited

number of risk factors for Gulf War illness identified by these studies were surprisingly consistent.

Information bias: Misclassification. An additional source of error that can occur in epidemiologic

studies stems from inaccurate classification of the exposures and/or health outcomes being assessed. This

is a particular concern in Gulf War studies, which have usually relied on self-reported information for

both exposures and health status. As a result, recall bias—the tendency for individuals to recall or report

information inaccurately—has the potential to be particularly problematic in Gulf War research.

No external, objective validation is possible for most veteran-reported exposures. However, several

studies have assessed the reliability with which veterans report exposures using test-retest

methods.988,1165,1767,1804 Overall, veterans have reported some exposures more reliably than others.

Generally, the most reliably reported exposures were those that veterans experienced first hand and were

unique to the war, including encountering smoke from oil well fires, taking pyridostigmine bromide, and

having a SCUD missile explode nearby. Lower, but fair reliability was associated with exposure to

substances such as pesticides and fuels, and hearing chemical alarms. Exposures about which veterans
Characteristics and Impact of Gulf War Illness: Epidemiologic Research  35

might have had little first-hand knowledge at the time of exposure, such as exposures to depleted uranium

and CARC paint, were reported least reliably. 988,1165,1767

Questions about the accuracy of veterans’ self-reported exposures require that identified risk factors for

Gulf War illness be assessed and interpreted with caution. Errors resulting from misclassification can

produce both overestimates and underestimates of the degree to which a particular exposure is actually

associated with illness. It is useful to note that studies of both U.S. and U.K. Gulf War veterans have

found that the reliability of self-reported exposures was unrelated to veterans’ health status, that is,

symptomatic veterans report exposures with the same degree of reliability as healthy veterans.988,1767,1804

This indicates a potential for “nondifferential” misclassification of exposures, that could lead to

underestimates of the degree of risk resulting from some Gulf War exposures, particularly those reported

less reliably.

Unlike exposures, Gulf War studies have generally found that veterans report medical conditions with a

high degree of reliability.692,751,789,989 For example, medical record reviews for a subset of veterans

participating in the U.S. national survey of Gulf War era veterans indicated that self-reported conditions

related to clinic visits and hospitalizations were reported accurately 93 percent of the time.751

Studies have assessed the impact of reporting biases on epidemiologic findings in Gulf War studies using

different approaches.692,988,1088,1165 One recent study, for example, reported that veterans in VA’s national

survey who had been notified that they were potentially exposed to nerve agents following weapons

demolitions at Khamisiyah, Iraq, were no more likely to report symptoms, medical conditions, or

healthcare visits than other veterans. Investigators concluded that, contrary to expectation, veterans who

believed they may have been exposed to nerve gas showed no tendency to “over report” health

problems.1165 A study of Gulf War veterans in the Pacific Northwest found that media coverage of both

the Khamisiyah weapons demolitions and studies showing adverse effects of Gulf War exposures had

very little impact on veterans’ reports of chemical agents and other exposures in theater.988 Iowa

investigators reported that Gulf War veterans were no more likely to respond to health questions in a

socially desirable way than nondeployed era veterans.692 And in a study of the Fort Devens cohort,

inclusion of a measure of recall bias in multivariable analyses had no impact on identified associations

between exposures and Gulf War illness.1804

Taken together, such studies suggest that despite obvious concerns related to the potential effect of recall

bias on Gulf War studies, its actual impact does not appear to have been extensive enough to render study

results uninformative. Still, the potential for error introduced by recall bias and other sources of

information bias is an important reason for considering patterns of results provided by multiple studies,

rather than relying on individual studies, especially when assessing relationships between experiences in

theater and Gulf War illness.
36  Gulf War Illness and the Health of Gulf War Veterans

Gulf War Illness Prognosis and the Need for Treatments

Are Veterans with Gulf War Illness Getting Better or Worse With Time?

The question of whether veterans with Gulf War illness have generally recovered or become worse is an

important one. Four studies have assessed the health of Gulf War veterans over time, all leading to the

same conclusion. In 1998, investigators from the Boston VA Environmental Hazards Center reported that

veterans in the Fort Devens cohort, evaluated at two time periods between 1992 and 1996, exhibited no

significant differences in either the types or average number of symptoms reported.1239 When veterans

from the same group were evaluated a third time two years later, 90 percent of those who had previously

been identified as CMI cases continued to meet defining criteria for CMI.1804

Similarly, a study of over 1,000 British Gulf War veterans found that their symptomatic ill health

remained relatively stable over time. In two evaluations, four years apart, British Gulf War veterans

exhibited a slight worsening of functional status, but improved slightly on measures of fatigue and

psychological distress.644 Declining health was most associated with veterans’ having more severe

symptoms at baseline, believing they had “Gulf War Syndrome,” and having more psychological

distress.643 Recently, New Jersey investigators also reported little change in the health of symptomatic

Gulf War veterans over time. Among nearly 400 U.S. Gulf War veterans surveyed in both 1995 and

2000, no significant changes in the average number or severity of symptoms were found. Veterans who

had been highly symptomatic in 1995 remained so in 2000, although as a group they experienced a slight

reduction in symptoms.1163

Additional insights into the development and prognosis of Gulf War illness were provided by preliminary

results from VA’s longitudinal study of nearly 6,000 Gulf War veterans, presented to the Committee by

Dr. Han Kang.745,748 In this national sample, 35 percent of Gulf War veterans indicated they had

developed multisymptom illness since the war, with most (67%) reporting that onset occurred between

1991 and 1993. Only two percent of those who had developed multisymptom illness said they had since

recovered. Seven percent felt they were “much improved” but 15 percent indicated their condition had

become “much worse” over time.

Results from all longitudinal Gulf War studies clearly indicate that few veterans with Gulf War illness

have recovered over time and only a small minority have substantially improved. Studies also indicate

that the majority of symptomatic Gulf War veterans have not become progressively worse with time.

However, a subgroup of veterans do appear to have become worse in the years since they first became ill.

The Urgent Need for Effective Treatments for Gulf War Illness

Gulf War illness has persisted for a very long time for most ill veterans—seventeen years for many.

Special panels and government committees assembled to address questions related to the health of Gulf

War veterans have consistently emphasized the importance of providing adequate treatments for affected

veterans. But effective treatments for Gulf War illness have not yet been identified. The federal

government has sponsored just three completed clinical trials to study treatments for Gulf War illness,

only two of which have published study results. In addition, many thousands of ill veterans have been

seen for this condition in government and private healthcare settings in the 17 years since the war. But

few systematic evaluations have reported on the degree to which the treatments veterans receive have

been useful in improving their health. The Committee’s 2004 report indicated that the federal

government had spent over 21 million dollars for treatment research up to that time, the majority ($15

million) for two large multi-center clinical trials. Additional funding was provided for an unpublished
Gulf War Illness Prognosis and the Need for Treatments  37

Table 4. Studies Reporting Effects of Treatments for Gulf War Veterans

with Multisymptom Illness

Study Sponsor

Number of

ill veterans Design Major Findings

Multiple courses of antibiotic

treatment for mycoplasma

infection1118,1119

none

2 series of

73, 14

veterans

case

series

In 1st report, 55 of 73 symptomatic veterans interviewed

indicated good response with doxycycline therapy; in 2

nd

report, 11 of 14 veterans who tested positive for mycoplasma

infection recovered after multiple cycles of antibiotic therapy.

Multidisciplinary Treatment for

Medically Unexplained

Symptoms406

DOD 109 veterans case

series

3 months after completion of 3 week multidisciplinary

treatment, mean increase of 1 point on SF36 PCS, women

improved more than men; little change in symptoms.

Louisiana Medical Foundation

Antibiotic Treatment Trial 332,670 DOD 36 veterans RCT

Antibiotic treatment group had significant reduction in

headaches and measures of fatigue and pain compared to

placebo. Treatment group had median improvement of 22

points on SF36 PCS.

Antibiotic Treatment of Gulf

War Veterans’ Illnesses355 DOD/VA 491 veterans

at 26 sites

multicenter

RCT

No significant difference between doxycycline treatment and

placebo on 10outcome (7 point improvement on SF36 PCS

over 12 months): 18% of treatment group improved and 17%

of placebo group improved. Treatment group had mean

increase of 2 points on SF36 PCS.

Exercise/Cognitive Behavioral

Therapy in Veterans with Gulf

War Illnesses354

DOD/VA

1,092

veterans at

20 sites

multicenter

RCT

CBT provided statistically significant benefit on 10outcome (7

point improvement on SF36 PCS over 12 months): 12% of

“usual care” and exercise only groups improved; 18% of both

CBT and CBT+exercise groups improved. CBT arm had

mean increase of 1 point on SF36 PCS.

Abbreviations: DOD = U.S. Department of Defense, VA = U.S. Department of Veterans Affairs, RCT= randomized, controlled trial,

SF36 PCS = Physical Component Score of the Medical Outcomes Short Form, CBT = cognitive behavioral therapy

antibiotic trial ($3 million) and for five VA case management demonstration projects ($3 million).

Findings from two published case series and the three federally-sponsored clinical trials are summarized

in Table 4.

Available information on Gulf War illness treatments. The two federal multi-center clinical

trials are the largest and best known of the Gulf War treatment studies. Briefly, the antibiotic treatment

trial evaluated whether a 12 month course of doxycycline treatment improved the health of Gulf War

veterans, as reflected in at least a seven point increase in the physical component score (PCS) of the

SF36.353 Veterans participating in the study were required to test positive for mycoplasma infection using

polymerase chain reaction methods. Although the study showed some benefit for the doxycycline

treatment group after three months, there were no differences between treatment and placebo groups after

12 and 18 months.355

The exercise/behavioral therapy trial studied the effects of 12 months of a directed exercise regimen and

cognitive behavioral therapy (CBT), individually and combined, on Gulf War illness. Again,

improvement was measured by a seven point increase in the SF36 PCS. Only CBT provided a

statistically significant benefit over usual treatment, with 18 percent of participants improving with CBT

compared to 12 percent with usual treatment.354 Despite the modest benefit provided by CBT, results of

the two large trials, conducted at a cost of over 15 million dollars, were generally disappointing in that

neither intervention provided improvement for a substantial number of veterans.639 Overall, mean
38  Gulf War Illness and the Health of Gulf War Veterans

improvement on veterans’ SF36 PCS scores was only one point for CBT and two points for doxycycline

treatment.

The only other completed Gulf War illness clinical trial was a study of a complex, high dose antibiotic

regimen conducted by the Louisiana Medical Foundation, headed by the late Dr. Edward Hyman.670 The

intervention was unconventional, and the theory on which it was based was controversial.331,671,672,1454,1455

Study results were never published, but were presented to the Committee by two of Dr. Hyman’s coinvestigators, Dr. Quentin Deming and Mr. William Weiss. Briefly, the study was a randomized, double

blind, placebo controlled trial of intravenous, then oral antibiotics over a four month period. Specific

regimens and dosages varied, according to the presence of excreted gram-positive cocci detected by

microscopic evaluation of patients’ urine, and by patients’ symptoms.332,670

Although both the theory and intervention were unconventional, investigators used standard methods to

evaluate the health status of veterans before and after treatment. Results shared with the Committee

indicated that the treatment group improved significantly compared to the placebo group, with reductions

in the mean number of headaches per month (from 12.5 to 2.5, p < 0.001), significantly improved scores

on two fatigue scales, and improvement on the McGill Pain Inventory. The median SF36 PCS score was

reported to improve 22 points for the treatment group, compared to seven points for the placebo group,

and investigators indicated that no excess of side effects had been observed in the treatment group. No

significant differences were seen on measures of sleep quality, neuropsychological impairment, or

frequency of diarrhea.332 The Committee was intrigued by the apparent benefit provided by the treatment,

but concerned that study results had not been scientifically peer reviewed and published. The biological

rationale for the treatment approach was also puzzling. So although the empirical results appeared

extremely promising they were overshadowed by questions surrounding the study, most prominently the

role of excreted bacteria and the lack of scientific review and successful publication. Therefore, the

Committee was unable to come to firm conclusions regarding the meaning and importance of the study

findings and appropriate follow up.

There are few other sources of systematically-collected data on the effects of treatments used for Gulf

War illness. Two investigators have published observational findings on treatment outcomes in case

series of ill Gulf War veterans, as shown in Table 5. Dr. Garth Nicolson reported substantial benefit for a

subset of Gulf War veterans treated with multiple courses of antibiotics,1118,1119 and Dr. Charles Engel

reported slight functional improvement in veterans treated with a multidisciplinary intervention that

included CBT.406

Gulf War veterans with multisymptom illness who participated in VA’s national longitudinal study were

asked about their experience with treatments and lifestyle practices in relation to their symptoms.

Preliminary findings were presented to the Committee by Dr. Han Kang.745 Symptomatic veterans

reported using prescription and over-the-counter medications most frequently, followed by physical

therapy and nutritional supplements. The most highly rated category was over-the-counter medication,

which eight percent of ill veterans said had provided benefit for their symptoms, most prominently

headache and joint pain. About the same proportion indicated that diet and nutritional supplements had

helped, mostly for fatigue, joint pain, and gastrointestinal symptoms. Six percent reported physical

therapy had helped with somatic pain and five percent indicated that antidepressants had been helpful for

improving depression symptoms and sleep difficulties. Among unconventional therapies, about two

percent of symptomatic veterans reported that relaxation therapy had been helpful for joint pain, fatigue,

and headache. A similar number indicated that herbal medicines had provided benefit for memory loss,

fatigue, and joint pain.

Veterans also reported whether different activities and lifestyle behaviors had affected their symptoms.

Factors most often associated with improved symptoms were avoiding stressful situations (25%),

maintaining a well-balanced diet (20%), and cutting back on work or social activities (18%). The factors
Gulf War Illness Prognosis and the Need for Treatments  39

most often said to make symptoms worse were vigorous exercise (35%) and maintaining a busy schedule

(23%). About the same number of veterans indicated that light exercise improved (16%) as worsened

(18%) their symptoms. These findings provide an interesting first look at the general types of approaches

veterans have used in addressing their illness. The Committee looks forward to reviewing additional

results from this study to learn, in more detail, about veterans’ appraisals of specific treatments.

No other systematically-collected data are available on effects of treatments for Gulf War illness. Two

physicians have provided public testimony on their clinical experience in treating a limited number of

veterans. In 1993, Dr. Myra Shayevitz provided testimony to Congress describing improvements in 25

symptomatic Gulf War veterans treated in an environmental clinic piloted at the Northampton,

Massachusetts VA Medical Center (VAMC).1399 The clinic intervention included reduced exposures to

chemicals, improved nutrition, and patient education and support. Several of Dr. Shayevitz’s patients also

provided written comments attesting to their improved health. Dr. David Root provided testimony to the

Presidential Special Oversight Board in 1998 and to the CDC Gulf War Research Planning Conference in

1999 about dramatic improvements observed in several highly symptomatic Gulf War veterans he had

treated with an intensive sauna/detoxification regimen used routinely for treatment of chemical injury and

substance abuse.1307,1308

VA’s Gulf War research portfolio currently includes three clinical studies that provide treatments for

symptomatic Gulf War veterans. A study conducted at the East Orange, New Jersey, VAMC is

evaluating the effectiveness of CBT administered by telephone to veterans with Gulf War illness.226 A

second study, conducted at the Northport, New York, VAMC, is evaluating continuous positive airway

pressure (CPAP) treatment for Gulf War veterans with disordered sleep. The third study, conducted by

investigators at the Salt Lake City VAMC, will treat small bowel bacterial overgrowth in veterans with

persistent diarrhea.

In addition, VA and DOD collaborated in convening expert panels that developed clinical guidelines for

evaluating veterans with post-deployment health concerns,1656 and for evaluation and management of

veterans with medically unexplained fatigue and pain.1655 Treatment guidelines for medically

unexplained symptoms were based on what was known about treatment of fibromyalgia and chronic

fatigue syndrome at the time the guidelines were developed in 2001. No information is available that

indicates whether government clinicians have used these guidelines in treating ill Gulf War veterans, or if

recommended treatments have been effective. The treatment guidelines have also become outdated.

Since 2001 a large amount of additional information has become available on medical treatments for

these conditions, particularly fibromyalgia, as will be described in a later chapter.

Future prospects for federally-sponsored Gulf War illness treatment research. As

described in the Committee’s 2004 report, there are two general approaches for identifying effective

therapeutic interventions. The first, an empirical approach, is based on clinical observations that certain

treatments provide improvements for certain conditions. Potentially beneficial treatments identified in

this way can be systematically assessed using outcomes research and randomized clinical trials to

scientifically determine their effectiveness. The second approach requires that specific biological

mechanisms underlying a disease be identified, so that treatments to counteract those processes can be

identified and tested for their effectiveness. For Gulf War illness, a complex condition for which specific

pathophysiological mechanisms are not well understood, both approaches will likely be needed in order to

identify the most effective treatments in the most timely way.

In response to recommendations in the Committee’s 2004 report, the Secretary of Veterans Affairs

announced that VA would fund a Gulf War illness treatment research initiative, largely focused on

identifying and evaluating treatments already available and being used to treat Gulf War illness and

conditions with similar features. Although a draft funding announcement for a treatment research center
40  Gulf War Illness and the Health of Gulf War Veterans

was provided for Committee review in late 2005, no final announcement was released and a treatment

research center has not been funded.

In 2006, two major changes occurred in federal funding for Gulf War illness research, as will be

described in detail in a later section. These changes included a total of 15 million dollars allocated in

FY2006 and FY2008 for a Gulf War illness research program managed by the Office of Congressionally

Directed Medical Research Programs (CDMRP) at DOD,1596 and a 15 million dollar annual allocation for

a comprehensive Gulf War illness research center at the University of Texas Southwestern (UTSW),

funded by VA. The two recently-funded programs have been directed to coordinate their efforts and will,

fundamentally, utilize the two approaches previously described for identifying effective treatments.

The initial funding solicitation issued by the CDMRP Gulf War illness research program indicated that

highest priority would be given to studies that identify and evaluate treatments for Gulf War illness. This

included funding for smaller scale studies to provide data on treatments currently being used for Gulf War

illness and similar conditions as well as treatments that address biological processes thought to underlie

Gulf War illness. The UTSW program, on the other hand, is focused on determining specific biological

mechanisms that underlie veterans’ symptoms, in order to identify treatments to address those processes.

Both programs have only recently begun implementing studies, and the Committee looks forward to

monitoring their progress. The CDMRP program announced, in 2007, that nine Gulf War illness studies

were funded with the initial program allocation. These included pilot trials of treatments for veterans

with Gulf War illness, and animal studies that will evaluate effects of treatments on biological processes

identified in animal models for Gulf War illness.737 The Committee regards both programmatic initiatives

to be positive steps forward in focusing Gulf War research on the highest priority objective, that is, to

improve the health of ill veterans.
Is There a Unique Gulf War Syndrome?  41

Is There a Unique Gulf War Syndrome?

The question of whether the multisymptom illness affecting Gulf War veterans should be considered a

“unique Gulf War Syndrome” has been widely discussed and interpreted.134,252,324,556,667,668,686,918,1089,1757

What is meant by the question has often been unclear, as have attempts to answer it. For some observers,

a “unique syndrome” has meant that there should be just one constellation of symptoms affecting Gulf

War veterans—a single symptom complex constituting a single syndrome. For others, a “unique

syndrome” has meant that a single, unique cause for the symptoms should be demonstrated. For still

others, a “unique syndrome” has meant that similar symptoms would not be found in people who did not

serve in the Gulf War. And for several researchers, the question has hinged on whether a particular

statistical technique, factor analysis, identifies symptom correlations in Gulf War veterans that are not

found in other groups.

However the question of a unique syndrome in interpreted, extensive descriptive and analytic research has

clearly demonstrated that an illness, characterized by a complex of multiple symptoms, resulted from

service in the Gulf War. The specific symptoms affecting individual veterans can differ from person to

person, but the general types of symptoms are remarkably consistent across diverse Gulf War veteran

populations. Whether this Gulf War-related symptom complex represents several syndromes, or one

syndrome with several subtypes, is an issue of taxonomy that can only be definitively resolved as

objective markers become more firmly established.

Gulf War illness, as a consistent complex of symptoms affecting a defined population, fits most

definitions of what constitutes a syndrome. But this syndrome might not be considered unique, from

different perspectives. That is, there could be more than one type of pathophysiological process affecting

Gulf War veterans that leads to similar, overlapping symptom profiles. There could also be more than

one cause for these symptoms. And, lastly, Gulf War illness has some similarities to multisymptom

conditions found in other populations, as will be discussed in detail in a later section of this report.

The central issue of importance is that at least one fourth of veterans who deployed to the Gulf War as

healthy men and women developed an identifiable pattern of persistent, difficult symptoms as a

consequence of their military service. Whether this illness should be referred to as one or more

syndromes—unique or otherwise—is of less consequence. There is overwhelming evidence

demonstrating that Gulf War illness, however labeled, is a widespread problem in Gulf War veterans and

no evidence to the contrary.

Is Gulf War illness the same thing that happens after every war? Several commentaries and

reviews have described Gulf War illness as a condition that parallels syndromes historically described in

soldiers after they return from war.669,720,721,1500 These have included “irritable heart” or “Da Costa’s

syndrome” in Civil War veterans,302 shell shock and “effort syndrome” in World War I veterans, battle

fatigue in World War II veterans, and posttraumatic stress disorder in Vietnam veterans. In all eras,

soldiers serving in war have suffered from acute and chronic health problems that often affect more troops

than the number injured and killed in battle. This has historically included the effects of infectious

disease and extreme environmental conditions, but in more recent times has also included effects of

radioactive fallout, chemical defoliants, and chemical weapons.191

Experiences common to all wars include combat and the hardships of deployment, both of which can

have long-term physical and psychological consequences. Commentators who have characterized Gulf

War illness in the context of other post war syndromes have suggested—explicitly or implicitly—that

because the psychological impact of war can have long-term consequences, Gulf War illness is probably

another post-war stress syndrome, the result of psychological factors. This idea was accepted by some at

face value before data that specifically addressed these issues became available.
42  Gulf War Illness and the Health of Gulf War Veterans

Research studies have not supported the view that Gulf War illness is the same type of problem that

occurs after every war, nor that it can accurately be considered a post-war stress syndrome. As early as

1994, a National Institutes of Health Technology Assessment panel observed that symptom profiles

affecting Gulf War veterans differed from those of Vietnam veterans. Data from VA registries indicated

that symptoms of fatigue, muscle pain, headache, joint pain, and shortness of breath were more common

in Gulf War than Vietnam veterans.

1121 British investigators have since systematically evaluated the

health and symptoms of military personnel who served in the 1990-1991 Gulf War, in Bosnia during the

1990s, and in Iraq in the current conflict. No “Gulf War syndrome”-like effect, that is, no pattern of

excess symptoms affecting a sizable number of veterans, was found in Bosnia or Iraq War

veterans.631,642,1698 The effect was only observed in veterans who served in the 1991 Gulf War.1088

Clinical reports on U.S. veterans who served in Operations Iraqi Freedom and Enduring Freedom also

have indicated that returning personnel have not been affected by high rates of symptomatic illness that is

not explained by diagnosable medical or psychiatric conditions.615,653

In contrast to Vietnam veterans and personnel returning from current conflicts in the Middle East,

population-based studies have consistently found that 1990-1991 Gulf War veterans have low rates of

posttraumatic stress disorder and other psychiatric conditions, as detailed in the next section of the report.

Further, studies that have comprehensively assessed risk factors associated with the Gulf War consistently

indicate that Gulf War illness is not associated with serving in combat or other stressors during

deployment.

Available evidence therefore indicates that Gulf War illness is not the same thing that happens after every

war and is not a post-war stress syndrome. Each war is unique, each has its own profile of risks and

health consequences.291,1216,1723 All wars present some degree of trauma for troops in battle, but many

wars also present other hazards. The effects of blister agents in World War I or the Iran-Iraq War, for

example, should not be equated to the psychological consequences of soldiers fearing for their lives or

seeing a buddy die on the battlefield. Neither should the effects of Agent Orange be confused with the

effects of the traumatic experiences many soldiers encountered in the jungles of Vietnam. Service in the

1991 Gulf War resulted in a complex health problem not typical of other wars that cannot be understood

simply as the expected result of deployment-related stress.
Other Gulf War Health Issues  43

Other Gulf War Health Issues

Gulf War illness is the most prevalent health problem affecting Gulf War veterans, but not the only health

issue related to Gulf War service. Additional important issues include rates of diagnosed medical and

psychiatric conditions in Gulf War veterans, particularly neurological conditions, cancers, and respiratory

diseases, as well as causes and rates of mortality. Although Gulf War epidemiologic studies have

commonly reported hospitalization and mortality rates, relatively little information is available concerning

diagnosed diseases not normally associated with hospitalization or premature death. In addition,

important questions about health problems affecting veterans’ children and other family members have

persisted since the Gulf War.

Diagnosed Diseases Affecting Gulf War Veterans

Amyotrophic lateral sclerosis. The most serious condition reported to affect Gulf War veterans at a

higher-than-expected rate is amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.

This serious and progressive neurodegenerative disease most often strikes individuals between age 55 and

75, affects men more often than women, and is almost universally fatal. A 2003 VA study reported that

Gulf War veterans were about twice as likely to have ALS as nondeployed era veterans based on 40

confirmed Gulf War-deployed ALS cases.636 The excess risk was particularly pronounced in Air Force

Gulf War veterans, who had ALS at nearly three times the rate of their nondeployed peers.

The VA research team made a concerted effort to determine whether the excess ALS rate observed in

Gulf War veterans could be an artifact of ascertainment error, that is, failure to detect some ALS cases

among the nondeployed. After adjusting for this potential bias using three different methods, results still

indicated a significant excess of ALS in Gulf War veterans.260,633 Research from the University of Texas

Southwestern raised additional concern that Gulf War veterans may have developed ALS at a youngerthan-normal age, finding that a large number of cases occurred in veterans under age 45.557 In addition,

military hospitalization data indicated that active duty personnel who had served in the Gulf War had a

1.7 times higher rate in ALS hospitalizations between 1991 and 1997, compared to nondeployed era

veterans, an excess that was not statistically significant.1432

A later report from a 2005 study of over 400,000 men in an American Cancer Society cohort indicated

that men who had served in the military, overall, were more likely to have died of ALS than men who

were not in the military.1759 This raised questions about whether an excess risk of ALS is related to

military service in general, rather than Gulf War service specifically.1206,1310 As a result, VA

commissioned a special report from the Insitute of Medicine, which concluded that there was limited, but

suggestive evidence that ALS is associated with military service in general.685

Results of the Cancer Society study are important in providing a preliminary indication that military

service could be a risk factor for ALS. But it is unclear why researchers and government officials have

suggested, based on findings from this study, that ALS may be linked to military service, but not

specifically with Gulf War service. The VA Gulf War ALS study found that ALS affected Gulf War

veterans at twice the rate of nondeployed Gulf War era military personnel. If military personnel are,

overall, at increased risk for ALS, the observed excess of ALS in Gulf War veterans compared to other

military personnel would be of particular concern.

The Cancer Society study provided information on ALS among military veterans serving from World

War II through the Vietnam eras, but no insights on rates of ALS in deployed vs. nondeployed veterans or

in Gulf War veterans compared to veterans of other eras.1759 Therefore, results of this study do not

diminish concerns raised by studies that have identified an excess of ALS specific to Gulf War
44  Gulf War Illness and the Health of Gulf War Veterans

deployment. This excess could be of greater concern if military service in general is also a risk factor for

ALS.

Recently, additional findings reported from the large VA ALS study indicated that most new ALS cases

among Gulf War veterans identified in the 10 years after the war had their initial onset by 1996. The

excess of ALS cases declined after that time—both in Gulf War veterans overall, and in those under age

45.634,635 Additional analyses also identified differences in ALS risk related to geographical areas where

troops were located during deployment.1052,1053 These recent reports indicate that ALS in Gulf War

veterans occurred in the pattern of a time-limited disease “outbreak,” resulting from events or exposures

during Gulf War deployment. If the post-1996 pattern of new onset ALS cases continues, the number of

excess ALS cases among Gulf War veterans will be less than had initially been suggested by early

studies. But it is not known if the risk of ALS, which normally increases after age 55, will differ in Gulf

War veterans as they age. The seriousness of this disorder requires that ALS rates in Gulf War veterans

continue to be monitored for the foreseeable future.

In response to early reports that ALS was associated with Gulf War service, VA developed an ALS

registry for Gulf War era veterans. That registry has since been expanded to include all veterans with

ALS who served in the military during any period.756 In addition, VA has developed a brain tissue bank

that will enroll and collect tissues from veterans with ALS identified in the registry.441,1225

Other neurological diseases. Very little information is available concerning rates of other diagnosed

neurological diseases in Gulf War veterans. In light of the excess of ALS in Gulf War veterans, as well as

consistent findings related to persistent neurological symptoms, it is important to determine if other

neurological diseases have disproportionately affected Gulf War veterans. In its 2004 report, the

Committee recommended that rates of multiple sclerosis (MS), Parkinson’s disease, brain cancers, and

difficult-to-characterize neurological disorders be identified in Gulf War veterans and suitable

comparison groups. Since the Committee’s report was issued, veterans’ organizations and members of

Congress have called on the federal government to conduct research to determine the rate of MS in Gulf

War veterans.1694,1721 In 2008, VA initiated a case/control study of veterans who were service-connected

for MS disability by the Veterans Benefits Administration (VBA).1747 This study will not identify

incidence or prevalence rates of MS in Gulf War veterans but may provide insights concerning

characteristics of MS and risk factors for MS potentially related to Gulf War service.

Other than limited information from hospitalization studies, the only other studies that have assessed

neurological disease in Gulf War veterans evaluated rates of mortality due to neurological disease. A

2005 study, conducted by investigators from the Washington, D.C., VAMC, identified an excess rate of

brain cancer deaths among Gulf War veterans who, according to DOD models, were potentially exposed

to low levels of nerve agents in relation to chemical weapons demolitions at Khamisiyah, Iraq, in 1991.192

Veterans in affected areas were twice as likely, overall, to have died from brain cancer between 1991 and

2000 as veterans in other locations. Excess rates were most apparent during the last few years of follow

up (1997-2000). A dose-response effect was also noted, wherein higher brain cancer mortality occurred

in veterans who were in affected areas for longer periods of time.190,192

Researchers are currently conducting an updated mortality study to evaluate causes of death in U.S. Gulf

War veterans through 2004.105 Preliminary results, shared with the Committee in 2008, are similar to

findings reported in 2005. Investigators continue to identify a significant excess of brain cancer deaths

among Gulf War veterans potentially exposed to nerve agents related to the Khamisiyah demolitions.

These mortality studies provide useful information on deaths due to brain cancer, and demonstrate the

importance of evaluating diseases in subgroups of Gulf War veterans with specific exposure and/or

location histories. However, other types of research are still needed to determine whether Gulf War

service is associated with excess rates of diagnosed neurological diseases that have not been fatal.
Other Gulf War Health Issues  45

Cancer in Gulf War veterans. Government committees and special panels have long called for

studies to determine if Gulf War veterans have developed cancer at higher-than-expected rates since

Desert Storm.1227,1673,1682 Identifying cancer rates in Gulf War veterans is especially important now, 17

years after the war, since many cancers first become apparent 10 to 20 years after an initiating event. The

most comprehensive study of cancer in Gulf War veterans comes from Great Britain. A 2003 study

identified the incidence of multiple types of cancer between the years 1991 and 2002 in the entire cohort

of U.K. Gulf War veterans and a matched comparison group, using data from the British National Health

Service.943 No differences were found between Gulf War and era veterans for rates of all cancers

combined, nor for any site-specific cancers.

In the absence of a similar cancer data resource in the United States, comprehensive information on

cancer rates in U.S. Gulf War veterans has not been reported. As previously described, results from a

national study found an excess of brain cancer deaths in relation to the Khamisiyah weapons demolitions.

The 2005 study identified 25 brain cancer deaths in veterans potentially exposed to nerve agents, an

excess of 14 brain cancer deaths per 100,000 exposed veterans.190 In contrast, in a population-based

survey of about 1,800 Gulf War veterans in five U.S. states, no excess of physician-diagnosed cancer was

reported by veterans who had been within 50 kilometers of Khamisiyah. Overall, however, three times as

many Gulf War veterans as nondeployed era veterans in this sample reported being diagnosed with some

type of cancer. The excess of reported cancer diagnoses—21 cases among Gulf War veterans, and three

cases among nondeployed veterans—did not reach statistical significance.989

Only limited information is available concerning verified cancer diagnoses in U.S. Gulf War era veterans.

An early hospitalization study reported that, in the months immediately following Desert Storm, active

duty Gulf War veterans were twice as likely to be hospitalized for testicular cancer as nondeployed era

veterans.523 This difference was no longer apparent after five months, leading investigators to conclude

that the temporary rate spike had been due to Gulf veterans deferring care for this condition until they

returned home from deployment.820

A later study, using 1991-1999 data from cancer registries in New Jersey and the District of Columbia

(D.C.), reported a two-fold proportional excess of testicular cancer in Gulf War veterans, compared to

nondeployed era veterans.894 Proportional excesses were also reported for non-Hodgkin’s lymphoma and

brain cancer from D.C. registry data, but not the New Jersey registry. This team has continued to collect

and analyze cancer data on Gulf War and era veterans from additional state cancer registries. Preliminary

results from a total of eight registries were shared with the Committee by Dr. Paul Levine. Data from

some states suggested slight excesses in the crude incidence of testicular and brain cancers in Gulf War

veterans compared to nondeployed era veterans between 1991 and 1999. Proportional differences were

not significant, however, after adjustments for age and race.892 This ongoing investigation currently

includes data from 28 state cancer registries, which cover about 83 percent of U.S. Gulf War and era

veterans.959 The Committee looks forward to reviewing additional results from this important research.

Although studies to date have raised only limited concerns about cancer in Gulf War veterans, a number

of important questions have not yet been adequately addressed. Very limited cancer data have been

reported for U.S. Gulf War veterans in general, and no published research on cases occurring after 1999.

Because of the extended latency periods associated with most cancers, it is important that cancer

information be brought up to date and that cancer rates be assessed in Gulf War veterans on an ongoing

basis. In addition, cancer rates should be evaluated in relation to identifiable exposure and location

subgroups, as was done in the 2003 British study and the U.S. mortality study related to Khamisiyah.

Data from VA’s longitudinal study can also be used to provide an indication of whether veteran-reported

cancers are associated with exposures in theater.

Other diagnosed conditions affecting Gulf War veterans. Limited information is available on

rates of other diagnosed diseases in Gulf War veterans. In addition to symptoms, epidemiologic studies
46  Gulf War Illness and the Health of Gulf War Veterans

have asked veterans to report if they had been diagnosed with a variety of medical conditions. Several

types of diagnoses are consistently reported at higher rates by Gulf War veterans than nondeployed era

veterans. These include migraines,527,751,1476,1698 seizures,748,751,989,1476 digestive conditions,527,748,751,1411,1476

respiratory conditions,527,751,1411,1476,1698 and skin disorders.527,751,1411,1476,1698 Generally, fewer excess

medical conditions have been reported by Australian and Danish Gulf War veterans than U.S. and U.K.

Gulf War veterans.696,789

Rates of respiratory conditions have been evaluated in several Gulf War studies.285,866,1434 As will be

described in more detail, one study reported that a higher proportion of Gulf War than nondeployed

veterans had been hospitalized for respiratory conditions, including asthma.528 In addition, one wellconducted study found that the subset of Gulf War veterans with greatest exposure to pollutants from oil

well fires had significantly elevated asthma rates.285

Multiple studies have evaluated rates of diagnosed psychiatric conditions in Gulf War veterans. Gulf War

veterans generally have higher rates of posttraumatic stress disorder and other psychiatric diagnoses than

nondeployed Gulf War era veterans,1488 but lower rates of psychiatric illness than combat veterans of

other wars. Findings on psychological stressors and psychiatric conditions are described in detail in the

next section of the report.

Most of the studies that have provided clinical examinations of Gulf War veterans have either included a

relatively small number of veterans464,565 or were case/control studies160 and so could not provide reliable

prevalence estimates for diagnosed conditions. Prevalence rates of selected diagnosed medical conditions

were provided in 2005 from Phase III of the U.S. National Survey of Gulf War era veterans.393 This

portion of the large U.S. national study provided clinical evaluations of 1,061 Gulf War veterans and

1,128 nondeployed era veterans 10 years after the war. Reported outcomes included SF36 PCS scores

and 12 medical conditions: fibromyalgia, chronic fatigue syndrome, skin conditions, dyspepsia,

hypertension, hepatitis, symptomatic arthralgias, obstructive lung disease, diabetes, peripheral

neuropathy, and both hypo- and hyperthyroidism.

Results from the U.S. national study indicated that Gulf War veterans had a dramatically higher rate of

chronic fatigue syndrome than nondeployed veterans (1.6% vs. 0.1%, OR = 40.6), and significantly

higher rates of fibromyalgia (2.0% vs.1.2%, OR = 2.3), skin conditions (34.6% vs. 26.8%, OR = 1.4), and

dyspepsia (9.1% vs. 6.0 %, OR = 1.9). None of the other 12 conditions were significantly more common

in Gulf War veterans. On average, the general health status of Gulf War veterans, measured by the SF36

PCS, was only slightly worse in Gulf War than nondeployed veterans (49 vs.51). This difference was

statistically significant, but of minor clinical significance. Abnormalities identified on clinical

examination and mean values for all laboratory tests were also similar for Gulf War and nondeployed

veterans.393

These long-awaited findings from the large VA clinical study provided useful information about the 12

conditions assessed but few additional insights concerning the health of Gulf War veterans. It is not clear

why the 12 outcomes assessed were selected for evaluation, since many had not been shown in earlier

phases of the study to be problematic for Gulf War veterans. For conditions like diabetes and hepatitis,

clinical evaluations largely provided validation of what veterans had already reported. Regrettably, this

large clinical study has not provided information on many of the conditions found to affect Gulf War

veterans at excess rates in earlier phases of the study, conditions like recurrent headaches and migraines,

diarrhea and colitis, seizures, and sinusitis. Neither was information provided on other medical

conditions of interest such as cancers, autoimmune disorders, and heart disease. Mean values for

deployed and nondeployed veterans were reported for all measures, but no information was provided on

subgroups of potential interest, for example, subgroups of veterans with abnormal findings on laboratory

tests, and subgroups of veterans who reported specific exposures.
Other Gulf War Health Issues  47

So, while additional insights have been provided from VA’s Phase III clinical study, important questions

remain about the extent to which Gulf War veterans may be disproportionately affected by diagnosed

medical conditions. It is important to determine if Gulf War veterans and, in particular, subgroups of

Gulf War veterans with specific exposures during the war, have excess rates of diagnosable neurological

conditions, cancer, respiratory diseases, or other chronic diseases.

Mortality Rates Among Gulf War Veterans

The question of whether there is an abnormally high rate of death among Gulf War veterans, or if

veterans have died at younger-than-expected ages, is of great interest and importance. In the seventeen

years since Desert Storm, government reports and research studies from both the U.S. and the U.K. have

consistently indicated that Gulf War veterans have not, overall, had higher rates of death due to diseases

but have had higher rates of accident-related deaths than nondeployed era veterans. Overall mortality

rates in both deployed and nondeployed era veterans are lower than in the general population, however.

Post-war mortality statistics are available from three published studies of U.S. Gulf War veterans and two

studies of British veterans, along with regular mortality reports provided by the U.K. Ministry of Defence.

The most recent published information on mortality in U.S. Gulf War and nondeployed veterans reports

on deaths through 1997, identified by VA’s Beneficiary Identification and Records Locator Subsystem

(BIRLS) and the Social Security Administration, with causes of death identified by the U.S. National

Death Index.749 That study reported that early post-war figures indicating lower disease-related mortality

in Gulf War veterans, and higher accident-related mortality, had become more similar over time. By

1996-1997, rates of mortality resulting from both disease and accidents were nearly identical in deployed

and nondeployed veterans. Later information has been published on mortality rates through the year 2000

for Gulf War veterans only, in relation to the Khamisiyah plume models, as previously described.192

Preliminary findings from an ongoing mortality study conducted by investigators at the Washington,

D.C.,VAMC were shared with the Committee in 2008.105 That study is evaluating overall and causespecific deaths that occurred among U.S. Gulf War and nondeployed era veterans through 2004. Early

results indicate that, overall, Gulf War veterans continue to have a lower mortality rate due to diseases,

and a higher mortality rate due to accidents, than nondeployed era veterans. However, investigators

reported that female Gulf War veterans have significantly greater mortality, overall, than nondeployed

female era veterans, and excess deaths due to digestive system diseases and external causes, including

motor vehicle accidents. Preliminary findings also continue to indicate that brain cancer mortality is

elevated among Gulf War veterans in relation to modeled levels of exposure to nerve agents. These

preliminary findings are provocative, and the Committee looks forward to further reviewing results of this

important study as they are finalized.

Mortality rates among British Gulf War veterans through 2006 have shown trends similar to those

observed in U.S. veterans. Over time, excess rates of accident-related deaths identified in the years just

after the war have become more comparable to those of nondeployed veterans. In a recent report,

however, the U.K. Ministry of Defence reported that between 1991 and 2007, veterans of the 1991 Gulf

War had a higher rate of suicide, or possible suicide, than nondeployed veterans of the same era.1569

Overall rates of death due to diseases remained somewhat lower in Gulf War veterans, compared to

nondeployed era veterans.1569 Additional details of interest are provided by a report on mortality in

British veterans in relation to experiences/exposures during the war.944 Just two associations were

identified, neither of which reached statistical significance. Veterans who reported handling pesticides

during the war were twice as likely as unexposed veterans to die from accident-related causes, and

veterans who reported depleted uranium exposure were twice as likely to die from disease-related causes.
48  Gulf War Illness and the Health of Gulf War Veterans

A number of theories have been put forward to explain why Gulf War veterans have experienced higher

rates of fatal accidents, most prominently motor vehicle accidents.124 These have included indications

that veterans have a greater propensity for risk taking behavior after hostile deployments,750 findings of

poorer attention and response speed in cognitively impaired veterans,554 reports of greater use of alcohol

by combat veterans,908 and the general similarities between characteristics of deployed military personnel

and people with the highest rates of motor vehicle accidents in the general population.629,908

Mortality studies have provided little indication that Gulf War veterans, overall, have suffered excess

rates of deaths due to diseases. However, the most recent comprehensive comparisons between U.S. Gulf

War and nondeployed veterans that have been published only include deaths that occurred before 1998.

Deaths due to diseases with longer latency periods would likely only have become apparent in more

recent years. Therefore, it is important that current figures for overall mortality, as well as diseasespecific mortality, for U.S. Gulf War era veterans be comprehensively evaluated and made publicly

available. Information on disease-specific mortality rates during the past 10 years are of particular

importance, and the Committee urges VA to make this information available at the earliest possible time.

Additional information on mortality rates among subgroups of Gulf War veterans—defined, for example,

by exposures and locations in theater and by branch of service—is also needed to determine if Gulf

veteran subgroups have been affected by any causes of death not apparent when all veterans are assessed

as a single group.

Hospitalization Rates Among Gulf War Veterans

Between 1996 and 2006, 14 studies reported rates of hospitalization in Gulf War veterans and comparison

groups.526,1428 Nearly all of these studies were limited to information on active duty military personnel

who were admitted to military hospitals. They therefore do not include the vast majority of Gulf War

veterans or hospital admissions. Recent VA figures indicate that over 90 percent of Gulf War veterans

had left the military by 2007.1650

Few differences between Gulf War and nondeployed era veterans have been reported from Gulf War

hospitalization studies. Both all-cause hospitalization rates and disease-specific hospitalizations have

been similar, overall, in comparisons between active duty Gulf War and nondeployed military personnel

from the same era. The few exceptions come from just three studies. The first reported that Gulf War

veterans were hospitalized for fibromyalgia at significantly excess rates between 1991 and 1997, but not

for lupus. Findings on ALS hospitalizations during this period were inconclusive due to small numbers,

as previously described.1432 No more recent information concerning hospitalizations for these conditions

has been reported. A second study found that a higher proportion of Gulf War Marine Corps veterans

than Vietnam Marine veterans were hospitalized for musculoskeletal conditions.148 The third study

included hospitalization information from nonmilitary hospitals. That study included 1991-1994 national

data from DOD and VA hospitals, as well as civilian hospitals in the state of California. Results indicated

a higher proportion of Gulf War than nondeployed era veterans had been hospitalized for injuries and for

respiratory and digestive diseases.528 Excess hospitalizations due to cardiac dysrythmia were also

reported among active-duty personnel who were, according to DOD models, potentially exposed to lowlevel nerve agents in relation to the Khamisiyah weapons demolitions.1433 Modeled exposure to

pollutants from oil well fire smoke was not associated with increased hospitalization risk.1434

As discussed in the Committee’s 2004 report, the large majority of cases of Gulf War illness would not be

identified using hospitalization data, since it is extremely uncommon for patients with undiagnosed,

symptom-defined illness to be hospitalized. There is also little reason to expect that a number of other

types of conditions reported to affect Gulf War veterans at excess rates would be identified by the

hospitalization studies conducted to date. Nearly all studies report only on hospitalizations among active

duty personnel in military hospitals. Veterans with serious conditions that might lead to hospitalization,
Other Gulf War Health Issues  49

but who were no longer in the military, would not have been included in the studies. In addition, medical

conditions shown by some studies to have affected subgroups of Gulf War veterans affected by a

particular exposure, such as asthma and brain cancer, would potentially go undetected in hospitalization

studies that simply compare all deployed veterans to nondeployed veterans. Further, diseases with long

latency periods, potentially detectable at their later stages using hospital admission data, would not likely

be found in studies evaluating hospital admissions before 2000, the most recent year for which Gulf

veteran hospitalization data have been reported.

An enormous amount of effort and care have been used to analyze and report military hospitalization rates

in Gulf War veterans. Results of these studies have been reassuring, to some degree, by indicating that

Gulf War veterans have not been admitted to military hospitals at exceedingly high rates in conjunction

with the types of injuries and acute and chronic diseases that normally lead to hospitalization.

Gulf War hospitalization studies have largely been used to report on disease rates that are easiest to

quantify using data routinely collected for administrative purposes. Unfortunately, this “low hanging

fruit” is not particularly informative with respect to the types of health problems known or expected to be

of greatest concern for Gulf War veterans. Consequently, hospitalization studies have added little to our

understanding of health issues related to Gulf War service. It is possible that hospitalization data may be

more informative in future years, if diseases of long latency that require hospitalization emerge in

sufficient numbers. It will be important, however, that any future studies of hospitalization rates in Gulf

War veterans include nonmilitary hospitalizations, and determine disease-specific rates in relation to Gulf

War veteran subgroups of interest.

Birth Defects and the Health of Gulf War Veterans’ Family Members

In addition to issues related specifically to the health of veterans, concerns have persisted since the mid

1990s that veterans’ family members, particularly their children born after the war, have had health

problems related to some aspect of veterans’ Gulf War service. These issues were reviewed and

discussed in detail in the Committee’s 2004 report, including results of studies conducted to assess rates

of birth defects in veterans’ children. Since that time, findings from a large VA study that evaluated

spouses of Gulf War veterans have been published, providing a first look at whether veterans’ spouses

have been affected by excess health problems in the wake of Desert Storm.

Birth defects in children of Gulf War veterans. In 1995, a cover story in Life magazine reported

on several children, born to Gulf War veterans, who had serious birth defects including Goldenhar

Syndrome, a congenital disorder characterized by abnormal development of facial structures.171 This,

along with reports of birth anomalies in a National Guard unit that had served in Desert Storm,1194 raised

public concern and stimulated research to determine whether children born to Gulf War veterans had

abnormally high rates of birth defects. As discussed in the Committee’s 2004 report, early studies found

little evidence of a problem284,285,1194 but had important limitations relating both to the samples and

sources of data used. Later studies used larger and/or more representative samples of Gulf War veterans,

and more comprehensive methods to identify health problems in children under one year. These studies

did find that a limited number of adverse birth outcomes, though rare, occurred more commonly in Gulf

War veterans than nondeployed veterans.

A study of over 75,0000 children born in military hospitals between 1991 and 1993 indicated that infants

born to Gulf War veterans were about three times more likely to have Goldenhar syndrome-related

diagnoses than infants born to nondeployed veterans.56 This excess was not statistically significant,

however, because the total number of cases in both Gulf War and nondeployed veterans was extremely

small. The first indication of a significant excess of birth defects related to Gulf War service came from a

2001 report from VA’s large national survey of Gulf War era veterans. Study results indicated that
50  Gulf War Illness and the Health of Gulf War Veterans

children born to male Gulf War veterans after the war had twice the rate of “likely” birth defects as

children born to nondeployed era veterans. Children born to female Gulf War veterans had three times

the rate of “likely” birth defects.747 Because these data relied on veterans’ self-reports, investigators

conducted medical record reviews to evaluate diagnoses for veteran-reported birth defects where possible.

These reviews, conducted for two-thirds of reported birth defects, confirmed veterans’ reports in 88

percent of cases. Resulting adjusted estimates continued to indicate that children of Gulf War veterans

had significantly more birth defects than children of era veterans.744

A large British survey of Gulf War veterans also reported a significant excess of veteran-reported birth

defects among children conceived between 1991 and 1997 by male Gulf War veterans, compared to

nondeployed veterans. Birth defects affecting the musculoskeletal and genitourinary systems were most

prominent.361 For the subset of birth defects confirmed by medical records, excess rates were similar but

less pronounced. Both the U.S. and U.K. national studies have therefore suggested that birth defect rates

were higher in children of Gulf War veterans than children of nondeployed veterans, but fell within the

normal range expected in the general population.

Results of an impressive data collection effort by the U.S. Naval Health Research Center also indicated an

excess of birth defects in children of Gulf War veterans. This study linked Gulf War military service

information to 1989-1993 data from six states with active birth defects surveillance programs.57 Results

indicated that three types of birth defects were significantly more common in children born to Gulf War

veterans, conceived after the war. Children of male veterans had higher rates of two types of heart valve

defects—tricuspid valve insufficiency and aortic valve stenosis. Male children of female Gulf War

veterans were more likely to be born with hypospadias, a defect in the urethral opening. In contrast, there

were similar rates of birth defects in children of Gulf War and nondeployed veterans who had been

conceived before the war.

Studies have also reported other adverse pregnancy outcomes in relation to Gulf War service. Military

hospital data revealed a significant excess of ectopic pregnancies and spontaneous abortions among

women Gulf War veterans whose pregnancies were conceived soon after their return from theater.55 In

addition, male Gulf War veterans in both the large U.S. and U.K. Gulf War surveys reported higher rates

of miscarriages, but not still births, in pregnancies they had fathered.361,747 British Gulf War veterans

were also reported to have higher rates of infertility than nondeployed veterans.949

Few additional studies related to pregnancy outcomes have been reported in the years since the

Committee’s 2004 report. A postal survey collected data on pregnancy outcomes between 1991 and 1995

reported by over 4,000 U.S. Gulf War and nondeployed era veterans. No significant excess of low birth

weight, ectopic pregnancies, stillbirths, or miscarriages were reported for male or female Gulf War

veterans, when analyzed separately.1761 Similar results were reported from a postal survey of Australian

Gulf War veterans.791 Neither study provided information on birth defects, however.

It is difficult to draw firm conclusions related to birth defects and pregnancy outcomes in Gulf War

veterans, due to the diversity and limitations of study results reported to date. The three studies most

representative of Gulf War era veterans in the U.S. and U.K. have all indicated significant, but modest,

excess rates of birth defects in children of Gulf War veterans. Information on specific types of birth

defects has been inconsistent, however,362 and overall rates are still within the normal range found in the

general population.

Some of the remaining important questions concerning birth defects in children of Gulf War veterans

might be answerable using existing data. For example, differences in specific types of birth defects

reported in different studies might relate to effects of combining all deployed Gulf War veterans into a

single group, rather than analyzing birth defects in relation to characteristics of the veteran parents’

deployment or health. Birth defect rates, if related to veterans’ service in the Gulf War, could be most
Other Gulf War Health Issues  51

pronounced in identifiable subgroups of veterans, for example, veterans with multisymptom illness,

veterans who were in certain areas of theater, or those exposed to certain hazardous substances. Birth

defects might also have been more problematic during certain periods after veterans returned, for

example, in pregnancies conceived soon after Desert Storm, as opposed to more recent conceptions.

Identifying patterns and risk factors for birth defects in defined populations can be extremely challenging,

particularly for birth defects that are uncommon.57 In addition to strategies aimed at obtaining additional

information from existing data, other research approaches will be needed to determine if birth defects

might be associated with Gulf War service generally, or with specific aspects of Gulf War service. This

could include case-control studies to evaluate Gulf War service and specific parental exposures as risk

factors for extremely rare types of birth defects.54 A study of this type recently reported that Gulf War

service was not a significant risk factor for new cases of Goldenhar Syndrome between 1996 and 2002,

although military service in the Army was a modest risk factor.1764

Another innovative approach for assembling and evaluating data on birth defects was presented to the

Committee by Ms. Betty Mekdeci. Ms. Mekdeci directs Birth Defect Research for Children (BDRC), a

private nonprofit organization that maintains special registries of children with birth defects, including

children of Gulf War veterans. The analytic approach of the organization involves comparing

proportional patterns of birth defects in different populations, in order to raise hypotheses about potential

problems in a given group. BDRC has identified a number of problems that appear to disproportionately

affect the over 3,000 children of Gulf War veterans in their birth defect registry. This includes 33

children with Goldenhar syndrome—substantially more cases than had been identified in the large

military hospital study. BDRC data also indicates that the majority of identified children with Goldenhar

Syndrome born to Gulf War veterans were born in 1992 and 1993, with fewer cases born after 1993.1020

Health problems in other family members. Media reports have also suggested that family

members and close contacts of Gulf War veterans have experienced anomalous health problems since

veterans returned from Desert Storm.130,1055,1250 Suggested causes have included transmissible infections

or contamination by chemical substances brought home on veterans’ uniforms and gear. A 1994 report

from the U.S. Senate Banking Committee indicated that many of the 1,200 ill veterans interviewed

reported that family members had developed health problems similar to their own.1688 In response to

these reports, VA provided free medical examinations to family members of Gulf War veterans who were

enrolled in the Gulf War Registry. No information from VA’s Gulf War family registry program has ever

been issued, however. Research studies have provided some information on the health of veterans’

family members, but have been limited to studies of birth defects among infants and the recent study on

veterans’ spouses. Research on rates of diagnosed diseases, symptomatic illness, and learning and

behavioral disorders among older children of Gulf War veterans is needed in order to determine whether

they have been affected by excess health problems, as has been suggested by media and veterans’ reports

and by the 1994 Senate investigation.

The large national U.S. study of Gulf War veterans included, in Phase III, clinical evaluations of a sample

of 539 spouses of Gulf War veterans and 600 spouses of nondeployed Gulf War era veterans.

Standardized medical, psychiatric, and neuropsychological examinations were performed ten years after

the war at 16 VA medical centers throughout the U.S. Nearly ninety percent of spouses evaluated in the

study were women. Health problems self-reported by Gulf veterans’ spouses were very similar to those

of nondeployed veterans’ spouses, except that Gulf veterans’ spouses were significantly more likely to

report having skin rashes (28%) and hepatitis (1%) than nondeployed spouses. There were no significant

differences between the two groups on medical examination, however, except that Gulf veterans’ spouses

had significantly fewer “group 1” or mild skin anomalies, such as moles, skin tags, and scars. There were

no significant differences in rates of fibromyalgia or chronic fatigue syndrome in veterans’ spouses. Nor

were there differences in diagnosed conditions such as diabetes, lung diseases, or hepatitis. Functional

status, as measured by the SF36 PCS, was also nearly identical in the two groups.394
52  Gulf War Illness and the Health of Gulf War Veterans

The long-anticipated results of this important study thus indicated that, overall, the health of spouses of

Gulf War veterans was similar to that of spouses of veterans who did not serve in the Gulf War. These

results are reassuring, in some measure. But additional information is needed before the question of Gulf

War illness, or other health problems in family members, can be laid to rest. As with Gulf War veterans,

the most prominent remaining questions about the health of veterans’ family members relate to

undiagnosed symptoms and symptom complexes. Specifically, are symptoms or groups of symptoms

more common in spouses of Gulf War veterans than nondeployed veterans? Are higher rates of

symptoms or diagnosed conditions experienced by spouses of veterans with Gulf War illness? And are

any health problems in veterans’ spouses associated with characteristics of veterans’ service in the Gulf

War, such as veterans’ locations, experiences, or exposures in theater? The majority of these questions

should be answerable using data already collected for the Phase III study.

Phase III of the U.S. national study also included clinical examinations of children of Gulf War and

nondeployed era veterans. Results have not yet been reported, but are of great interest and importance.

Reported information should include rates of symptoms and symptom complexes in veterans’ children, as

well as comprehensive information on diagnosed medical and behavioral conditions. Comparisons

should also be made between health outcomes in children of veteran subgroups of interest, as described

previously. The Committee urges investigators to complete and publish results of the children’s

evaluations, as well as additional results from the spouses’ evaluations, as soon as possible.
Special Committee and Government Reports  53

Special Committee and Government Reports

on the Health of Gulf War Veterans

In the seventeen years since Desert Storm, numerous government committees and specially-appointed

expert panels have been assembled to investigate the health problems affecting Gulf War veterans and/or

the government’s response to these problems. Relatively few scientific studies were available to inform

the conclusions of early panels. Their reports routinely called for more research, specifically

epidemiologic studies, to better characterize the health of Gulf War veterans. As described throughout

the present report, many studies of the types recommended by previous panels have now been completed,

allowing a more comprehensive evaluation of Gulf War-related health issues.

In 1994, the Defense Science Board Task Force on Persian Gulf War Health Effects reported that

“veterans in the hundreds have complained of a range of symptoms not yet explained by any clear-cut

diagnosis” and indicated that research was needed to determine if these complaints were precipitated by

service in Desert Storm.1595 In the same year, a panel convened at the National Institutes of Health

recommended that comprehensive epidemiologic studies be undertaken to better characterize health

problems affecting Gulf War veterans and their causes.1121 The Senate Banking Committee also issued

reports in 1994 that detailed their investigations of chemical exposures in the Gulf War and unexplained

health problems affecting veterans and their families. This report also called for in-depth epidemiologic

investigations to determine the nature and causes of veterans’ conditions.1688

The Presidential Advisory Committee on Gulf War Veterans’ Illnesses, a panel of scientists and veterans

appointed by President Clinton, issued reports in 1996 and 1997 that recommended additional research to

characterize veterans’ health problems. The panel indicated that research was needed on effects of

individual and combined chemical exposures, and physical responses to stress.1227 Similarly, reports

issued by the Institute of Medicine (IOM) during this period called for additional research focused on

priority questions about the health of Gulf War veterans and emphasized the importance of coordinating

data collection efforts between the federal agencies involved in this effort.675,676

Perception of Gulf War veterans’ unexplained health problems and federal efforts to address them

changed markedly when DOD announced, in 1996, that demolition of Iraqi munitions caches at

Khamisiyah, Iraq, in March of 1991 had potentially exposed thousands of U.S. troops to low levels of the

nerve agents sarin and cyclosarin. The Department of Defense established the Office of the Special

Assistant for Gulf War Illnesses (OSAGWI), which initiated an extensive series of investigations, and

commissioned the RAND Corporation to provide scientific reports on specific topics of concern. Special

House and Senate committees undertook investigations and issued comprehensive reports detailing their

findings.1684,1690 Federal research conferences were held to highlight emerging results from scientific

studies on the health of Gulf War veterans. At the direction of Congress, the U.S. General Accounting

Office (GAO) investigated diverse Gulf War health and programmatic issues, issuing multiple reports that

evaluated the status of the federal response and gaps that had not been adequately addressed. A second

committee, the Presidential Special Oversight Board (PSOB) for Department of Defense Investigations of

Chemical and Biological Incidents, was appointed by President Clinton in 1998. The PSOB issued its

final report in 2000, providing general support for DOD’s investigations of exposures during the Gulf

War, but again calling for additional scientific research to better characterize the relationship of toxic

exposures to Gulf War illness.1232

The Institute of Medicine’s Gulf War and Health reports. In 1998, with few conclusive answers

to continuing questions about Gulf War illness and the federal response to this problem, Congress

directed VA to contract with the National Academy of Sciences (NAS) to review available research in

order to assist the Secretary of Veterans Affairs in making decisions about Gulf War-related disability

compensation. Public Laws 105-277 and 105-3681242,1243 directed that this review identify conditions that
54  Gulf War Illness and the Health of Gulf War Veterans

affect Gulf War veterans at excess rates and assess the scientific evidence concerning associations

between those conditions and a detailed list of Gulf War exposures. In response, VA commissioned the

Institute of Medicine (IOM), of the National Academies, to conduct a series of reviews using a

methodology previously established to evaluate diseases affecting Vietnam veterans in relation to Agent

Orange.663 To date, the resulting Gulf War and Health series has included nine reports, including two

updated reports, and provided hundreds of conclusions.177,679,682-689,1740 The Committee was concerned to

find that the IOM reviews were not conducted in accordance with the laws that mandated them. As a

result, the Gulf War and Health reports have provided little information that is directly relevant to health

conditions that affect Gulf War veterans at excess rates, or their association with Gulf War exposures.

The 1998 legislation specifically directed that VA commission reviews that identify both diagnosed and

undiagnosed illnesses that affect Gulf War veterans at excess rates and, based on a comprehensive

consideration of available research, determine whether there is evidence that those illnesses are associated

with Gulf War exposures or Gulf War service. However, the health conditions considered in the IOM

Gulf War and Health reports have primarily included multiple types of cancer and a number of other

diagnosed diseases—conditions for which there are no indications that Gulf War veterans have been

affected at excess rates. In contrast, the IOM reports have provided almost no information on conditions

that do occur at excess rates in Gulf War veterans. That is, the Gulf War and Health reports have not

provided findings on possible associations between Gulf War illness or ALS and most Gulf War

exposures. Nor do they provide findings on conditions like migraines and seizures, which preliminary

information suggests may affect Gulf War veterans at excess rates, in relation to Gulf War exposures.

The legislation also directed that determinations be based on scientific evidence provided by both human

and animal studies. Most studies that evaluate biological effects of hazardous exposures are done in

animals, for ethical reasons. In recent years, a large number of animal studies have identified biological

effects of Gulf War exposures and combinations of exposures that were previously unknown. Although

animal research was sometimes described in the IOM reports, findings from animal studies were not

considered in drawing conclusions about the evidence that Gulf War exposures were associated with

health outcomes. Unlike IOM’s earlier Agent Orange reports, the standards used to determine levels of

evidence for the Gulf War and Health reports were expressly limited to consideration of results from

human studies.137,678,679 The omission of animal studies was especially striking in IOM’s updated report

on sarin, which had been requested by the Secretary of Veterans Affairs in 2003 specifically because of

new research in animals that demonstrated adverse effects of low-level sarin exposure.683,1641

A very limited number of exposure-disease associations have been identified in the IOM reviews. For

example, in Volume 3 of the series, the IOM panel concluded that there is sufficient evidence to indicate

that lung cancer is associated with petroleum combustion products.684 Findings of this type might

potentially be relevant to the health of Gulf War veterans in future years. But there has been no indication

that lung cancer, or the vast majority of conditions considered in the IOM Gulf War and Health reports,

have affected Gulf War veterans at excess rates. The hundreds of findings provided in the IOM reports

are largely inconclusive, indicating that there is insufficient evidence to determine if the diseases

considered are associated with the exposures considered, based on the types of studies considered.

The specific information included in the Gulf War and Health reports is also problematic, in that it

appears to reflect a process of reporting selected results from subgroups of studies, rather than integrating

and analyzing results from all available research. This is a pervasive problem, but several examples are

illustrative. A very prominent example relates to the limited or complete lack of consideration, in all Gulf

War and Health reports, of results from the many epidemiologic studies that have assessed associations

between Gulf War exposures and Gulf War multisymptom illness. Another straightforward example

comes from Volume 4, which reported the rate of multisymptom illness in Gulf War veterans from just

one study, as opposed to the seven studies identified by the present report. The one Gulf War illness

prevalence estimate provided was atypical, and substantially lower than all other studies.686 An additional
Special Committee and Government Reports  55

example relates to a highly publicized finding that, although Gulf War veterans have multiple excess

symptoms, there is no unique Gulf War syndrome.232,686 This conclusion was based solely on several

studies that had unsuccessfully attempted to identify a unique syndrome using factor analysis and a

related statistical technique, as previously described. The finding did not consider basic questions about

whether the statistical techniques were capable of identifying syndromes—unique or otherwise.

Unfortunately, this conclusion was widely misinterpreted in media reports to indicate that there was no

widespread problem associated with multisymptom illness in Gulf War veterans.

In short, IOM’s Gulf War and Health series of reports have been skewed and limited by a restrictive

approach to the scientific tasks mandated by Congress, an approach directed by VA in commissioning the

reports. These limitations are most notably reflected in the selective types of information reviewed and

the lack of in-depth analysis of the research literature and scientific questions associated with the health of

Gulf War veterans. There is a fundamental disconnect between the Congressional directive to VA and

VA’s charge to IOM for reviewing evidence on Gulf War exposures and their association with illnesses

affecting Gulf War veterans. The reports have particularly fallen short in advancing understanding of

associations between Gulf War exposures and Gulf War illness, the most prominent health issue affecting

Gulf War veterans.
56  Gulf War Illness and the Health of Gulf War Veterans

Recommendations

Despite the brief duration and successful execution of the 1990-1991 Gulf War, 25-32 percent of Gulf

War veterans developed the chronic multisymptom condition known as Gulf War illness as a consequence

of their Gulf War service. Longitudinal studies indicate that few veterans with Gulf War illness have

recovered or significantly improved with time. The Committee gives highest priority to research focused

on identifying effective treatments for Gulf War illness. This research should include:

 Studies that identify and systematically evaluate the effectiveness of currently available treatments

used for Gulf War illness or conditions with similarities to Gulf War illness. Preliminary research

should include pilot trials and/or observational studies capable of identifying promising treatments

suitable for evaluation in larger clinical trials.

 Research to identify specific pathophysiological mechanisms underlying Gulf War illness that are

potentially amenable to treatment interventions.

 Research to evaluate novel therapies based on scientific findings as they emerge.

The Committee considers the information provided by VA’s national longitudinal study of Gulf War

veterans and continued monitoring of the health of Gulf War veterans over time to be extremely important

and recommends that VA:

 Make results from the national longitudinal study of Gulf War veterans publicly available at the

earliest possible time, including comprehensive findings related to multisymptom illness, treatments

and practices used by veterans to address their symptoms, and rates of medical diagnoses. Results

should include outcomes assessed according to the guidelines for epidemiologic research provided

below.

 Continue to monitor health and disease outcomes among veterans assessed in the National Survey of

Gulf War Era Veterans and Their Families, conducting longitudinal surveys and appropriate clinical

follow-up studies at five year intervals.

Although it is the most prevalent health problem affecting Gulf War veterans, Gulf War illness is just one

of a number of important Gulf War health issues. To provide needed information on other health issues

of concern for Gulf War veterans, the Committee recommends the following research:

 Epidemiologic research to identify rates of diagnosed neurological diseases (including multiple

sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and brain cancers), as well as central

nervous system abnormalities that are difficult to precisely diagnose, in Gulf War veterans and

appropriate comparison groups.

 Completion of current research comparing cancer rates in Gulf War and nondeployed era veterans,

and repeated assessment of cancer rates in Gulf War era veterans at regular intervals.

 Provide current information on overall and cause-specific mortality rates in Gulf War veterans, and

update this information, at minimum, at five year intervals. This should include information on

mortality in subgroups of Gulf War veterans identified by deployment locations, branch of service,

and exposures reported in the National Survey of Gulf War-era Veterans and Their Families.
Recommendations  57

 Further evaluate indications of possible increased risk of specific types of birth defects, and other

health problems in children of Gulf War veterans, using innovative study designs.

 That VA make available comprehensive information on family members of Gulf War veterans

from the national study of Gulf War era veterans and family members. This should include

information on diagnosed conditions, multisymptom illness, behavioral problems, and birth

defects. Health parameters should also be assessed in subgroups of interest, such as family

members of veterans with/without Gulf War illness, and subgroups defined by Gulf War exposures

and other characteristics of veterans’ wartime service.

Because of shortcomings and limitations in many epidemiologic studies of Gulf War veterans, the

Committee recommends the following principles for collecting and analyzing data on Gulf War illness

and the health of Gulf War veterans in ongoing and future studies and, where indicated, for reanalyzing

data in studies already completed.

 Studies of Gulf War veterans should use well-constructed and clearly-described case definitions for

Gulf War illness and illness subgroups. Pending more widespread acceptance of an established

case definition, preferred case definitions are those that most clearly distinguish the pattern of

symptoms in Gulf War veterans from those in nondeployed era veterans, such as the Kansas Gulf

War illness case definition.

 In addition to general comparisons between Gulf War and nondeployed veterans, Gulf War

research studies should analyze results in relation to Gulf War veteran subgroups of interest,

including ill vs. well veterans and subgroups defined according to veterans’ locations in theater,

exposures, and other military and deployment characteristics potentially relevant to the outcomes

evaluated.

 Associations between deployment-related exposures and health outcomes in Gulf War veterans

should be evaluated using analytic methods that appropriately control for the effects of

confounding introduced by multiple exposures during deployment.

The Department of Veterans Affairs has not adhered to requirements set forth by Congress in

commissioning the Gulf War and Health series of reports produced by the Institute of Medicine. As a

result, these reports have not addressed fundamental questions regarding Gulf War-related health

conditions and their relation to Gulf War exposures. The Committee therefore recommends:

 That VA, in commissioning reports mandated by Congress in PL 105-277 and 105-368,

substantially change the approach designated for reviewing scientific information and preparing the

reports. As directed by Congress, these reports should address both diagnosed and undiagnosed

illnesses affecting Gulf War veterans. Conclusions should be based on findings from the full range

of Gulf War epidemiologic studies, animal studies, and other research that provides information on

effects of Gulf War-related exposures.

 That VA contract with the Institute of Medicine to redo previously completed Gulf War and Health

reports to adhere to requirements set forth by Congress.

 That responsibility for contracting reports mandated by PL 105-277 and PL 105-368 be reassigned

from VA’s Office of Public Health and Environmental Hazards to another office within VA, to be

designated by the Secretary.
58  Effects of Gulf War Experiences and Exposures

Operation Desert Storm:

Summary of the Offensive in the Four Day Ground War

U.S. Department of Defense
Effects of Gulf War Experiences and Exposures  59

2| What Caused Gulf War Illness?

Effects of Gulf War Experiences and Exposures

In addition to the many physical and psychological challenges that come with serving in a war zone,

military personnel in the 1990-1991 Gulf War encountered a unique mix of exposures during deployment.

These included a number of substances used for the first time by the military on a widespread basis—

pyridostigmine bromide pills given to protect troops from the effects of nerve agents, depleted uranium

munitions, and anthrax and botulinum toxoid vaccines. The oil and smoke that spewed for months from

hundreds of burning oil wells presented another exposure hazard not previously encountered in a war

zone. Military personnel also had to cope with teeming and biting insects, especially in the warmer

months, that required persistent environmental pest control measures and ample use of personal

pesticides. In some areas, troops frequently donned their chemical protective gear as chemical alarms

sounded again and again. Personnel were usually told the alarms were false and given the all clear, and

some units eventually turned off the alarms because they were thought to be malfunctioning. Years later,

the Department of Defense verified that chemical agents had been released in southeastern Iraq when U.S.

troops destroyed Iraqi weapons stored in a large compound, and launched multiple investigations into

other reported chemical incidents.

As an increasing number of reports of a mysterious Gulf War syndrome emerged in the months and years

after the war, many believed that veterans were suffering from effects of hazardous exposures they had

encountered during their deployment. Government officials and special committee reports maintained

that there was little evidence that this was the case, and suggested that veterans’ symptoms could be due

to the stress of deployment. In the first years after the war, scientific committees and government panels

attempted to investigate veterans’ unexplained health problems, but there were few facts to go on. Little

documentation was available about specific types and levels of exposures in theater, and relatively little

research had been done to evaluate veterans’ health problems.

Now, 17 years after the war, the situation is markedly different. Although there are relatively few data

from real time exposure measurements taken during the war, federal agencies have worked to provide

information on likely exposure patterns and levels using a variety of wide-ranging and innovative efforts.

For example, weather and satellite information has been used to determine daily patterns of wind

dispersion of smoke from oil well fires and chemical plumes resulting from weapons demolitions.

Sophisticated simulations have measured levels of depleted uranium that soldiers might have inhaled or

gotten on their skin if their vehicles had mistakenly been hit by friendly fire rounds containing depleted

uranium. Attempts have been made to gather immunization logs from units that administered anthrax

vaccine to their troops, but did not record the vaccine in soldiers’ individual shot records. As a result of

these efforts, a substantial amount of information is now available that provides important insights into

the types, levels, and patterns of exposures likely encountered by Gulf War military personnel during

deployment.

There is also an extensive body of epidemiologic research that makes it possible to identify patterns of

health problems in Gulf War veterans and to evaluate associations between veterans’ health and their

deployment experiences across a broad spectrum of studies. In addition, a large number of toxicological

studies have been conducted in recent years that provide insights concerning biological effects of

exposures associated with the Gulf War. These have yielded extensive information on effects of

exposures that had previously not been known, and effects of combinations of exposures that had never

before been looked at.
60  Effects of Gulf War Experiences and Exposures

The Committee used a standardized approach for evaluating available evidence related to psychological

stressors in theater and each of the other hazards of possible concern. Three major categories of evidence

were considered. First, the Committee reviewed what was 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 was known, in general, about health effects of each

exposure. This included consideration of effects of exposures identified in 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.

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 exposure patterns in theater and findings

from toxicological research, a coherent picture emerged about the most likely causes of Gulf War illness.
Psychological Stressors and the Health of Gulf War Veterans  61

Psychological Stressors and the Health of Gulf War Veterans

Major BK, a career Army pilot who had passed 15 flight physicals in the 11 years prior to

deployment to the Gulf War began to feel increasingly ill in April 1991 but dismissed the

symptoms as related to the harsh desert environment. On May 8 he reported ‘violent nausea,

vomiting, diarrhea attack.’ On May 28, now back in Germany, he was admitted to a military

hospital with ‘cardiac arrhythmias, severely bleeding gums, cough with sputum production,

shortness of breath, severe fatigue, diarrhea, hair loss, skin rashes/lesions, and abdominal

discomfort.’ Military doctors diagnosed Major BK with ‘post traumatic stress.’ With severe

brain, nerve, heart and gastrointestinal problems but still being diagnosed with ‘somatoform

disorder’ he was given a discharge from the Army.

--1997 Congressional report on Gulf War Army pilot1684

Since soon after the Gulf War, when reports of poorly understood symptoms and conditions in veterans

first became widely known, the most prominent controversy to emerge was whether these illnesses were

the result of psychological factors or hazardous exposures during deployment. In those early years,

opinion camps formed on both sides of the issue. Both sides relied to a large extent on assumptions and

conjecture to support their views, with little scientific data to settle the debate. This is no longer the case,

17 years after Desert Storm. Hundreds of studies have explored population patterns of veterans’ health

problems, and provided important insights concerning their biological and psychological correlates.

Commentators have pointed out that it is somewhat artificial, perhaps even harmful, to label Gulf War

illness as being one or the other—psychiatric or medical.404,405,654 This is an important consideration in

relation to any health problem, including Gulf War illness, with all that has been learned in recent decades

about biological aspects of psychiatric illness and psychological aspects of medical conditions.23 But the

question of the essential nature of Gulf War illness remains an important one for veterans, who want to

know why they are ill, for clinicians and researchers working to identify useful treatments, and for policy

makers tasked with preventing similar problems in the future.

The “mental or physical” quandary has played out both on a national level and in the lives of individual

veterans seeking care for Gulf War illness whose healthcare providers, lacking objective information from

diagnostic tests, find their condition difficult to diagnose and treat. A survey of clinicians at two VA

medical centers in the Pacific Northwest found that mental healthcare providers were more likely to

consider Gulf War illness to have resulted from a chemical or infectious exposure, whereas general

internal medicine clinicians more often considered Gulf War illness a “mental disorder” attributable to

psychological factors.1282 Consequently, mental health clinicians were more likely to support biological

treatments for veterans’ conditions, and medical providers more often favored psychological

interventions. This supports the general impression conveyed by veterans that clinicians, unable to

adequately diagnose or treat Gulf War illness using tools from their own armamentaria, are sometimes

inclined to attribute symptoms and conditions to realms outside their own areas of expertise. This

scenario leaves both veterans and their providers with more questions than answers, and provides no clear

basis for providing rational treatment options.

Similarly, on the national level in the 1990s, little scientific information was available to shed light on the

nature and causes of Gulf War illness. When no single cause or biological explanation was readily

apparent, those who developed research programs and healthcare policy for ill Gulf War veterans largely

focused on psychiatric issues, likely assuming that Gulf War illness was the result of deployment stress.

In the intervening years, however, numerous scientific studies have been conducted that, in aggregate,

provide insights regarding the nature and causes of Gulf War illness. Most prominently, this research

consistently indicates that Gulf War illness is not the result of psychological trauma or stressors during

the Gulf War. This information can be used to focus Gulf War illness-related policy and research

questions more precisely on the causes and biological mechanisms underlying Gulf War illness.
62  Effects of Gulf War Experiences and Exposures

The word “stress” is used in a variety of contexts and carries diverse meanings in both scientific and lay

usage. In its review of scientific studies and other available information concerning the health of Gulf

War veterans, the Committee thought it important to underscore the distinction between (1) psychological

stressors, that is, stressful experiences that occurred during deployment, versus (2) stress-related

disorders, that is, psychiatric diagnoses or other persistent health problems that may result from trauma or

other psychological stressors during deployment. This distinction between the concept of “stress” as a

challenging experience and “stress” as a health outcome is often not apparent to casual observers. It can

be illustrated by the observation that “stressful” experiences (more precisely, psychological stressors)

might lead to the development of psychiatric conditions such as posttraumatic stress disorder (PTSD), so

would be considered the “cause” for those conditions, whereas PTSD or other psychiatric conditions

would be considered the “result” of stressors. More simply put, “stress” may cause PTSD but it is not the

same thing as PTSD.

The Committee reviewed research findings related to both psychological stressors and psychiatric

disorders in Gulf War veterans. Evidence concerning the degree to which psychological stressors in

theater are associated with Gulf War illness was reviewed in the same way as evidence related to other

deployment-related exposures. In addition, research on psychiatric disorders in Gulf War veterans was

reviewed in the same way as other health outcomes such as Gulf War illness, asthma, or cancer.

The central question in the mental-versus-physical Gulf War illness debate is “Why are veterans ill?” In

reviewing the extensive amount of research conducted to address this question, the Committee has found

that, of the many complex issues associated with understanding Gulf War illness, the evidence that

informs the “mental or physical” debate is the most voluminous, the most consistent, and the most

straightforward to interpret.

SSG CK reported: ‘While still in the Gulf I began experiencing symptoms that continue to this

day. I had difficulty remembering significant events that happened days earlier... my knees

and shoulders were especially painful and fatigue stayed with me constantly.’ After the war,

his symptoms worsened and included intestinal problems and headaches. He sought

treatment in 1992 from VA doctors who—without any physical exam—referred him to the

mental health clinic where he was diagnosed ‘PTSD’. ‘I reported blinding headaches with only

offers of aspirin, I reported memory loss...dismissed as stress.’

--1997 Congressional report on Gulf War Army Reservist1684

Traumatic Experiences and Psychological Stressors in the Gulf War

There is considerable information concerning the types of psychological stressors experienced by Gulf

War veterans during the war. It is one of the few areas for which “exposure” data were collected during

deployment. In 1990 and 1991, a team from Walter Reed Army Institute of Research (WRAIR)

conducted interviews and surveys of personnel in combat units at different periods during deployment to

assess sources of psychological stress and the proportion of troops affected.966 Both qualitative and

quantitative data were collected from thousands of individuals in multiple precombat and post combat

interviews and surveys. Overall, investigators found that the morale of troops was good, and commitment

to the mission was high. In the early months of deployment, the most common stressors related to

disruption of individuals’ normal lives at home and adaptation to their living circumstances in theater.

The most frequently-cited stressors during this period were “not having the opposite sex around” (69%),

flies (54%), lack of family contact (46%), and lack of privacy (43%).966

Stressors reported by members of these combat units during the combat period were more typical of those

expected in war. The most frequently reported stressors during that time were seeing an enemy soldier

killed or wounded (60%), being attacked by enemy fire (43%), and having a buddy wounded in action

(30%). Having a buddy killed in action was considered the most extreme stressor for those who
Psychological Stressors and the Health of Gulf War Veterans  63

experienced it (9%). Data also indicated that personnel experienced much lower levels of combat-related

stress than they had anticipated prior to combat, owing largely to the short duration of the ground war and

the one-sided nature of the fighting. In fact, during interviews many personnel were said to have

expressed sympathy for their Iraqi prisoners, whose war fighting efforts had been so “utterly outclassed”

by the Americans.966 Unfortunately, these data did not allow assessment of whether stressors in theater

were associated with subsequent development of chronic multisymptom illness. But they did provide real

time data indicating that traumatic combat exposure put military personnel at increased risk for

developing PTSD.

Many epidemiologic studies have provided retrospective assessments of veteran-reported stressors during

deployment, ranging from severe trauma (e.g., witnessing deaths, sexual assault) to experiences that,

while stressful, would not ordinarily be considered traumatic (e.g., having a family problem during

deployment, uncertainty about the use of chemical weapons). Representative rates of veteran-reported

stressful experiences during deployment are provided in Table 1. Overall, about 30 percent of U.S. and

U.K. veterans report they had participated in combat. A higher proportion report hearing chemical alarms

sound or being in the vicinity of a SCUD missile, but only about 10 percent thought they had been

attacked by chemical weapons. Additional studies indicate that, overall, psychological stressors were

reported at lower rates in Navy and Air Force veterans than in samples that included all branches of

service.241,1124

Table 1. Psychological Stressors Reported by U.S. and U.K. Gulf War Veterans

U.S. National

Survey751

U.K. National

Survey1698

Heard chemical alarms 66 % 71 %

SCUD missile explosion within 1 mile 43 % 32 %

Participated in combat 27 % 32 %

Witnessed death 26 % 19 %

Experienced a chemical/nerve gas attack 10 % 9 %

Sexually assaulted 1 %

Health Effects of Psychological Stressors

It has long been observed that psychologically stressful experiences, most prominently those associated

with acute trauma or significant sustained distress, can lead to different types of health problems—

psychiatric illness, psychological symptoms, and biological changes that affect different bodily

systems.23,247,801 A 2000 report prepared by the RAND National Defense Research Institute for the

Department of Defense provided an excellent summary of the extensive research literature in this area,

with special attention to information available on Gulf War veterans at that time.969 Among other

findings, the report summarizes information indicating that stress-related symptoms and psychiatric

difficulties typically appear soon after the traumatic experience but can take longer, sometimes decades,

to emerge. Psychological problems related to time-limited stressful events are generally short-lived,

typically disappearing within six to 18 months, but can last longer in some individuals. The RAND report

concluded that a limited amount of evidence suggested a link between stressful exposures in theater and

PTSD in Gulf War veterans, with less evidence regarding other psychiatric disorders. The report also

indicated that few studies had directly assessed associations between stressful experiences in the Gulf
64  Effects of Gulf War Experiences and Exposures

War and the subsequent development of chronic somatic health problems. As a result, the report

concluded that “it is inappropriate to rely upon stress exposure as a default explanation for the myriad

health problems reported by Gulf War veterans” and that it is “equally inappropriate to assume that stress

played no role.”969

Animal studies evaluating the interaction of stress with Gulf War exposures. In the past

decade, concerns have been raised about the potential for psychological and/or physiological stressors to

have interacted with, and perhaps exacerbated, effects of chemical exposures encountered by Gulf War

veterans. Attention was drawn to this issue over a decade ago by research indicating that stress and

adrenergic stimulation increased the biological effects of pyridostigmine bromide (PB) in mice.227,460

Ethical considerations prohibit studies of the effects of most toxic exposures in humans, so nearly all

research on interactions between stress and Gulf War-related exposures has been done in animal models.

Results of these studies should be applied to the human situation with caution, however, due to limitations

in the comparability of war-related human stressors to stressors used in animal research. In humans, for

example, stressful experiences can be predominantly of a psychological (e.g., trauma, emotional

challenge, mental stress) or physical nature (e.g. physical exertion, extreme temperatures) but in animals

this distinction is often not possible.

Stress and the effects of pyridostigmine bromide. In 1996, a study conducted by Israeli investigators

reported that mice subjected to an intense stressor, forced swimming, had a strikingly enhanced brain

response to PB compared to unstressed mice.460 Under normal conditions it was generally believed that

PB does not cross the blood brain barrier and very high doses are required to affect a marked decrease in

brain acetylcholinesterase (AChE) activity. But this study reported that in stressed mice, just one one

hundredth the dose of PB was required to cause a 50 percent reduction in brain AChE activity, compared

to unstressed mice. Researchers suggested that stressful conditions may have allowed PB to cross the

blood brain barrier.

This unexpected finding raised a great deal of attention and concern, prompting additional research

related to the potential for stress to alter effects of PB and other Gulf War-related exposures. The largest

number of studies were done to evaluate the hypothesis raised by the Israeli study, that is, that stress

enhances central nervous system effects of PB. Multiple studies failed to support the Israeli study,

finding that stressors of various types and intensities did not cause PB to cross the blood brain barrier or

reduce AChE activity in the brain.519,857,1394,1414,1444,1539

Other studies that addressed different questions related to specific chemical or regional responses, have

found that stress may interact with PB in causing central nervous system effects. Studies from the East

Orange, New Jersey, VAMC found that stressed rats treated with PB had significantly reduced levels of

AChE activity in the basal forebrain and striatum but not in other brain regions.115,116 A 2005 study from

France reported that a combination of stressors led to elevated levels of circulating glucocorticoids and

associated increases in serotonin (5-HT) in several regions of the brain. Concurrent administration of PB

at dosages similar to those used in the Gulf War resulted in increased levels of the serotonin metabolite 5-

HIAA in additional brain regions, as well as increased dopamine levels in the striatum/hippocampus.1528

In addition, researchers from Wright State University School of Medicine demonstrated a significant

interactive effect between PB and stress on autonomic function, as reflected in enhanced heart rate

variability and baroreflex sensitivity.714 The combination of low-dose PB and exercise stress has also

been shown to decrease plasma levels of butyrylcholinesterase (BChE) and muscle AChE levels, and to

increase indicators of oxidative stress in peripheral muscle.658,703,1442

Interaction of stress with multiple combined exposures. Studies evaluating the effects of stress in

combination with two or more Gulf War-related exposures of potential concern, including PB, have

consistently found this combination to have greater effects than either stress or chemicals alone.
Psychological Stressors and the Health of Gulf War Veterans  65

Neurotoxicologists at Duke University have conducted extensive research evaluating interactive effects of

Gulf War-related exposures using protocols designed to parallel levels actually encountered by Gulf War

veterans in theater, in the presence and absence of stress. This has included studies of the combined

effects of low-level exposures to PB, permethrin, and DEET together—both with and without concurrent

exposure to a moderate level of restraint stress. Results indicated that combined exposure to PB, DEET,

and permethrin, in combination with stress, produced disruption of the blood brain barrier and neuronal

cell death in four specific brain regions—the cingulate cortex, the dentate gyrus, the thalamus, and the

hypothalamus.6 The combination of chemicals plus stress also produced reduced AChE activity in the

forebrain. These effects were not observed with either stress or low-dose chemicals alone. A second

report indicated that, in areas of the brain where there was no apparent disruption of the blood brain

barrier, AChE activity was decreased in the midbrain, brainstem, and cerebellum. Significant neuronal

cell death and evidence of glial cell activation were also observed in the cerebral cortex and hippocampus.

Again, these changes were observed only following combined exposure to stress and low-level exposure

to the three chemicals, and not as a result of stress or chemicals alone.3

Studies from Southern Illinois University have reported that exercise stress, when combined with both PB

and low-dose sarin, reduced levels of neurotoxic esterase (NTE), an enzyme that metabolizes neurotoxic

chemicals) in the cerebral cortex, spinal cord, and sciatic nerve. This combination was also found to

increase lipid peroxidation and reduce AChE activity in skeletal muscle.658

A limited number of studies have evaluated the potential for other types of Gulf War exposures to interact

with stress-related changes in animal models. A recent study from Great Britain demonstrated that

differing combinations of vaccines and PB did not produce peripheral indicators of an enhanced stress

response or impaired immune function.632 A study from the Boston University School of Medicine,

however, suggested that if PB and vaccines do interact with stress, the effects may more likely be

observed in the brain than in peripheral immune parameters. The Boston study found that production of

stress-activated kinases in the mouse brain was significantly enhanced and prolonged by immunization

with KLH, a vaccine analog, and that these effects were further enhanced by PB.1752 Researchers

concluded that the combined effects of stress, vaccines, and PB may produce neuroinflammatory damage

in the brain.

There is little indication that stress potentiates effects of depleted uranium or exposure to

organophosphate pesticides.727 Multiple studies have reported that stress does not enhance effects of

depleted uranium (DU) on the brain or on reproduction.35,97,98,125,906,1343 On the contrary, research

conducted at the University of Florida suggested that stress may increase clearance of DU from the

brain, thereby ameliorating its effects.97-99 Studies have also demonstrated no, or only limited

interactive effects between various stressors and organophosphate insecticides in animal

models.576,728,1244,1393

Human studies: Stress and Gulf War-related chemical exposures. Several studies have

evaluated effects of stress, in combination with relatively low doses of Gulf War-related exposures, in

humans. Reports on American and Israeli soldiers who used PB during the Gulf War indicated that side

effects were greater than had been predicted by clinical studies, and hypothesized that taking PB during

wartime, under stressful conditions, may enhance PB’s potential to cause biological side effects.781,1396

Clinical studies involving healthy subjects had not found heat stress or physical exercise to exacerbate

symptoms or significantly alter physiological or cognitive performance in relation to PB.53,411,1386 More

recently, a clinical trial demonstrated that one hour stress sessions that included both exercise and mental

stressors had minimal or no effects on physical and cognitive performance following exposure to

permethrin, DEET, and PB. Chemical exposures occurred over a 24 hour period, at dosages similar to

those currently directed by military policy.1323 Plasma PB levels were found to be significantly elevated

during and immediately after stress sessions, but were comparable to unstressed subjects within three

hours.
66  Effects of Gulf War Experiences and Exposures

Taken together, human and animal studies indicate that extreme and/or sustained stressful experiences can

precipitate short term somatic health problems as well as sustained psychiatric illness. There is no

evidence indicating whether more moderate stressors, of limited duration, is associated with the

development of the types of symptom complexes associated with Gulf War illness, particularly symptoms

that persist for an extended period—17 years—after cessation of the stressful experience. Questions also

remain concerning the potential for stressors in theater to have altered or amplified the biological effects

of some chemical exposures encountered in the Gulf War. Early suggestions that stress allows PB to

enter the brain through a general disruption of the blood brain barrier have not been supported, but more

recent studies have suggested that stress may exacerbate effects of PB in more delineated ways, for

example, enhancing its effects on autonomic regulation. Animal studies have also demonstrated

biological effects resulting from stress in conjunction with combined chemical exposures—effects that

exceed those of chemicals or stress alone. Human studies that have evaluated effects of stress in relation

to low-level exposure to PB, permethrin, and DEET for short periods have found no significant effects on

cognitive or physical performance.

The Gulf War involved a complex mix of extreme and less extreme stressors of relatively short duration,

in combination with diverse chemical exposures in a unique environment. Neither general studies from

human populations nor animal studies provide evidence that can specifically determine whether

psychological stressors experienced during the Gulf War are responsible for the types of chronic symptom

complexes that constitute Gulf War illness. As with other wartime exposures, it is important not to

assume that because psychological stressors might have adverse health effects that they actually did so in

a large proportion of Gulf War veterans and are responsible for Gulf War illness. A more complete

understanding of the connection between Gulf War-related stressors and the health of Gulf War veterans

requires consideration of the many studies of Gulf War veterans that have specifically evaluated this

relationship.

Research on the Health of Gulf War Veterans in Relation to Psychological Stressors

Symptoms, symptom complexes, and Gulf War multisymptom illness. As detailed in

Appendix A-8, a large number of epidemiologic studies have provided information on many different

types of psychological stressors that Gulf War veterans experienced in theater, and the degree to which

those stressors are associated with chronic symptoms and multisymptom illness. Similar to other

exposure-illness assessments, many of these studies provided results only from preliminary analyses, that

is, analyses that did not consider confounding effects of other exposures during deployment. The most

valid and informative results were provided by studies that determined independent associations between

stressful experiences and health outcomes, while controlling for effects of other deployment-related

exposures.

As shown in Appendix A-8, results of preliminary analyses frequently indicated that psychologically

stressful experiences in theater were associated with increased rates of chronic symptomatic illness. In

these analyses, symptomatic illness was associated with a variety of extreme and less extreme

psychological stressors, for example, being sexually assaulted during deployment,752 seeing someone

killed or dismembered,527,1264 coming under fire1124,1264,1507,1698 and reports of family problems back

home.1124

In contrast, when analyses controlled for effects of other exposures during deployment, studies

consistently found that psychological stressors were not significantly associated with Gulf War illness.

Diverse stress-related variables assessed in six different Gulf War veteran populations, were consistently

not identified as significant risk factors for Gulf War illness, when effects of other exposures were

considered. This included extreme stressors, such as being in combat or seeing dead bodies,241,527,1124
Psychological Stressors and the Health of Gulf War Veterans  67

Table 2. Participation in Combat as a Risk Factor for Chronic Symptoms

and Multisymptom illness in Gulf War Veterans

Study Sample Combat Association Evaluated

Unadjusted

Association

Association Adjusted

For Other Exposures

Cherry241

2001

7,971 U.K.

Gulf War vets

Correlation of combat with seven

symptom domains, overall

symptom severity, peripheral

neuropathy, widespread pain

Not reported None significant

Gray527

2002

3,831 Navy

Seabees

Combat as a risk factor for studydefined Gulf War illnessOR = 2.6* Not significant

Nisenbaum1124

2000

1,002 Air

Force vets

Combat duty in relation to severe

or mild-moderate CMI

Coming under attack in relation to

severe or mild-moderate CMI

Not significant

OR (severe) = 2.4*

OR (mild-moderate) = 1.1

Not significant

OR (severe) = 1.2

OR (mild-moderate) = 0.7

Abbreviations: OR = odds ratio, CMI = chronic multisymptom illness464

* = statistically significant

and less acute stressors, such as having family problems during deployment.1124 Only one stress related

variable in one study was significantly associated with Gulf War illness after controlling for effects of

other wartime exposures. The large study of Navy Seabees used two different modeling approaches to

assess associations between stressors and Gulf War illness. “Seeing someone killed” was reported to be

modestly associated with Gulf War illness (OR = 1.6) in one model but not the other.527

Although not listed as a “psychological stressor” in Appendix A-8, several studies indicated that variables

related to chemical weapons exposures were significantly associated with multisymptom illness, after

controlling for effects of other exposures.564,1124,1239 As will be described in detail in a later section,

chemical alarms and other indicators of possible chemical weapons exposures were fairly common during

the Gulf War. There are many uncertainties, however, related to who was actually exposed to low levels

of chemical agents and where. Veterans’ ability to know whether or not they had been exposed to

chemical weapons is especially problematic. Reported associations between Gulf War illness and

veteran-reported chemical weapons exposures might reflect effects of psychological stress, chemical

exposure, both, or neither. It is not possible to disentangle psychological effects related to concern about

chemical exposures from physical effects that might relate to actual exposure. Associations between Gulf

War illness and variables associated with chemical weapons exposures are therefore summarized

separately, in Appendix A-2, and considered in a later section of the report.

A consistent, but somewhat unexpected, finding is that serving in combat is not identified as a significant

risk factor for Gulf War illness, when effects of deployment exposures are considered. As shown in

Table 2, Gulf War veterans who report being in combat or coming under enemy attack during deployment

did not have elevated rates of chronic symptoms or multisymptom illness in any of the studies that

adjusted for effects of multiple exposures in theater.241,527,1124 Further, many studies that reported

unadjusted results, which typically over-identified exposure risk, also found no link between serving in

combat and multisymptom illness.161,564,697,752,1124,1802 The consistency of this finding across multiple

studies of different veteran populations, particularly studies that controlled for confounding by multiple

exposures, provides strong evidence that serving in combat during the Gulf War was not a cause of Gulf

War illness. This is an important observation, since interviews with Gulf War veterans during

deployment and after their return from theater indicate that combat-related events were their most

stressful experiences.966,969
68  Effects of Gulf War Experiences and Exposures

The lack of association between combat and multisymptom illness parallels general findings from the

broader range of studies of psychological stressors in theater. Taken together, these studies consistently

indicate that psychological stressors during deployment were not risk factors for Gulf War illness.

Possible exceptions may include veterans who were sexually assaulted during deployment. This severe

stressor was associated with a high risk (OR = 8.3) for a unique symptom complex in one study750 but was

not evaluated in adjusted analyses. In addition, one study reported that seeing someone killed in theater

was mildly associated with Gulf War illness using one modeling method, but not another. 527

Results from these studies also provide an excellent example of how epidemiologic studies that do not

adequately account for effects of multiple exposures during deployment routinely misidentify risk factors

for Gulf War illness. This is well illustrated by the apparent association of Gulf War illness with several

psychological stressors in studies that did not consider effects of other exposures, as opposed to consistent

findings that psychological stressors are not risk factors for Gulf War illness in studies that did adjust for

effects of other exposures. As previously described, studies have consistently found that Gulf Warrelated exposures are highly correlated with one another and cluster in groups.161,241,458,1466 These data

suggest that some personnel who experienced the most extreme levels of psychological stressors during

the war (e.g., being in combat, seeing casualties, witnessing deaths) would also have more frequently had

other exposures that were most prominent in combat areas such as the use of pyridostigmine bromide,

smoke from oil well fires, and spent depleted uranium munitions.

Psychiatric conditions in relation to psychological stressors in theater. In addition to Gulf

War illness, a limited number of diagnosed conditions have been associated with service in the 1990-1991

Gulf War. Psychiatric conditions have been evaluated in more studies of Gulf War veterans than any

other type of diagnosis.969,1488 These studies have consistently found that veterans who served in the Gulf

War have higher rates of psychiatric conditions, prominently posttraumatic stress disorder (PTSD), than

era veterans who did not serve in the war. The Gulf War, although brief, was like other hostile

deployments in a number of important respects. Hard fought battles resulted in casualties, death, and

trauma for some American soldiers in the war zone. Some troops returned from Desert Storm with

psychological wounds that are slow to heal. The actual and expected consequence of the Gulf War, as

with other wars, is that returning veterans have higher rates of psychiatric conditions than veterans who

did not serve in war. But it might also be expected that, given the short duration and decisive victory of

the 1991 Gulf War, rates of psychiatric conditions in Gulf War veterans would be lower than rates found

after other wars.

In contrast to the lack of association between Gulf War illness and psychological stressors in theater,

studies have consistently found that Gulf War veterans who experienced more extreme stressors during

deployment have higher rates of PTSD.80,501,746,753,855,1195,1456,1480,1729 For example, a report on a small

cohort of Gulf War veterans referred for psychiatric evaluation as part of the CCEP indicated that

veterans who reported combat-related stressors (direct combat, wounded in action, witnessed casualties,

witnessed SCUD attacks, chemical alarms) were significantly more likely to be diagnosed with PTSD

than those who did not.855 Similarly, personnel tasked with grave registration duty during the war were

found to have an extremely high rate of PTSD (48%) six months after their return.1519,1520 The rate of

PTSD was also extremely high (49%) among Gulf War veterans who reported being sexually assaulted

during deployment.746

In more representative samples, findings from both the U.S. National Survey of Gulf War era veterans

and the Iowa Gulf War study indicate that veterans who participated in combat were significantly more

likely to have PTSD than those who were not in combat.103,746,753 There is also evidence of a doseresponse effect between wartime stressors and the development of PTSD. This includes findings from a

large study of Australian Gulf War veterans indicating that military personnel who experienced

intermediate levels of deployment stressors had four times the rate of PTSD of veterans with minimal

deployment stress, and those with the highest level of stressors had 14 times the rate of PTSD.674
Psychological Stressors and the Health of Gulf War Veterans  69

Table 3. Prevalence of Clinically Diagnosed Post Traumatic Stress Disorder

in Gulf War and Nondeployed Gulf War Era Veterans

PTSD Prevalence

Study Sample PTSD Measure

Gulf War

Veterans

Nondeployed

Veterans

Population-based samples

Blanchard142

Toomey1548

2,189 U.S. vets CIDI

CAPS

3.3 %

6.2 %

2.0 %

1.1 %

Ikin674 2,758 Australian vets CIDI 5.1 % 1.7 %

Wolfe1803 252 U.S. Army vets CAPS, SCID 5.4, 7.2 % 0 %

Gulf War Registries

Engel408 21,232 U.S. vets in CCEP Clinical diagnosis 5.6 %

VA1651 70,385 U.S. vets in VA Registry Clinical diagnosis 3.8 %

Lee879 3,233 in U.K. MAP Clinical diagnosis 12.0 %

Abbreviations: CCEP = DOD Comprehensive Clinical Evaluation Program, MAP = British Medical Assessment Program, CIDI =

Composite International Diagnostic Interview, CAPS = Clinical Assessment of PTSD, SCID = Structured Clinical Interview for DSM-III-R

Findings from the U.S. national survey indicate that PTSD rates in Gulf War era veterans increased across

six levels of stressor intensity, ranging from three percent among veterans with little or no deploymentrelated stress, to 22 percent among veterans who reported the greatest number of combat-related

stressors.753

How many Gulf War veterans have PTSD? Rates of PTSD have been assessed in multiple studies

of Gulf War veterans. Overall, identified PTSD rates are generally below 10 percent in population-based

samples of Gulf War veterans but are somewhat variable, with differences related to the type of PTSD

assessment done and the measures used.969 Table 3 summarizes results of studies that have assessed

PTSD using clinical evaluations, the preferred and most reliable method of diagnosing PTSD.688 As

shown, estimates of PTSD prevalence among Gulf War veterans who were clinically evaluated are

surprisingly consistent. In U.S. Registry and two population-based samples that included all service

branches, PTSD rates in clinically-evaluated veterans range from 3.3 to 6.2 percent, with modestly higher

rates (5.4%, 7.2 %) in two small cohorts of Army Gulf War veterans.1803 The prevalence of PTSD in

veterans participating in Gulf War registries would normally be expected to exceed rates from population

studies of Gulf War veterans, since most veterans who request evaluation in Gulf War registries have

health concerns. This was not the case in the U.S. CCEP but may explain, in part, why the rate of

diagnosed PTSD in the U.K. Ministry of Defence’s registry, the Medical Assessment Program (MAP),

was higher than in any other clinically evaluated sample of Gulf War veterans.879

Because clinical evaluation was not practical in most of the large Gulf War epidemiologic studies, PTSD

prevalence was typically estimated using screening instruments that rely on symptom checklists. As

shown in Table 4, PTSD estimates from these studies were more variable, yielding both higher and lower

rates than clinically evaluated samples. The variability in PTSD rates reflected in the table appears to

result, in part, from the methods and instruments used. For example, when the PTSD Checklist was used

in the U.S. National Survey of Gulf War era veterans the estimated PTSD rate of 10.1 percent753 was

three times higher than the 3.3 percent rate obtained when a subset of those veterans was clinically
70  Effects of Gulf War Experiences and Exposures

Table 4. Prevalence of Post Traumatic Stress Disorder Assessed by Questionnaire

in Population Studies of Gulf War and Nondeployed Gulf War Era Veterans

PTSD Prevalence

Study Sample PTSD Measure/cutoff

Gulf War

Veterans

Nondeployed

Veterans

Barrett103 3,695 Iowa vets PTSD Checklist > 50 1.9 % 0.8 %

Goss Gilroy511 6,552 Canadian vets PTSD symptoms 2.1 % 0.6 %

Fiedler436 1,767 U.S. vets CIDI (telephone interview) 3.4 % 0.9 %

Holmes620 1,090 vets in Air Guard unit Mississippi Scale > 89 6.8 % 1.7 %

McKenzie1003 2,791 Australian vets PTSD Checklist > 50 7.9 % 4.6 %

Stretch1503 4,334 PA, HI vets WRAIR algorithm 8.6 % 1.6 %

Kang753 20,917 U.S. vets PTSD Checklist > 50 10.1 % 4.9 %

Unwin1698 5,177 U.K. vets Selected questions from

Mississippi Scale

13.2 % 4.1 %

Abbreviations: Mississippi Scale = Mississippi Scale for Combat-Related PTSD, CIDI = Composite International Diagnostic Interview,

WRAIR = Walter Reed Army Institute of Research algorithm for determining PTSD

evaluated.142 Similarly, the large population survey of British Gulf War veterans estimated PTSD

prevalence at 13.2 percent1698 based on questions selected from the Mississippi Scale. Later clinical

evaluation of a subset of those veterans, however, identified a PTSD rate of only three percent in the most

disabled subgroup and one percent in Gulf War veterans that were not disabled.699

It is important to point out, in this regard, that the validity of using screening tests such as the Mississippi

Scale for PTSD and PTSD Checklist to identify PTSD rates in Gulf War veterans has been

questioned.553,688 A number of symptoms included in these instruments, such as sleep disturbances and

memory problems, parallel symptoms associated with Gulf War illness. The number of PTSD cases

identified using these checklists depends on the cut-off score used by investigators.1805 Cut-off scores

have varied in different studies, and no validation studies have determined the optimal use of PTSD

screening instruments in Gulf War veterans.553,555,1805 As a result, PTSD case ascertainment based on

these checklists may overestimate PTSD rates, particularly in symptomatic Gulf War veterans who may

or may not have problems resulting from intense psychological stressors.

Even in light of the potential for over diagnosing PTSD and the variability of prevalence estimates,

identified rates of PTSD in Gulf War veterans are generally low—lower than rates reported in veterans of

previous and current wars. The rate of PTSD in Gulf War veterans is more comparable to that in the U.S.

adult population, reported to be five percent in males, and eight percent overall.799 In studies of Vietnam

veterans estimates of PTSD prevalence are also variable, as well as controversial,1008 but have generally

ranged between 15 and 30 percent.223,352,844,845,1159,1834 Substantially higher PTSD rates are found in

cohorts of combat veterans and former prisoners of war.384,1138,1517

Rates of PTSD and psychiatric illness are beginning to be reported for U.S. military personnel returning

from current deployments in Iraq and Afghanistan. Studies have indicated that PTSD may not become

apparent in veterans for months or even years after their return from the war zone, so actual rates may not

be known for some time.127,530,1048,1456,1803 Combat and traumatic experiences for U.S. personnel in the

current Iraq War have been more widespread and more intense than in the 1991 Gulf War,447 with one
Psychological Stressors and the Health of Gulf War Veterans  71

survey indicating that 93 percent of U.S. veterans in combat units reported being shot at during

deployment and 95 percent reported seeing dead bodies.614 Not surprisingly, studies also indicate that

psychiatric problems are more prevalent in returning veterans.447 Recent studies have reported that 35

percent of Iraq War veterans accessed mental health services within a year of returning from the war, 17

percent of returning Army combat veterans have PTSD, and that between 20 and 42 percent of OIF

personnel screened longitudinally are identified by clinicians as having a mental health

problem.613,616,1048,1380

Other psychiatric conditions affecting Gulf War veterans. Research studies have also evaluated

rates and population patterns of psychiatric disorders other than PTSD in Gulf War veterans. Several

have reported that, like PTSD, rates of other psychiatric conditions are significantly associated with

psychological stressors that occurred during deployment.139,674,1195,1728 PTSD commonly co-occurs with

conditions such as depression and generalized anxiety disorder.450,799,1156,1834 Like PTSD, both depression

and anxiety disorders occur at higher rates in Gulf War veterans than in nondeployed era veterans, with

somewhat variable prevalence estimates. Low rates of both conditions were diagnosed in Gulf War

veterans evaluated in the U.S. CCEP (3.0% depression, 0.4% anxiety disorder) and the U.K. MAP

program (3% depression, 1% anxiety disorder).408,879 Relatively low rates were also reported in the Ft.

Devens cohort (6.6% depression, 0.8% anxiety disorder).1803 Higher estimates for rates of depression and

anxiety disorder, each from one study, come from national samples that used the CIDI structured

interview to identify cases. The U.S. National Gulf War era study reported that eight percent of Gulf War

veterans had major depression, and 21 percent had anxiety disorders.142 Nearly reversed rates come from

a second national sample that administered the CIDI by telephone interview (15% depression, 6% anxiety

disorder).436 Variability in these estimates may be a function of the measures used, since both studies that

reported higher rates of these conditions in Gulf War veterans used the CIDI, and also found relatively

high rates of psychiatric disorders in nondeployed era veterans.

Relationship of postwar psychiatric Illness to chronic symptoms and multisymptom

illness. There has been an extensive amount of scientific research conducted on the psychological

sequelae of war, including factors associated with persistent psychiatric morbidity in some

veterans.1518,1729 It has long been observed that veterans and others with psychiatric conditions,

particularly PTSD, experience somatic symptoms at higher rates than individuals with no psychiatric

illness.616,1468,1710 Conversely, people with chronic medical conditions are often reported to have higher

rates of psychiatric illness than those who are medically well. For example, the prevalence of major

depression in people age 15 to 54 in the U.S. was estimated to be seven percent in 2002.798 Major

depression is more common in patients with chronic illness, affecting about 15 percent of cancer

patients,640 15-30 percent of patients with multiple sclerosis,249,1177 and 20-40 percent of Parkinson’s

disease patients.300,1134,1423

This phenomenon has been well documented in studies of Gulf War veterans. Multiple studies have

reported that Gulf War veterans with PTSD have higher rates of self-reported symptoms than veterans

without PTSD.88,103,407,850,1741,1803 For example, in a population-based sample of Iowa Gulf War era

veterans, investigators report that veterans with PTSD endorse significantly more symptoms than veterans

without PTSD in a broad range of categories. This occurred in both Gulf War and nondeployed era

veterans with PTSD103 and parallels what is known about veterans from other eras—that veterans with

PTSD typically experience more symptoms than veterans with no psychiatric disorders.117,1834 Several

studies have also reported this association from the opposite perspective, that is, that Gulf War veterans

with multisymptom illness have higher rates of PTSD and depression than veterans without

multisymptom illness.142,449,699,1496

The largest national study of U.S. Gulf War veterans found that six percent of Gulf War veterans with

multisymptom illness had PTSD, compared to two percent of Gulf War veterans without multisymptom

illness.142 This relative excess was also seen in nondeployed era veterans with multisymptom illness.
72  Effects of Gulf War Experiences and Exposures

Other studies have reported both higher and lower rates of psychiatric diagnoses in Gulf War veterans

with multisymptom conditions. For example, no cases of PTSD were identified among veterans with any

of three defined symptom syndromes in the Texas study of Gulf War veterans from a Navy Seabees

battalion.565 In the Fort Devens cohort, Army veterans with the highest number of symptoms also had

elevated rates of psychiatric disorders – 14 percent had PTSD and 15 percent had depression. Still, the

large majority of the highly symptomatic veterans, 73 percent, had neither depression nor PTSD.1803

Similarly, a clinical study of British Gulf War veterans indicated that, in the subset of veterans with the

highest degree of disability, three percent had PTSD and 24 percent had any psychiatric disorder—

findings similar to those for disabled veterans who had not deployed to the Gulf War. Seventy-six

percent of ill Gulf War veterans in this population had no identifiable psychiatric disorder.699

Studies indicating that Gulf War veterans with multisymptom conditions have higher rates of psychiatric

conditions and that veterans with psychiatric disorders report more symptoms are consistent with similar

findings from other civilian and veteran populations affected by chronic illness. They are important in

underscoring the need to identify subgroups of ill veterans with conditions that may benefit from

established treatments. They do not, however, support assumptions that Gulf War illness was caused by

deployment stressors or that Gulf War illness is a psychiatric disorder. Studies of Gulf War veterans

consistently indicate that Gulf War illness was not caused by psychological stressors during the war.

And, although some veterans with Gulf War illness also have psychiatric disorders, the large majority do

not.

From a clinical perspective, it is important that those ill Gulf War veterans who have diagnosable

psychiatric conditions are identified and appropriately treated.405,407 There is little evidence, however, that

standard treatments for mood disorders will benefit the broader range of symptoms associated with Gulf

War illness.427,1072,1358 And, given the consistency of findings that most veterans with Gulf War illness do

not have psychiatric conditions, it is also extremely important that clinicians not assume that diverse

undiagnosed symptoms affecting Gulf War veterans are primarily a psychiatric problem.

From a research perspective, the potential for confusion between undiagnosed multisymptom illness in

Gulf War veterans and diagnosable psychiatric disorders emphasizes the need for careful study design and

the use of rigorous methods in assigning psychiatric case status. It also underscores the need for careful

data analysis that considers possible confounding effects of concurrent conditions associated with

concurrent exposures during the war.

Epidemiologic studies consistently indicate that the etiology of Gulf War illness is very different from

that of PTSD. It is likely that veterans with Gulf War illness are distinct in multiple ways from veterans

with PTSD and other psychiatric conditions, as has been suggested by preliminary studies.435,502,864,1496 To

minimize confusing characteristics of Gulf War illness with those of psychiatric conditions, it is important

that Gulf War illness research studies distinguish subsets of veteran participants who have psychiatric

disorders, or limit study enrollment to Gulf War illness patients who do not have psychiatric disorders.

Summary. Psychological stressors and the health of Gulf War veterans. Although it is well

recognized that excess rates of multisymptom illness resulted from service in the 1990-1991 Gulf War,

the question of whether Gulf War illness was caused by hazardous exposures or psychological stressors

has long been debated. Early views that Gulf War illness was likely the result of deployment-related

stress were largely speculative, drawing on general information related to psychological and somatic

effects of sustained or severe stressors. Research studies of Gulf War veterans have not supported these

assumptions, however, consistently indicating that psychological stressors during deployment are not

significantly associated with Gulf War illness. Neither intense stressors, such as serving in combat, nor

less severe stressors evaluated in studies of Gulf War veterans are associated with higher rates of Gulf

War illness, when effects of other deployment exposures are considered.
Psychological Stressors and the Health of Gulf War Veterans  73

General research related to the effects of stress in humans provides useful insights about the potential for

extreme and/or sustained stressors to precipitate short term somatic problems as well as sustained

psychiatric illness. Animal studies also raise the possibility that stressors may alter or amplify effects of

chemical exposures associated with Gulf War service. Some Gulf War veterans did experience trauma

and the kinds of intense psychological stressors common to other wars—being in combat, coming under

fire, witnessing death. Consequently, rates of posttraumatic stress disorder (PTSD) and other psychiatric

conditions occur at higher rates in Gulf War veterans than era veterans who did not deploy to the Persian

Gulf theater. But overall, the impact of wartime trauma and stress were less extensive in the Gulf War

than in other wars and rates of PTSD and other psychiatric conditions are lower in Gulf War veterans than

in veterans of other wars.

Studies indicate that the large majority of Gulf War veterans with chronic multisymptom illness do not

have psychiatric disorders. It is therefore important that healthcare, research, and policy decisions

concerning ill Gulf War veterans not be based on unsupported assumptions that Gulf War illness is

primarily a psychiatric condition or that it was caused by psychological stressors during deployment.

However, some veterans with Gulf War illness are also affected by psychiatric disorders, and it is

important that those veterans are properly diagnosed and treated for those conditions.
74  Effects of Gulf War Experiences and Exposures

Recommendation

Evidence from multiple studies consistently indicates that Gulf War illness was not caused by

psychological stressors during the war and the large majority of ill Gulf War veterans do not have

psychiatric conditions. The Committee therefore recommends that federal funding for Gulf War illness

research not be provided for studies of posttraumatic stress disorder or other psychiatric conditions, or

studies that focus on psychological factors as the central cause of Gulf War illness.
Kuwaiti Oil Well Fires and the Health of Gulf War Veterans  75

Kuwaiti Oil Well Fires and the Health of Gulf War Veterans

There were no less than three days when the smoke ‘hugged’ the ground, and turned the

sunlit, bright day into a dark of night. Myself and others traveled the ‘coastal highway’ from

Kuwait City down to Saudi Arabia on April 1st, 1991, and the petroleum-thickened air was so

impregnated that we choked on oil while breathing through our doubled-up scarves and we

were forced to stop and clear the raw petroleum off vehicle windshields and our goggles

constantly. At some points on the highway the oil-thickened air was so thick our vehicle

headlights could not penetrate the air further than 10-15 feet, and Marine escorts were

needed to walk on foot ahead of the vehicles to keep us on the highway.

–-Marine Corps Captain965

As the outcome of the U.S. and allied forces’ campaign became increasingly evident in February of 1991,

Iraqi forces set out to destroy Kuwait’s oil infrastructure as they withdrew from the region. Valves were

opened at the Sea Island oil terminal near Kuwait City, releasing large amounts of crude oil into the Gulf

of Kuwait.1689 Oil tankers moored in the area were ransacked and their cargo off-loaded into the waters.

At the same time, over 600 Kuwaiti oil wells were damaged or ignited. By the end of February, at the

peak of the oil well problem, an estimated 605 wells were on fire with another 46 gushing oil. Between

four and six million barrels of oil per day were either burned or spewed onto the sand,1621 creating plumes

of smoke and lakes of crude oil collecting on the ground.

Throughout this time, images of plumes of dense black smoke pouring from the oil wells were prominent

in newscasts, and medical and environmental scientists feared that exposure to the fires and smoke would

result in catastrophic acute and chronic health effects for exposed military personnel.1461,1621 After the

ceasefire, U.S. and international teams quickly arrived in Kuwait to assist in extinguishing the fires and

cleaning up the environmental disaster. The first oil well fire was extinguished by mid-June and, despite

expert predictions that it would take 2-3 years to extinguish all fires, the last open well was capped on

November 6, 1991.1621

Heavy exposure to smoke, oil, and other contaminants from the Kuwaiti oil well fires have long been

suspected causes of the diverse chronic symptoms affecting Gulf War veterans. The oil fires are unique

among Gulf War exposures, both with respect to their high public profile and because information is

available on measured levels of oil fire-related pollutants in theater. These measures have been used to

estimate the likely risk of diagnosed medical conditions resulting from oil fire smoke exposure but have

done little to shed light on the extent to which the Kuwaiti oil fires might have caused or contributed to

Gulf War illness.

Exposure to Oil Well Fires and Smoke During Gulf War Deployment

It was a Monday, the sky was so dark it was like night. People’s eyes were running with black

tears, your saliva was black, you had to have a bandana over your nose to breathe.

- Army Sergeant1608

At the time the oil well fires were at their peak, between 550,000 and 600,000 U.S. troops were present in

the Persian Gulf theater.1461 Although most military personnel experienced exposure to smoke from the

fires, the intensity and duration of exposure were highly variable. Many soldiers have reported that the

smoke was at times so thick that a sunlit bright day was turned into the dark of night. At times, troops

reported being soaked with unburned oil that rained from the sky. At other times, however,

environmental conditions were reported to be less severe. During more favorable weather conditions,
76  Effects of Gulf War Experiences and Exposures

winds helped to rapidly dissipate the smoke, and plumes rose above ground level where the smoke no

longer posed noticeable difficulties for troops working in the area.1621

Epidemiologic studies indicate that 60-85 percent of U.S. and British Gulf War veterans report some

exposure to smoke from oil well fires during deployment,241,692,751,988,1239,1698 with exposure less common

among Air Force and Navy personnel.241,1124 The U.S. Army Environmental Hygiene Agency (USAEHA)

estimated that over 40 percent of U.S. troops were, at some time, within one mile of a burning

well.1586,1587 In addition, nearly one-third of soldiers have reported eating food contaminated with oil or

smoke.

751 For troops located in areas of precipitating crude oil and dense ground-level smoke, little was

provided in the way of training or protective equipment. Protective measures for veterans in those areas

consisted mostly of tying scarves or shirts over their noses and mouths, and rolling down their sleeves to

cover exposed skin.1668,1669

Oil fire pollutants of possible concern. The hundreds of burning oil wells presented a complex

mix of potentially hazardous substances to those covered with oil or breathing the heavy black smoke.

The composition of crude oil varies by region and strata, but burning crude typically produces a smoke

composed of a mixture of particulates and gases that include carbon dioxide (CO2), carbon monoxide

(CO), sulfur dioxide (SO2), oxides of nitrogen (NOX), volatile organic compounds (VOCs), ozone (O3),

various polycyclic aromatic hydrocarbons (PAHs), acid aerosols, and soot.1461 Extensive analysis of the

Kuwaiti oil fire smoke found that the smoke contained the expected mixture of pollutants. In addition,

hydrogen sulfide (H2S), a major component of natural gas, was present at varying concentrations. The

most visible components of the mix were the particulate matter and carbonized particles (soot) that

formed the huge smoke plumes. The smoke contained other components, including small amounts of

various heavy metals such as nickel, vanadium, iron, aluminum, beryllium, cadmium, calcium, chromium,

arsenic, silicon, zinc, and lead, all present in crude oil as impurities.1621

Pollutants associated with combustion of crude oil have been the subject of extensive toxicological testing

as part of established U.S. and international environment and occupational safety programs. For some,

but not all pollutants, standards have been established that are intended to represent exposure levels that

can be experienced without increased risk of identified adverse effects. When inhaled or ingested at

sufficient concentrations and durations, many of these compounds have the potential to cause known

health effects, primarily acute and chronic respiratory conditions and cancers. However, little

occupational or animal research has been done to evaluate the potential for oil fire pollutants to cause a

constellation of chronic symptoms resembling Gulf War illness. Oil fire-related compounds have been

associated with some categories of chronic symptoms that affect Gulf War veterans. Particulate

exposures can cause the development of chronic respiratory symptoms1663 and VOCs and heavy metals

have the potential to cause neurological symptoms.1661 Carbon monoxide is highly toxic and exposure is

associated with a variety of symptoms such as fatigue, headache, confusion, nausea, and impaired vision

and coordination, some of which can persist for many years.1662

Environmental monitoring and measured pollutants. Widespread concern about the potential

for serious health effects from the burning oil wells prompted environmental monitoring efforts by

international agencies and organizations. Results of these monitoring efforts are summarized in Table 1.

As shown, environmental samples were collected by multiple teams, testing for a wide range of

potentially toxic pollutants. Early efforts to monitor air quality in the region were limited. During March

13-27, 1991, a U.S. Interagency Team measured particulates, SO2, PAHs, inorganic acids, VOCs, and

metals in Kuwait and Saudi Arabia. These early assessments identified high particulate levels and SO2

levels that exceeded 24 hour standards at the Burgan Oil Field.

1660 Later analyses determined that the

portable samplers utilized in this monitoring effort tended to underestimate levels of particulates of

inhalable size (10 micron diameter or smaller, or PM10).1337 The most extensive monitoring program was

undertaken by USAEHA, which was commissioned to assess levels of pollutants from oil fire emissions

in areas where most U.S. troops would be affected. The USAEHA program analyzed samples for more
Kuwaiti Oil Well Fires and the Health of Gulf War Veterans  77

Table 1. Measured Air Pollutants in Kuwait and Saudi Arabia, 1991

Monitoring

Agency/Team

Monitoring

Dates (1991) Monitoring Locations Pollutants Measured

Pollutants exceeding

applicable standards

Umwelt Bundesamt1692 Mar 3–Apr 27 Not described SO2 None

U.S. Interagency Air

Assessment Team1660

Mar 13–27 15 locations in Kuwait,

3 in Saudi Arabia

SO2, VOCs, TSPs, H2S,

PAHs, metals, inorganic

acids, formaldehyde

TSPs in 12 of 28

measurements; SO2 at

Burgan oil field

King Fahd University of

Petroleum806

Mar – May Dharan, Saudi Arabia PM10, PAH, TSPs, lead,

nickel, vanadium, cadmium,

cobalt, copper

PM10; lead, cadmium,

cobalt in inhalable

particles

British Meteorological

Office717

Mar 22-Apr 2 7 flights through smoke

plume, 100 km from

Kuwait

SO2, O3, NOx Peak SO2levels

AIRPARIF1515 Mar 27-Apr 4 5 sites in and around

Kuwait City, 3 in oil fields

SO2, CO, NO, NO2, PAHs,

VOCs, O3, TSPs

Average SO2 at 2 sites;

TSPs

Kuwait Environment

Protection Council849,1669

Apr–Jun 2 locations in Kuwait:

Kuwait City and Rega

SO2, H2S, CO, NO2, O3,

particulates

Particulates

Japan Environment

Agency

1145,1621

Apr 28-May 5 4 locations in Kuwait SO2, NO2 Peak SO2

U.S. Army Environmental

Hygiene Agency1586

May 5–Dec 3 6 locations in Kuwait,

4 in Saudi Arabia

VOCs, TSPs, PM10, metals,

O3, PAHs, nitrates, SO4, NO,

NO2, SO2, acidic gases

TSPs at all locations;

PM10 in some locations

Norwegian Institute for Air

Research1416

May 15-Jun 17 Umm Quasr, Iraq (100 km

from largest oil field fires)

SO2, soot (particulates),

PAHs

Soot

U.S. National Institute of

Standards and Technology1083

May 15 Al Maqwa oil field in

Kuwait

Particulates, PAHs Particulates

National Toxics Campaign

Fund1105

May 15-21 Al Jubayl, Saudi Arabia 1,4-dichlorobenzene, 1,2-

dichlorobenzene, diethyl

phthalate, dimethyl phthalate,

napthalene

1,4-dichlorobenzene in all

samples

National Science

Foundation1104

May 16-Jun 12 Flights through smoke

plume

O3, NOx, CO, SO2,

particulates

Particulates; SO2 peak

levels occasionally

exceeded

U.S. Environmental

Protection Agency,

National Aeronautics and

Space Administration1487,1669

Jul 28–Aug 8 Flights through plume,

ground samples at Kuwait

City and near Al Wafra,

Al Burgan oil fields

SO2, SO4, VOCs, PAHs, CO2,

CO, metals, particulates

None

Arabian Gulf University,

Bahrain950

Jul 31-Aug 4 Bahrain Particulates, 32 PAHs,

heavy metals

Particulates, PAHs, metals

elevated over usual levels

Abbreviations: VOCs = volatile organic compounds, TSPs = total suspended particulates, PM10 = particulate matter 10 microns or smaller,

O3 = ozone, PAHs = polycyclic aromatic hydrocarbons, COx = oxides of carbon, NOx = oxides of nitrogen, SOx = oxides of sulfur

than 50 chemicals and compounds but, unfortunately, did not begin monitoring until May of 1991.

1586 By

the time the USAEHA team arrived in theater, the “shamal” winds, strong northwesterly winds prevalent

in the region during the spring and summer, had begun to blow and had helped to dissipate the smoke

present at ground level.
78  Effects of Gulf War Experiences and Exposures

Overall, results from environmental monitoring in the Kuwait theater provide a perspective in surprising

contrast to the environmental conditions described by soldiers serving in areas where oil fires were

burning. Measured levels of airborne particulates were excessive, but mean concentrations of VOCs,

PAHs, metals, O3, CO, SO2, NOx and lead in collected samples were much lower than initially

anticipated. Concentrations of these pollutants were consistent across studies, and maximum levels were

found to be comparable to those in suburban areas in the U.S, lower than levels in large urban centers, and

significantly lower than the U.S. recommended occupational exposure limits.1575,1587 In contrast, airborne

particulates were consistently found to be present at high levels at all monitoring sites. Particulate

concentrations frequently exceeded EPA National Ambient Air Quality Standard limits, and were much

higher than levels observed in the United States. In addition, several teams identified occasional excess

SO2 levels, and isolated findings of excess concentrations of heavy metals1337 and 1,4 dichlorobenzene.1669

Information provided by air monitoring efforts in theater was limited, however, to the time periods and

locations in which measurements were taken. For example, little information is available on measured

levels of particulates and chemical toxins in areas close to the burning wells, particularly in February and

March, before seasonal winds routinely dispersed the heavy black clouds of smoke near the ground. In

order to estimate oil fire pollutants encountered by service members in areas where no measurements

were taken, USAEHA utilized environmental monitoring data, meteorological data, and satellite imagery

to generate models of pollutant concentrations in all areas of theater throughout the period that oil fires

burned. Periods prior to the initiation of USAEHA monitoring were supplemented with monitoring data

from other agencies. These exposure models, in conjunction with the Department of Defense’s Gulf War

troop location databases, have been used to estimate oil fire smoke exposures in epidemiologic studies,

and for oil fire health risk assessments available to individual Gulf War veterans online at

https://gulfwarfires.apgea.army.mil.

Two sets of health risk assessments were created by the U.S. Army’s Center for Health Promotion and

Preventive Medicine (USACHPPM, formerly referred to as USAEHA). One represented health risks

associated with exposure to measured pollutant levels from all sources (including natural background

particulates, industrial and vehicle pollution, etc.). The second used modeled pollutant levels and

assessed risk only related to the excess pollution directly attributable to the burning oil fires.1575 In

addition, risk estimates were made for two broad categories of health outcomes: cancer and non-cancer

risk. Overall, the final risk assessments concluded that the potential for significant long-term adverse

health effects from the Kuwaiti oil fires was minimal, with exposures for all units below acceptable

hazard index limits established by EPA.1575 It is important to note, however, that this assessment relates

to diagnosable medical conditions and does not provide information directly related to the risk of

developing undiagnosed conditions, chronic symptoms, or symptom complexes. In addition, methods

used to compute health risks considered only the subset of pollutants for which established toxicity

coefficients were available.1575 Consequently, the potential effects of exposure to high levels of

particulates were not included in the health risk assessments. Oil exposure through ingestion of food or

water was considered to be unlikely and also not included in the models.

A 1998 RAND Report commissioned by the Department of Defense1461 also concluded that, even

assuming a worst-case scenario, concentrations of pollutants were below levels likely to cause known

health effects. Again, this assessment did not specifically address health questions related to Gulf War

illness. Particulate levels were noted to be extremely high in the region and the report suggested that this

might explain some of the respiratory complaints reported by veterans. The RAND report also pointed

out that little is known about health effects of simultaneous exposure to multiple contaminants, and called

for further investigation of this issue.1461 The 2002 Environmental Exposure Report on Oil Well Fires

from the Department of Defense generally concurred with conclusions of prior reports but identified three

areas that required further study: particulate matter exposures and related health effects, health risks

associated with dermal and inhalation exposures to “oil rain” during the Gulf War, and comprehensive

health risk assessments that take into account all oil fire-related pollutants of concern.1621
Kuwaiti Oil Well Fires and the Health of Gulf War Veterans  79

Health Effects of Kuwaiti Oil Fire-Related Exposures

No published studies have specifically evaluated Gulf War veterans who experienced the most extreme

exposures to oil and smoke, that is, those in close proximity to burning oil wells in the early months of

1991. However, there are several reports on the health of U.S. civilian firefighters who came to Kuwait to

assist in extinguishing the oil well fires.312,413,461 These firefighters worked close-in for extended periods,

at the base of the fires, and wore no protective equipment aside from the occasional use of particle

masks.312,413,461

A 1992 study found that levels of DNA adducts, a biomarker for exposure to PAHs, were not elevated in

civilian firefighters in Kuwait, but that some firefighters reported symptoms of eye, nose and throat

irritation during their time in theater.312 In a separate study, blood VOC levels—ethylbenzene, benzene,

xylene, toluene, and styrene—were significantly higher in a group of 40 civilian firefighters in the

Kuwaiti oil fields than in military personnel located twenty kilometers away.413 None of the firefighters

in the study required treatment for health conditions while working in the vicinity of the fires and there

were no lost work days due to illness.312 Dr. Gary Friedman, a Texas physician who evaluated a cohort of

civilian firefighters after their return from Kuwait, reported to the Committee that his follow-up

assessments through 1994 revealed no evidence of disease or illnesses with delayed onset, no indication

of lost time due to illness, and no unexpected compensation claims filed among these workers.461 In

particular, he had seen no evidence of multisymptom illnesses resembling Gulf War illness among these

firefighters.

The experience of professional firefighters working in the region is informative, but might not be wholly

generalizable to Gulf War veterans for two reasons. First, the exposure milieu for military personnel in

theater was distinct, involving exposure to oil fires in combination with other potentially hazardous

substances, as described in this report. Second, a healthy worker effect likely exists among professional

firefighters that would exclude individuals with particular susceptibilities to the types of exposures

associated with the Kuwaiti oil fires. Although military personnel, in general, also exhibit a high degree

of physical fitness, those serving in the region might have included individuals with greater vulnerability

to effects of oil, smoke, and particulates.

Reports based on hospital and clinic records have suggested that local populations in areas affected by oil

well fires may have experienced some adverse effects. For example, the number of visits to Kuwaiti

health clinics and emergency rooms due to respiratory conditions increased over prewar rates in the

months during and after the oil fires, peaking in April and declining thru September when many fires had

been extinguished.1158 No reports have provided information on the occurrence of symptoms or symptom

complexes similar to Gulf War illness in local populations.

In 2002 scientists at the Harvard School of Public Health, in collaboration with an international team of

investigators, initiated a project to assess the health effects of environmental exposures on the local

Kuwaiti population during and after the 1991 oil fires. This project, “Monitoring and Assessment

Program of Environmental Consequences of the Iraqi Aggression in Kuwait,” was commissioned by the

government of Kuwait.591 The project is ongoing, but investigators have reported that postwar mortality

rates were 20 percent higher among Kuwaiti adults who remained in Kuwait during the conflict,

compared to those who fled the region. Explanations for this mortality excess are unclear, and the

Committee looks forward to reviewing additional information to be provided by this project.349,592

Animal studies have provided very limited information on the toxicity of exposures related to the Kuwaiti

oil fires. One study compared pulmonary toxicity effects, in hamsters, of particulates collected downwind

from the Kuwaiti oil fires to particulates from the St. Louis area and found the two to be comparable.

Investigators concluded, however, that the substantially higher concentrations present in Kuwait remained

a concern.165 Another study evaluated respiratory tissues in feral cats collected in Kuwait eight months
80  Effects of Gulf War Experiences and Exposures

after ignition of the oil wells. Accumulations of black sooty materials in 17 of 26 cats were described,

and minor cellular changes in bronchial and tracheal tissues.1056

Occupational studies of the effects of exposure to smoke and fuel combustion products.

Studies of health outcomes among individuals occupationally exposed to burning fires and fuel exhaust

may also provide insights relating to health effects potentially resulting from the Kuwaiti oil fires. The

direct applicability of such studies to the experiences of Gulf War veterans is limited by a number of

factors, however. Occupational studies typically identify health effects resulting from exposures

occurring over multiple years, as opposed to those lasting weeks or months as was the case for Gulf War

veterans during deployment. In addition, the physical and chemical constituents of smoke and other

exhaust products typically encountered by occupational cohorts would likely differ from those associated

with the Kuwaiti oil well fires.

A 2005 report from the Institute of Medicine (IOM) reviewed, in some detail, evidence on health

outcomes related to occupational exposure to combustion products such as fuel exhaust, wood smoke, and

their chemical constituents.684 The primary health outcomes considered were those commonly evaluated

in occupational cohorts—cancers, nonmalignant respiratory diseases, cardiovascular diseases, and

reproductive outcomes. The IOM panel concluded that there is sufficient evidence to indicate a positive

association between exposure to combustion products and lung cancer and suggestive evidence of an

association between combustion products and other respiratory cancers and bladder cancer. This

represents one of the few conclusions from IOM’s Gulf War and Health series indicating sufficient

evidence of an association between any exposure and any health outcome. These conclusions do not

specifically address whether exposure to the Kuwaiti oil fires are likely to be related to cancer outcomes

in Gulf War veterans, for whom no elevation in cancers of the respiratory system or bladder have been

identified. More importantly, the IOM review provides little information on the more immediate question

of possible links between oil well fires and Gulf War illness, the health problem most prominently

associated with Gulf War service.

The Research Advisory Committee, in its review of the occupational literature, also found few studies

specifically relevant to the question of Gulf War illness. Studies of petroleum workers, potentially

exposed to many of the chemicals found in uncombusted Kuwaiti crude, have found that these workers

may be at increased risk for a number of cancer types, as previously described.541,542,898,1327,1354,1808 Studies

of urban firefighters have suggested that chronic exposure to smoke from burning structures may also be

associated with some cancers including multiple myeloma, non-Hodgkin’s lymphoma, and genitourinary

cancers.100,108,341,539,882 One small study of firefighters in India found these workers to experience

significantly higher rates of transient memory loss, burning sensations in the extremities, tingling/

numbness, and depression than a reference group, as well as elevated blood levels of epinephrine and

norepinephrine.1260

Studies Evaluating the Health of Gulf War Veterans in Relation to the Kuwaiti Oil Fires

At one point during the war, we were staying near the oil wells, and your uniform would be

completely covered with black, like soot all over you. Your arms were exposed, your food,

everything, your water where you took showers. It was constantly dark; there was no such

thing as daylight.

- Army Gulf War veteran716

Association of symptoms and multisymptom Illness with oil fire exposure. The largest

study that evaluated Gulf War veterans’ symptoms while they were still in theater was conducted by a

team of Navy epidemiologists in March of 1991, while the oil well fires were still burning.1687 That study
Kuwaiti Oil Well Fires and the Health of Gulf War Veterans  81

surveyed over 2,700 Marines in three groups, defined by the locations in which they served during the

preceding months. The group closest to the oil well fires for the longest period of time (about five weeks)

experienced significantly higher rates of respiratory symptoms (wheezing, cough, sore throat, runny nose)

and gastrointestinal symptoms (diarrhea, stomach cramps, nausea, and vomiting) than groups more distant

from the burning wells. An additional study evaluated symptoms among nearly 1,600 Army personnel

before, during, and three months following their service near Doha after the end of Operation Desert

Storm. Respiratory symptoms, rashes, and fatigue were generally increased in association with soldiers’

proximity to the oil well fires during the time soldiers were in Kuwait. All symptoms except cough had

resolved by one month post deployment.1203

Seventeen years after the war, the question of whether exposure to the Kuwaiti oil well fires is a likely

cause of the persistent symptoms of Gulf War illness can best be addressed by considering evidence from

studies of Gulf War veterans. Numerous epidemiologic studies have evaluated symptoms and

multisymptom illness in relation to veterans’ self-reported exposure to oil well fire smoke, although the

amount of detail evaluated with respect to duration and intensity of smoke exposure is highly variable.

Results of these studies are summarized in Appendix A-6. As shown, epidemiologic studies have

commonly reported elevated illness rates in relation to oil fire exposures using preliminary or crude

analyses, that is, analyses that do not account for effects of other exposures present in theater. Many

studies reported results of this type, suggesting associations between oil fire smoke and increased risk for

both symptoms524 and multisymptom illness up to nine years after deployment.527,692,752,1124,1264,1466,1698,1804

Several studies supported a possible dose-response effect, indicating that veterans who report more

prolonged exposure to oil fire smoke had higher rates of Gulf War illness than veterans exposed more

transiently.241,564,1466 Also of note, the U.S. National Survey of Gulf War veterans found that veterans

who reported consuming food contaminated with oil or smoke had a nearly 11-fold excess risk for the

unique neurological symptom complex identified by this study.752

As previously described, in complex exposure scenarios like the Gulf War theater, exposure risk estimates

based on unadjusted analyses often generate spurious results, due to the confounding effects of multiple

concurrent exposures. More informative and reliable results require analyses that adjust for effects of

other exposures in theater. The four studies that reported findings of this type in relation to oil fire

exposure produced mixed results. Two found that self-reported exposure to oil fire smoke was associated

with a significantly higher rate of symptoms and multisymptom illness,

241,1804 although the excess risk

was modest. One of these studies also indicated a dose-response effect, with longer duration exposures

associated with higher symptom scores.241 In contrast, two studies reported that, after adjusting for other

exposures, multisymptom illness was not significantly elevated among veterans who reported exposure to

smoke from oil well fires.527,1124

Conflicting results from these studies cannot be conclusively explained. However, the dose-response

effect demonstrated by several studies suggests that study populations that included a higher proportion of

veterans who were closer to fires for longer durations would more likely have identified links between oil

smoke exposure and chronic symptoms. In fact, the two studies that reported significant, albeit modest,

associations between symptoms and oil fire exposure included predominantly Army personnel, while the

two studies that did not find this association included only Air Force and Navy personnel. The most

unexpected finding related to oil smoke exposure comes from the large Navy Seabees study. Using

USACHPPM models to estimate exposure to oil fire-related pollutants, the study found that veterans with

the highest modeled oil fire exposures had significantly lower rates of Gulf War illness.

527

Taken together, epidemiologic studies do not provide consistent support for oil well fires as a prominent

risk factor for Gulf War illness. Just two of the four studies providing fully adjusted analyses indicated

that self-reported oil well smoke exposure was a statistically significant, but modest, risk factor for

multisymptom illness. But several studies suggested that the Kuwaiti oil well fires may have contributed
82  Effects of Gulf War Experiences and Exposures

to the risk of developing Gulf War illness for veterans who experienced longer duration

exposures241,564,1466 and/or veterans in close enough proximity to have eaten oil-contaminated food.752

Diagnosed conditions potentially associated with oil well fire exposure. In addition to Gulf

War illness, several studies have indicated that Gulf War veterans, as a group, are significantly more

likely to have symptoms of or report being diagnosed with respiratory conditions such as asthma and

chronic bronchitis, compared to nondeployed era veterans.511,527,692,790,1476,1698 Although these studies

generally have found that less than 10 percent of all Gulf War veterans report these conditions, identified

rates are consistently about twice as high in Gulf War veterans as in nondeployed era veterans. In the

U.S. National Survey of Gulf War era veterans, Gulf War veterans did not report elevated asthma rates,

but did report significantly higher rates of bronchitis, emphysema, and “other lung conditions.”751

Clinical examination of a subset of study participants, however, did not find an excess of diagnosable

lung disease among Gulf War veterans, when evaluated as a single group,393 and results of pulmonary

function tests were similar in Gulf War and nondeployed era veterans.755

The question most relevant to oil fire exposures, however, is whether Gulf War veterans have developed

respiratory diseases at excess rates as a result of the Kuwaiti oil well fires. Several studies have addressed

this question, using different methods to identify disease and degree of exposure, as summarized in Table

2. As shown, results of these studies are somewhat mixed, with two finding that asthma rates are

significantly associated with self-reported exposure to oil well fire smoke and two indicating that modeled

oil fire smoke exposure is not associated with symptoms suggestive of asthma/bronchitis or with

hospitalization for these conditions.

Table 2. Association of Oil Fire Exposure with Respiratory Diseases

in U.S. Gulf War Veterans

Study

Study

Population

Outcome

Measures

Assessment of

Oil Fire Exposure Major Findings

Cowan285

2002

873 asthma cases,

2,463 controls; Army

CCEP participants

physiciandiagnosed

asthma

self reported

CHPPM models

Asthma sign. associated with self-reported

exposure (OR = 1.6)

Asthma sign. associated with the number of

high-exposure days and cumulative smoke

exposure levels; sign dose/response effect

Lange866

2002

1,560 Iowa GW

veterans

symptoms

suggestive of

asthma, bronchitis

self reported

CHPPM models

Asthma and bronchitis sign. associated with

exposure (ORs = 1.8-2.8)

Neither associated with modeled exposures

Smith1434

2002

405,142 GW veterans military

hospitalizations,

1988-1999

CHPPM models Hospitalizations for asthma, bronchitis were

not sign. associated with modeled exposures

Abbreviations: CCEP = Comprehensive Clinical Evaluation Program, OR = odds ratio, CHPPM = U.S. Army Center for Health Promotion

and Preventive Medicine, GW = Gulf War, sign. = statistically significant

The study of respiratory disease in relation to oil fire exposure that is strongest methodologically, in

several respects, was the 2002 study led by Dr. David Cowan. It assessed asthma cases among Army

veterans enrolled in the CCEP, and is likely to have provided the most accurate information. This study

was unique among Gulf War studies in that it evaluated the rate of a medical condition that had been

clinically diagnosed, in relation to modeled exposure levels. Case ascertainment and level of exposure in

this study were therefore less susceptible to bias, and so presumably provide the most valid results. The
Kuwaiti Oil Well Fires and the Health of Gulf War Veterans  83

study found that asthma rates were significantly higher in Gulf War veterans exposed to higher levels of

oil fire pollutants—both in terms of the number of days exposed and cumulative exposure levels. The

study also identified a clear dose-response effect, with asthma risk increased about 20 percent in veterans

with intermediate exposure levels, and 40 percent in veterans with highest exposure levels.

285

There is evidence from other occupational groups to indicate that chronic exposure to petroleum

combustion products is associated with increased risk for respiratory cancers, as previously described.684

Although no studies have thus far identified excess rates of respiratory cancers in Gulf War veterans,892,943

research in this area continues to be important, given the extended latency period required for many

cancers to be diagnosed. The only information relating cancer rates specifically to the Kuwaiti oil fires

comes from a study limited to data from military hospitalizations, which found no excess cancer

hospitalizations in relation to modeled smoke exposure levels.1434

Remaining questions. Although an extensive amount of information is available from diverse

sources concerning exposures associated with the Kuwaiti oil fires and their likely health effects, a

number of questions specifically related to the health of Gulf War veterans remain unanswered. These

include questions concerning levels of toxic exposures likely encountered by the subgroup of veterans

who were very close to the burning wells for a prolonged period during February and March of 1991.

Little information is available on health effects potentially resulting from prolonged inhalation of oily

smoke, possibly combined with oil ingestion and dermal oil exposures. In addition, no information is

available from epidemiologic or toxicology studies concerning the potential for oil fire exposures to act

synergistically with other Gulf War-related exposures. Preliminary evidence indicates that oil fire

exposure has not been associated with increased cancer rates, but may have contributed to increased

asthma rates in Gulf War veterans. Additional studies are needed to provide more conclusive answers

with respect to asthma and other chronic respiratory conditions in relation to oil fire exposures.

Continued monitoring of cancer rates in Gulf War veterans is also important, in part to determine whether

cancers with long latency periods may be associated with oil fire exposures in the Gulf War.

Summary. Gulf War illness and the Kuwaiti oil well fires. The roaring flames, darkened smokefilled sky, and petroleum rain from the hundreds of Kuwaiti oil fires burning from February through

November of 1991 are among the most vivid images of the Gulf War. Measurements taken by

environmental assessment teams in theater, particularly after May of 1991, indicate that the primary oil

fire-related pollutants of concern were high levels of particulates, but that chemical air pollutants were

generally below established standards. Little information is available, however, on measured levels of oil

fire-related pollutants in close proximity to the burning wells, particularly in the early months of 1991

before seasonal winds dissipated the heavy clouds of smoke at ground level.

The majority of Gulf War veterans encountered some level of smoke from the Kuwaiti oil well fires,

although exposure was transient for many. Epidemiologic studies have routinely evaluated rates of Gulf

War multisymptom illness in relation to oil fire exposure, using diverse assessment methods and

providing mixed results. Overall, the lack of consistent findings relating oil well fires to Gulf War illness,

particularly from the methodologically stronger studies, and the modest degree of risk identified by

studies that found a significant association, indicate that the Kuwaiti oil well fires are not likely to have

been the primary cause of Gulf War multisymptom illness for the majority of affected veterans. This

general conclusion is qualified, however, by indications from several studies that more intense or

sustained exposures may be associated with multisymptom illness, and the lack of information concerning

the subset of veterans with particularly high exposures. In addition, one high-quality study has provided

evidence that smoke exposure from the Kuwaiti oil fires is associated with an excess rate of asthma in the

subset of Gulf War veterans with higher-level exposures.
84  Effects of Gulf War Experiences and Exposures

Recommendations

Based on available research and exposure information, the Committee finds that Kuwaiti oil well fires are

not likely to be the primary cause of Gulf War illness for the majority of affected veterans. However,

additional information is required to determine if higher level oil well fire exposures may have

contributed to the risk of Gulf War illness or diagnosed medical conditions in identifiable subsets of Gulf

War veterans. To address remaining questions related to long-term health effects of the Kuwaiti oil fires,

the Committee recommends the following research:

 Analyze data collected from completed and ongoing epidemiologic studies to determine whether

the subset of Gulf War veterans with the highest level exposures to smoke, oil, and particulates

from the Kuwaiti oil well fires have elevated rates of Gulf War illness or other conditions. Such

analyses should properly adjust for confounding effects of other Gulf War exposures.

 Conduct additional analyses of existing data from the U.S. national survey of Gulf War veterans

and the Phase III clinical study to determine if rates of upper and lower respiratory conditions,

pulmonary function abnormalities, or other medical conditions are significantly associated with

modeled or self-reported levels of oil fire exposures.

 Continue monitoring cancer rates in Gulf War veterans, including assessment of cancer rates

among subsets of veterans identified by modeled levels of oil fire exposures, self-reported oil fire

exposure levels, and/or locations and time periods of deployment
Depleted Uranium and the Health of Gulf War Veterans  85

Depleted Uranium and the Health of Gulf War Veterans

After everything was over, we went back through the areas we had shot up and climbed all

over the vehicles we had destroyed. We wanted to see the damage our tanks had done, and

we were looking for souvenirs. I know of one guy who found a spent DU penetrator rod and

kept it. I knew we were shooting DU rounds, but we were never told to stay away from

vehicles that were hit by DU rounds. Now I know that we probably got DU dust all over us.

But we didn’t know any better, and we were dipping, smoking, and eating without having

washed our hands. Right after the war we saw lots of guys from other units climbing on the

vehicles we had shot with DU rounds. ... In April, 1991, while we were in Kuwait, I started

getting diarrhea, nausea, stomach cramps, headaches, and tightness in my chest. My

problems have gotten worse since then.

--Gulf War veteran, 2nd Armored Division425

The 1990-1991 Gulf War was the first conflict in which armaments containing depleted uranium, or DU,

were widely used in a war zone. Depleted uranium is a dense, weakly radioactive metal with physical

properties that make it particularly useful in weapons. Troops on the ground in the 1991 war were often

unaware that the U.S. was firing DU munitions, that some U.S. tanks were shielded with DU armoring, or

that precautions should be taken against possible health hazards related to this substance. After military

personnel began reporting unexplained health problems in the aftermath of Desert Storm, questions have

been raised concerning DU’s possible role in causing or contributing to these conditions.

Like other potentially hazardous substances encountered in the Gulf War, no measurements or records

exist that quantify the amount of DU to which individuals were exposed. Unlike other Gulf War-related

exposures, however, there is relatively little information available from epidemiologic studies concerning

veterans’ exposure to DU and its possible link to Gulf War illness. To address some of the unknown

factors related to DU exposure in the Gulf War, the U.S. Department of Defense (DOD) mounted an

extensive effort to model and/or recreate DU exposure scenarios in order to estimate likely exposure

levels under specific circumstances.1172,1620 Such efforts have provided information on likely levels of DU

exposures for some personnel who served in Desert Storm, particularly those involved in friendly fire

incidents.1173 Measured and modeled DU exposure levels have, in turn, been used to estimate the risks of

specific health problems such as cancer and kidney damage that might be expected from those exposures.

What has not been assessed to a meaningful degree by these models, however, is the extent to which the

multisymptom illness affecting Gulf War veterans may be associated with DU exposures during

deployment.

Depleted uranium is a byproduct of the process that converts natural uranium to enriched uranium for use

in nuclear weapons and reactors. What remains, “depleted” uranium, is about 60 percent as radioactive as

natural uranium.1620 In addition to potential hazards associated with its radioactivity DU, a heavy metal,

also presents a possible chemical hazard. It is its extreme density that makes DU exceptionally valuable

in armor-piercing rounds and as an armoring material for tanks. The effectiveness of DU in weaponry

was evidenced by the thousands of Iraqi tanks that were destroyed during the Gulf War by the 120 mm

armor-piercing DU penetrators fired by Abrams tanks and the 25 and 30 mm DU rounds fired by the Air

Force’s A10 aircraft and the Marine Corps’ AV-8B Harriers. DU was also remarkably effective as an

armoring material. DOD reports indicate that no American tanks protected by DU armoring were

penetrated by Iraqi fire.1620

In addition to its extreme density, DU has another property that enhances its effectiveness in weapons.

Depleted uranium is pyrophoric, that is, DU rounds burst into flames when they hit their target, causing

fire and frequently explosions when the targets’ fuel tank or munitions are ignited. The resulting fire and

exhaust contain DU dust and aerosol, which can be inhaled or ingested by personnel in the area, and

absorbed onto their clothing and skin. This dust also settles on what is left of the target vehicle and in the

surrounding area.
86  Effects of Gulf War Experiences and Exposures

About 320 tons of DU was used during the Gulf War1620 and much of that material is believed to still be

present in the local environment. Since the 1990-1991 Gulf War, the U.S. and its allies have also used

DU in conflicts in the Balkans and in operations in Afghanistan and Iraq. A number of agencies and

groups have raised concerns about the potential for long-term environmental damage that may result from

DU’s persistence in soils and water in areas where it has been used in warfare.181 International attention

to this issue has resulted in a number of reports concerning DU’s environmental and health

effects.1325,1696,1811 Questions related to environmental contamination associated with the use of DU will

not be addressed by the present report, however, since they do not directly pertain to the Committee’s

charge of reviewing research on the health of Gulf War veterans.

Current military policy now directs soldiers who come into contact with spent DU munitions or areas

contaminated by DU to wear protective clothing, to shower immediately following exposure, and to be

medically evaluated.1598 Because no such information or training was provided during the 1990-1991

Gulf War1671 it is important to determine whether chronic health problems may have resulted from DU

exposures.

Depleted Uranium Exposure in the Gulf War

The largest number of military personnel exposed to DU during the Gulf War were the thousands who

were in areas of and/or came into contact with destroyed Iraqi vehicles—those in or around burning or

destroyed vehicles as part of their official duties and those just interested in these vehicles—climbing on

them, getting inside, and taking souvenirs after the battle. DU exposures for the majority of those in the

Gulf War, then, would have primarily been through inhalation, ingestion, and dermal contact.

The highest dosage DU exposures during the war, although they involved considerably fewer individuals,

were those in which vehicles carrying U.S. troops were mistakenly hit by DU rounds in friendly fire

incidents. These U.S. vehicles may or may not have themselves been loaded with DU munitions or DU

armoring. American personnel in or on tanks hit by DU rounds would have experienced more

concentrated levels of inhaled DU. Some individuals were actually hit by DU munitions or shrapnel, and

may continue to carry DU fragments in their bodies to this day.

We were in a congested area with burning vehicles all around. Suddenly, the tank in front of

us caught fire. The ammunition blew, but the blowout panel saved the lives of the crew. We

saw DU penetrators flipping end over end over our heads. We immediately rushed to the tank

to rescue the guys in it. We were breathing smoke from the burning ammo, but we had no

concern about DU and took no protective measures. Afterwards, we stayed around that area

for two or three hours but we were buttoned up due to exploding vehicles and ordnance

around us.

--Gulf War veteran, 24

th Infantry Division425

The Camp Doha fire. A major DU incident of concern involves a July, 1991, fire at a U.S. military

base in Doha, Kuwait.1361 The fire began in an M992 ammunition carrier loaded with artillery shells, then

spread to stored munitions and vehicles loaded with ammunition. The scene has been described as a

chaotic series of explosions and fires that scattered munitions and debris over a wide area, with vehicles

and shells exploding for over six hours, and fires burning for a full 24 hours.425,1620 The fire damaged or

destroyed almost $15 million in ammunition, over 100 vehicles, and over 20 buildings.1620 When the fire

was out, the area remained extremely hazardous due to the dispersion of massive amounts of debris

containing live ordnance, and settling of oxidized DU dust in the area. Injuries and three deaths are

reported to have resulted from unintentional detonations of the ordnance.1361 Afterwards, the Army

cleared the area and removed most of the contaminated soil. Tests conducted by the International Atomic

Energy Agency (IAEA) in 2001 determined that high levels of DU were still present in soil removed from
Depleted Uranium and the Health of Gulf War Veterans  87

the area during the 1991 clean up operation.691 DOD reports indicate that as many as 4,000 people were

in the area during the fire and that afterwards, over 600 individuals were directly involved in cleanup and

decontamination.

1620 Cleanup efforts took months to complete, during summer temperatures that typically

exceeded 110 degrees, with workers often engulfed by smoke from the burning oil well fires nearby.1620

Recovery workers were reported not to have used protective measures during cleanup, with many

unaware of the hazards potentially associated with DU.1361

Others who likely experienced higher levels of DU during deployment were personnel whose duties

included disposing of or cleaning up enemy and U.S. vehicles damaged or destroyed during the war. This

included members of a Battle Damage Assessment Team charged with evaluating U.S. vehicles hit by DU

munitions and members of the 144th Service and Supply Company who processed damaged equipment,

including vehicles hit by DU.1620

For three months after the fighting stopped, R. and his buddies in the 3rd Armored Division

combat engineer squadron were ordered to crawl around in the black dust left over from

successful shots of depleted uranium. He was ordered to live and breathe in it while finishing

the job of destroying damaged Iraqi tanks and munitions, to make sure the enemy’s

equipment couldn’t be used again. ‘We actually slept underneath destroyed tanks and stuff

because we figured they wouldn’t fire at their own destroyed vehicles,’ R said. For months,

the black dust covered many of those vehicles, rubbing off on R’s clothing, getting on his skin,

and often into his food and water.

--Interview with Gulf War veteran, 3rd Armored Division415

How many Gulf War veterans were exposed to DU during the war? The IAEA has estimated

that over 860,000 DU rounds were fired in the Gulf War.691 Government reports have not provided

information cataloguing specific sites where DU munitions were fired or individual units likely to have

had the greatest exposures, as has been done in relation to oil well fires and low-level nerve agent

exposure. An exposure analysis conducted by a veterans’ group involved in the DU issue concluded that

“several hundred thousand Gulf War veterans may have inhaled, ingested, or incurred wound

contamination by depleted uranium dust”425 but there are no official government estimates of the total

number exposed. A DOD map provided to the Presidential Special Oversight Board in 1998 indicated

that the highest concentration of DU munitions were fired in southern Iraq and Eastern Kuwait, within

100-200 kilometers of Iraqi borders with Kuwait and Saudi Arabia.1232,1612 It is likely that the greatest

concentration of DU-exposed military personnel would be those in locations where air assaults and

ground battles took place. Epidemiologic studies have indicated that about 30 percent of Gulf War

veterans participated in ground combat751 and about 40 percent were in areas where combat took place.1476

In a 2000 Environmental Exposure Report, DOD’s Office of the Special Assistant for Gulf War Illnesses

classified DU exposure into three categories. The report estimated that up to 164 individuals experienced

Level I exposures—the highest level—in association with friendly fire incidents. Over 700 more were

estimated to have experienced Level II exposures in connection with processing of enemy and U.S.

vehicles hit by DU munitions and with cleanup operations after the Doha fire. The report indicates that

the number of personnel who experienced Level III exposures, those in areas of burning or destroyed

vehicles, is “unknown.”1620

Health Effects of DU Exposure

Despite the large number of military personnel and civilians potentially exposed to DU during and since

the 1991 Gulf War, relatively few studies have directly evaluated human health effects associated with

DU exposure. Some scientists and commentators have concluded that DU exposure is a likely

explanation for the multisymptom conditions affecting Gulf War veterans, given its potential for both
88  Effects of Gulf War Experiences and Exposures

radiological and chemical effects.132,359,373,375,1303 Yet the specific types of human health effects that have

been described in relation to DU and uranium exposure have little apparent relationship to the pattern of

chronic symptoms associated with Gulf War illness.

Uranium is a dense heavy metal that is ubiquitous in the natural environment, present in differing

concentrations in different areas. Like other heavy metals, it can be taken into the body through

inhalation, ingestion, or dermal exposure. Most uranium that enters the body is excreted through the

digestive system and kidneys.183 Scientific studies, as well as government and special panel reports have

generally concluded that, at exposure levels encountered by most Gulf War veterans, the chemical effects

of DU are of greater concern than the radiological effects.377,769,1235,1325,1326,1571 The specific types of health

hazards generally believed to be of greatest concern are those affecting tissues where DU accumulates in

highest concentrations, cells that are most vulnerable to its effects, and biological processes known to be

affected by metal and/or radiological toxicity. As a result, health and risk assessments have primarily

focused on DU’s effects on kidney function and on DU’s potential for causing cancer, particularly lung

and bone cancers.183,1000

Research on DU-exposed populations. News articles have reported that rates of cancer and birth

defects in Iraq increased dramatically during the 1990s, specifically in regions where the greatest quantity

of DU was used in the Gulf War.28,1309 Conference reports describing an increased incidence of

congenital anomalies in Basrah43 and increased numbers of cancer cases, both in Iraqi military personnel

who served in the war and in four Iraqi hospitals, lend some support to these contentions.38,931,1078

Limitations in the data make clear interpretation of these reports impossible, however, and no formal

studies have been conducted to clarify this issue.

About 14 tons of DU-containing munitions were used by U.S. forces in the Balkan conflicts during the

1990s.1624 News reports of a perceived excess of leukemia among European soldiers who served in the

Balkans raised concerns about a possible “Balkans Syndrome” resulting from DU exposure.373,454,859,1346

Although no “Balkans Syndrome” issue has been raised among U.S. troops, one study reported that urine

uranium levels were increased in a small cohort of U.S. soldiers during and after their deployment to

Bosnia. The study did not provide information on symptoms or other health parameters, and uranium

levels in this cohort remained below mean levels in the U.S. population.985 In addition, British veterans

who served in Bosnia were not found to have higher rates of symptoms or physical impairment than their

nondeployed peers.642,1698 Several research studies have assessed cancer rates among U.N. soldiers

deployed to the Balkans but have not found excess rates of leukemia.547,1495 One study has reported an

excess of bone cancers among Danish troops who served in the region, based on four identified cases,1495

and another study reported a slight increase in the rate of all cancers combined among Swedish troops

who served in the region.547

Studies have also reported elevated rates of chromosomal and cellular abnormalities, particularly

micronuclei formations, among individuals who live in areas where NATO forces used DU munitions in

the Balkans.

673,841,1029 Health implications of these findings are unknown, since affected individuals were

not reported to have any clinical indications of disease. An additional study found no post-war increase in

the rates of childhood leukemia in Croatian counties in which DU was used during the war.854 Studies of

people living in the Sarajevo region during and after the war in Bosnia and Herzegovina indicate that

rates of several types of cancer have increased in recent years, including lung and laryngeal cancer, breast

cancer, bladder cancer, bone cancers, and malignant lymphomas. These increases were said by

investigators to parallel those in other countries in Southeastern Europe over the same period.

Researchers were unable to determine whether increased cancer rates in the Sarajevo region may have

some relation to DU contamination, to other war-related nutritional, environmental, or psychological

factors, or to other risk factors such as smoking, which is extremely prominent in the region.1108,1137
Depleted Uranium and the Health of Gulf War Veterans  89

Depleted uranium munitions and armoring have also been used extensively in current conflicts in Iraq and

Afghanistan. One study has reported elevated levels of excreted uranium in a small group of civilians

living in an area of Afghanistan where DU munitions were used in 2002 .

375,376 No information was

provided concerning symptoms or medical conditions in relation to the presence/absence of uranium in

these individuals, however. There have been no indications of a widespread problem with undiagnosed,

multisymptom illness in military personnel returning from service in Iraq or Afghanistan.631 Members of

one U.S. Army National Guard police unit that served in Operation Iraqi Freedom (OIF) did report

unexplained health problems after their return from the war in 2004, however.

507,508 This unit was not

directly involved in combat but had been camped in a former train depot near Samawah, Iraq, with

destroyed Iraqi tanks in the area. In news reports, veterans described the living environment in the camp

as “disgusting. Oil, dirt, and bird droppings everywhere, insects crawling all around us.”507 Believing

their problems could be related to DU contamination, some members of the unit have been tested for DU

levels by both the Army and a private laboratory, with contradictory results.508,803 The specific cause or

causes of the health problems in this unit have not been resolved.

Studies of workers occupationally exposed to uranium can also provide insights into possible effects of

DU exposure. Uranium’s chemical properties are identical to those of DU and its radiological effects

exceed those of DU. Studies of uranium miners and mill workers provide information on effects of

exposure to uranium dust sustained over a prolonged period of time. Multiple studies have identified

elevated rates of lung and laryngeal cancer among workers occupationally exposed to

uranium58,184,371,848,1000,1342,1546 and additional studies have indicated that uranium mining may be

associated with increased rates of leukemia1057,1266 and other cancers.372 Recent reviews and government

reports have concluded that the apparent association between occupational uranium exposure and cancer

is questionable, due to multiple confounding factors.769,1571 Most prominently, studies have indicated that

the elevated rate of lung cancer in uranium miners is likely caused by radon exposure in uranium mines

rather than from the uranium itself, except at very high exposure levels.1000,1571 Kidney function has also

long been a concern in relation to uranium exposure. Studies have documented impaired kidney function

in uranium workers,1538 although none have found an excess of mortality from renal disease.1000

Due to worldwide concern about possible long-term health and environmental effects resulting from the

use of DU munitions, a number of scientific bodies and government agencies have sponsored scientific

reviews to assess DU’s likely health effects. Key findings from these reports are summarized in Table 1.

Overall, these reviews have consistently found that available evidence indicates that DU exposures, at

levels experienced by the majority of Gulf War veterans, are not expected to produce long-term health

effects, specifically in relation to excess cancer rates and chronic renal disease. Several of these reports

indicated that there may be a minimal excess in cancer risk among the relatively few personnel with the

highest level exposures—those involved in friendly fire incidents and those whose work included

processing of DU-contaminated vehicles for extended periods. It is important to note, however, that risk

assessments provided by all of these reports are based on toxicological and epidemiologic studies focused

on specific health outcomes—primarily cancers and kidney disease. They do not provide information

concerning risk associated with the development of chronic symptoms or symptom complexes.

Modeled risk assessments, while informative, do not supplant the need for research that directly and

systematically evaluates health outcomes of interest in relation to uranium and DU exposure, particularly

health outcomes not previously evaluated in occupational studies. Almost no information is available that

directly supports or refutes a possible association between uranium exposure and chronic symptom

complexes that resemble Gulf War illness. On one hand, there has been no mention in the medical

literature of a multisymptom syndrome in workers occupationally exposed to uranium, as has been

described for some other occupational groups exposed to neurotoxicants.

735 On the other, no studies were

identified that specifically evaluated the occurrence of chronic symptoms in uranium-exposed

populations. Several case reports have described neurological effects following extremely high levels of

uranium exposure.495 For example, workers accidentally exposed to a high dose of uranium aerosol
90  Effects of Gulf War Experiences and Exposures

Table 1. Health Effects of Depleted Uranium: Key Findings of U.S. and International Reports

Report Year(s) Key Findings

RAND581 1999 Little concern related to radiological effects and cancer or other health outcomes. Chemical

effects potentially associated with hematological and renal changes, but evidence does not

suggest long-term excess morbidity or mortality.

Institute of

Medicine679,690

2000

2008

Evidence is inadequate to determine whether there is an association between uranium

exposure and lung cancer or other identified cancers. There is also insufficient evidence to

determine whether uranium exposures is associated with nonmalignant renal diseases,

respiratory disease, or reproductive effects.

USACHPPM1576 2000 In the Gulf War, Level I exposures may have exceeded radiation and chemical standards,

warranting medical follow-up of individuals in friendly fire incidents; Levels II and III exposures

are not likely to cause health effects.

DOD Environmental

Exposure Report1620

2000 DU potentially poses a chemical hazard at very high levels, but Gulf War exposure levels are

not expected to produce adverse health effects due to chemical or radiological effects.

World Health

Organization1811

2001 DU may produce transient dose-related effects on renal function; Insoluble inhaled particles

may cause radiological damage in lung tissues, dermal effects are unlikely. Environmental

clean up operations are recommended in high exposure areas, but population screening is not

necessary.

British Royal

Society1325,1326

2002 Higher level DU exposures are potentially associated with increased rates of kidney damage,

lung cancer. Excess risk associated with radiation, primarily for lung cancer, is extremely

small. Chemical toxicity may cause acute kidney effects in relation to very high exposure.

International Atomic

Energy Agency691

2003 Based on measurements taken of environmental samples at 11 sites in Kuwait in 2001, DUrelated radiation exposure to the local population is low and does not present a health hazard.

Capstone Report1173 2004 Modeled health risks from DU inhalation, based on simulated friendly fire exposures, indicate

that health effects from radiation are generally unlikely for personnel in, on, or near vehicles hit

by DU munitions. Minimal increase in cancer risk and short-term kidney effects possible for

personnel in unventilated Abrams tanks. Individuals working in DU contaminated vehicles for

long periods may also exceed occupational exposure standards.

Sandia National

Laboratories967

2005 Minimal excess cancer risk expected for DU-exposed veterans—too small to detect in veterans

with less than Level I exposures, with most excess due to lung cancer. Renal effects are

unlikely, but neurotoxic effects cannot be ruled out based on limited available evidence.

Continued monitoring for long-term or unexpected health effects is recommended.

Abbreviations: DU = depleted uranium, USACHPPM = U.S. Army Center for Health Promotion and Preventive Medicine,

DOD = Department of Defense

during World War II were reported to have “mental status changes believed to be in excess of what would

be caused by a fear reaction” but no clinical effects were noted when two of the workers were reevaluated

38 years later.770 A case report of long term effects of a massive skin exposure to uranium indicated that,

seven years later, the patient continued to experience chronic tiredness, dizziness, and headache.1837 In

general, however, there is little reliable information concerning the presence or absence of chronic

symptoms and neurological abnormalities in relation to uranium exposures.

Taken together, human research on the effects of uranium exposures indicate that the potential for DU to

cause some cancers, particularly for those with higher-level exposures, cannot be ruled out. No excess of

symptomatic illness has been reported in studies of workers occupationally exposed to uranium or people

living in areas where DU has been used. However, there is also no indication that symptomatic health

outcomes have been assessed in these populations. Overall, the extensive use of DU in current conflicts,
Depleted Uranium and the Health of Gulf War Veterans  91

and the absence of a widespread “Gulf War illness”-type problem, argues against a major role for DU in

the etiology of Gulf War illness. In addition, the types of diagnosed conditions that have been assessed in

relation to uranium exposure, such as lung cancer and renal disease, have thus far not been associated

with Gulf War service.

Animal research on the effects of DU. As with other potentially toxic exposures, ethical

considerations prohibit experimental studies involving human exposure to DU. Information on specific

biological effects of DU exposure is obtained, therefore, from animal studies and studies involving in

vitro exposure of cells and tissues to uranium compounds. A large number of studies investigating

biological effects of DU have been reported in the medical literature in recent years—nearly a hundred in

the past decade. Uranium and DU toxicity depend on dosage and route of exposure, and on the chemical

form of the uranium compound, particularly its level of solubility. Studies have evaluated effects of DU

administered in diverse ways to different animals and tissues at varying dosage levels and durations.

DU effects potentially relevant to Gulf War illness. Gulf War illness and associated symptoms cannot

specifically be evaluated in animal models, but recently-demonstrated biological effects of DU may have

relevance to Gulf War illness. Kidneys and lungs have traditionally been considered the primary target

organs for uranium toxicity, but animal studies have recently shown that uranium exposure can also target

the brain.21,288,713,1168 Early studies of uranium-exposed animals rarely evaluated effects on the central

nervous system,873 although several studies conducted prior to 1950 had indicated that very high uranium

exposures can lead to muscle weakness and gait disturbances in cats and dogs383 and cellular degeneration

in the choroid plexi in dogs and rabbits.1246,1715

More recent studies, summarized in Table 2, indicate that uranium and/or DU can accumulate in the

brain, where it can be associated with biological and behavioral effects. Neurological effects have been

demonstrated in multiple studies, mostly in relation to prolonged exposure to soluble forms of DU, and

also in relation to prolonged exposure to DU pellets implanted under the skin. Uranium appears to cross

the blood brain barrier883,1192 and accumulate differentially in specific brain regions, most consistently the

hippocampus, cortex, midbrain, and cerebellum. Of particular relevance to the Gulf War experience, two

studies610,896,1061 have shown that inhaled uranium aerosols can access the brain directly, crossing the

“nose-brain barrier,” in ways similar to those documented for other heavy metals356,357,897 and independent

of circulating uranium levels. Of particular interest are findings from an ongoing study at the University

of New Mexico indicating that DU penetration into the brain through the nose is enhanced in the presence

of nasal inflammation.896

DU and uranium have also been shown to affect learning and behavior in animal studies, in some cases at

dosages below those associated with renal toxicity.12,97,174,647,890,1061 In addition, one study has provided

preliminary evidence that some neurological effects may result from uranium’s radiological, and not just

its chemical properties. French researchers have reported that ingested enriched uranium accumulates in

the hippocampus and hypothalamus at levels that exceed those of DU, and produces greater alterations in

sleep patterns and behavior.647

Taken together, this group of studies indicates that DU and uranium can accumulate in the brain and can

produce biochemical and behavioral alterations in animal models. It remains to be determined, however,

if DU exposures like those encountered by the largest number of Gulf War veterans, that is, exposure to

more insoluble forms of DU via inhalation or ingestion for more limited time periods, can produce

chronic neurological or behavioral effects. The New Mexico study is an important example of a

particularly relevant approach, involving dosage and exposure scenarios that parallel those of Gulf War

veterans.

896 The Committee looks forward to reviewing final results from this project as they become

available.
92  Effects of Gulf War Experiences and Exposures

Table 2. Brain and Behavioral Effects of Uranium and Depleted Uranium in Animals

Study Model Exposure Major Finding(s)

Pellmar1192

1999

rat DU pellets implanted for 6,12, 18

months

Brain is a reservoir for DU; differential brain accumulation at 18

months, elevated in cortex, midbrain, vermis

Abou-Donia12

2002

rat Uranyl acetate injected IM, 0.1 and

1mg/kg, 1x/day, 7 days

30 days post exposure, nitric oxide increased in midbrain and

cortex, increased AChE activity in cortex, reduced neurobehavioral

performance on inclined plane, grip time, beam walk

Briner173

2002

rat Uranyl acetate in drinking water,

varied doses for 2 weeks, 6 months

Time-dependent behavioral changes (line crossing, rearing)

Lewis610,896

2004

rat Inhalation of uranium aerosols in

dosages and durations to parallel

Gulf War scenarios

Limited brain uptake of uranium evident in a fraction of animals,

primarily in olfactory bulb. Evidence of neuroinflammation (glial

fibrillary acidic protein) with more soluble forms and with concurrent

nasal inflammation.

Barber98

2005

rat Single uranyl acetate IP injection,

1mg/kg

Uranium entered brain rapidly, cleared slowly, distributed

heterogeneously; elevated in cortex, hippocampus, cerebellum after

7 days; stress enhanced uranium clearance

Briner174

2005

rat Uranyl acetate in drinking water,

varied doses, 2 weeks or 6 months

Dose-dependent behavioral changes (increased line crossing,

rearing), appeared earlier in males; increased brain lipid oxidation

Houpert647

2005

rat Enriched (EU) or DU in drinking

water, 1.5 months

Both accumulated in brain, particularly the striatum; EU also

accumulated in hippocampus and hypothalamus; EU but not DU

increased paradoxical sleep, reduced spatial working memory,

increased anxiety-like behavior

Lestaevel890

2005

rat Uranyl nitrate injected IP at 70,

144 ug/kg

Decreased food intake, reduced paradoxical sleep

Lestaevel889

2005

rat Uranyl nitrate in drinking water

(40 mg/l) for 90 days

EEG changes after 30 days: increased rapid eye movement sleep

and theta band power during light period

Monleau1061

2005

rat Inhalation of U02 aerosol for 30

min, 4 days/wk, 3 wks

Differential accumulation in brain: olfactory bulb > hippocampus >

frontal cortex >cerebellum; increased locomotor and rearing

activity, impaired spatial working memory

Bussy202

2006

rat Uranyl nitrate in drinking water

(40mg/l) up to 9 months

Uranium accumulated in striatum, hippocampus, frontal cortex;

dopamine level decreased at 1.5 months in hypothalamus, AChE

decreased in cerebellum after 6 months; decreases in dopamine,

serotonin levels and turnover ratios in frontal cortex and striatum

Fitsanakis444

2006

rat Implanted DU pellets, 3 or 6

months

DU accumulates in brain, significantly elevated in cortex, midbrain,

and cerebellum at 6 months

Arfsten60

2007

rat 0-20 DU pellets, implanted 150

days

No evidence of significant neurobehavioral effects

Barber99

2007

rat Single injection of uranyl acetate,

varying doses (0.1-1.0 mg U/kg).

Brain levels of uranium remained elevated after serum levels

normalized at 7 days. Highest dosage sign. reduced motor activity,

grip strength. Striatal dopamine transiently reduced after highest

dose. Effects modulated by stress prior to exposure.

Abbreviations: DU = depleted uranium, IP = intraperitoneal, IM = intramuscular, AChE = acetylcholinesterase, U0x= oxides of uranium
Depleted Uranium and the Health of Gulf War Veterans  93

Additional DU studies that may also have relevance to Gulf War illness include those demonstrating that

DU exposure can produce immunological changes, including macrophage apoptosis, increased production

of proinflammatory cytokines, and indicators of oxidative stress in exposed cells and animal

tissues.365,739,1061,1196,1751 At sufficient doses DU exposure, like other heavy metals, may also affect the

liver’s ability to effectively process other toxic compounds.538,1222,1452

Genotoxic and mutagenic effects of DU. In addition to Gulf War illness, concerns have been raised

about the potential for DU exposures to lead to increased rates of cancer, particularly cancers that develop

over longer latency periods and might not yet have been detected in Gulf War veterans. Early animal

studies had suggested that prolonged inhalation of uranium aerosol can lead to delayed development of

lung tumors in dogs.873 In recent years, multiple studies have shown that DU and uranium have genotoxic

and mutagenic effects on cells, producing changes associated with tumor growth in animals, as

summarized in Table 3. Much of this research has been conducted by scientists at the U.S. Armed Forces

Radiobiology Research Institute (AFRRI). As shown, studies have addressed cancer-related questions on

multiple levels using diverse models. Exposure of a variety of cultured cell lines to soluble and insoluble

forms of DU has been shown to produce genotoxic effects, including increased frequencies of DNA

strand breaks, adducts, micronuclei, chromosome aberrations, dicentrics, and sister chromatid

exchanges.280,1031,1034,1040,1821 One study reported that these effects can be carried through multiple cell

generations,

1034 and two studies have indicated that genotoxic effects of inhaled uranium aerosols may be

potentiated by repeat exposures.1062,1063 Recent in vitro studies also suggest that genotoxic effects of

lower-dose DU exposures are more likely to be reversible than higher dose exposures.1532

Additional studies have shown that soluble and insoluble forms of DU can cause mutagenic cellular

changes and transformation, and that these transformed cells are highly tumorigenic.1031,1039,1040 Of direct

concern for Gulf War veterans who continue to carry DU-containing shrapnel fragments in their tissues,

New Mexico investigators have found that animals with DU fragments implanted in their muscles

develop soft tissue sarcomas at increased rates around those fragments.551 In addition, rats with

embedded DU pellets developed leukemia at a significantly elevated rate after being injected with

hematopoietic cells.1032 These studies indicate that continued concerns related to possible carcinogenic

effects of DU are warranted, particularly in relation to embedded DU shrapnel fragments, and support

continued monitoring of exposed populations.

Taken together, animal studies have indicated that DU and/or uranium, in different forms and by various

exposure routes, is differentially distributed in organs and tissues, where it can have effects that have

become known only in recent years.991,1036,1192 Depleted uranium can accumulate differentially in brain

tissues, where it has been associated with physiological, biochemical, and behavioral effects. In addition,

a growing body of research indicates that uranium solutions and aerosols can cause genetic and cellular

changes associated with tumor growth and that embedded DU fragments can be associated with the

formation of tumors. It is important to note, however, that many of the recently-identified effects of DU

developed after prolonged exposure to DU, at doses and in forms not encountered by most veterans

during the Gulf War. Demonstration of the potential for DU, or other Gulf War-related exposures, to

cause adverse effects is not equivalent to demonstrating that those exposures caused Gulf War illness or

other adverse health outcomes in Gulf war veterans. It is important, therefore, to consider information

from toxicology studies in animals in the context of findings from studies of human populations exposed

to uranium and DU and, in particular, studies evaluating the health of Gulf War veterans.
94  Effects of Gulf War Experiences and Exposures

Table 3. Genotoxic, Mutagenic, and Tumorigenic Effects of Depleted Uranium and Uranium

Study Model Exposure Major Finding(s)

Lin905

1993

hamster ovary

cells

Uranyl nitrate, varied

doses

Increased frequency of micronuclei, chromosome aberrations,

sister chromatid exchanges

Miller1031

1998

human osteosarcoma cellsDU-uranyl chloride 2-fold increase in sister chromatid exchanges; 9.6-fold increase in

cell neoplastic transformation frequency; tumorigenic when

injected into nude mice

Miller1035

1998

Ames reversion

assay

Urine from DU-exposed

rats

Dose/time-dependent increased mutagenesis

Miller1039

2001

human osteosarcoma cellsInsoluble DU-O2 Tumorigenic transformation, prevented by phenyl acetate

Miller1040

2002

human osteosarcoma cellsInsoluble DU-O2 25-fold increase in transformation frequency, tumorigenic in nude

mice; genotoxicity (increased sister chromatid exchanges,

micronuclei, DNA breaks); increased dicentric formations

Miller1037

2002

calf thymus DNA DU-UO2(NO3)2 solution Catalyzed oxidative DNA damage at pH 7 in absence of significant

alpha decay

Miller1038

2002

human osteosarcoma cells3 uranyl nitrate

compounds,

50 uM, 24 hrs

Sign. more dicentric formations than nickel; neoplastic

transformation increased with specific activity of uranyl nitrate

Hahn551

2002

rat Implanted DU fragments,

varied sizes

Fragment size-dependent increase in soft tissue sarcomas around

DU fragments

Miller1034

2003

human osteosarcoma cellsDU-UO2NO2 solution Genomic instability in cell progeny (36 days, 30 doublings);

delayed lethality, production of micronuclei up to 36 days post

exposure

Yazzie1821

2003

pBluescript

plasmid DNA

DU-uranyl acetate

dehydrate in the presence

of ascorbate

6-8-fold increase in DNA strand breaks vs. either UA or ascorbate

alone; suggests uranyl ascorbate catalyzes DNA hydrolysis

Miller1033

2004

human liver

carcinoma cells

Insoluble DU-O2, varied

doses

Dose-dependent induction of gene promoters through multiple

pathways

Miller1032

2005

mouse Hematopoietic cells

injected into mice with DU

pellets

Leukemia developed in 76% of mice with DU pellets compared to

12% of controls

Monleau1063

2005

rat Inhalation of UO2

(insoluble) and UO4

(soluble) aerosols

DNA strand breaks in bronchoalveolar cells, potentiated by repeat

inhalations

Stearns1475

2005

hamster ovary

cells

Uranyl acetate dihydrate,

varied doses

Formation of U-DNA adducts and mutations; DNA strand breaks

and cell death greater in EM9 than AA8 cells

Coryell280

2006

hamster ovary

cells

Uranyl acetate, 200μM,

24 hours

Unique pattern of genetic mutations at hprt locus: fewer base

deletions, more multiexon insertions and deletions

Monleau1062

2006

rat Inhalation of UO2

(insoluble) and UO4

(soluble) aerosols

Repeated UO2 preexposure increases genotoxic effects of UO4

inhalation, no effect of UO4 alone

Abbreviation: DU = depleted uranium, U0x= oxides of uranium, N0x = oxides of nitrogen
Depleted Uranium and the Health of Gulf War Veterans  95

Research on the Health of Gulf War Veterans in Relation to DU Exposure

Laboratory assessment of DU and uranium levels in Gulf War veterans. Several groups have

evaluated DU and uranium levels detectable in Gulf War veterans since Desert Storm, using a variety of

testing methods. One research team, using thermal ionization mass spectrometry to identify specific

isotopes at low concentrations, evaluated urine uranium levels in 25 British, Canadian, and U.S. Gulf War

veterans with inhalation exposure to DU, 8-9 years after the Gulf War.630 No uranium was detected in 2

individuals, 11 had evidence of natural uranium, and 14 tested positive for DU, in varying proportions. A

separate study evaluated genotoxicity in peripheral lymphocytes of British veterans who believed they

had been exposed to DU—14 in the Gulf War and 3 in the Balkans. Analyses indicated an excess of

chromosomal aberrations in this group, particularly dicentric and centric ring chromosomes, but no

elevation in sister chromatid exchanges.1369

Since 1998, VA has sponsored a program to evaluate uranium levels in veterans who have concerns

relating to DU exposure. Between 1998 and 2002, 446 samples were analyzed using 24 hour urine

collections submitted to the Baltimore VA for analysis.993,999 The large majority of samples contained no

detectable uranium, but 22 (5%) were determined to have uranium levels in the “high” range (>0.05 ug/g

creatinine), the upper limit of uranium distribution in the general population. Risk factors most strongly

associated with elevated levels of uranium were having retained shrapnel in the body, being involved in a

friendly fire incident, and being hit by enemy fire.

The Canadian Ministry of National Defence has also provided a testing program for personnel concerned

about DU exposures. A 2002 report provided results for 104 veterans who had submitted 24 hour urine

samples up to that time: 65 had served in the Gulf War, 25 served in Bosnia, and 14 had served in both.

Hair samples were collected and a bone sample from a deceased Gulf War veteran was also tested.

Values from all urine and hair samples were reported to be in the normal range and isotopic analyses

indicated that the uranium present was consistent with natural uranium. Analysis of the bone sample

from the deceased veteran indicated a higher-than-normal uranium concentration, but isotopic analysis

results were also reported to be consistent with natural uranium.1162 A later report indicated that all 227

Canadian veterans tested in the program had normal 24 hour urine uranium levels.1376

Reports on small groups of Gulf War veterans tested by private laboratories have reported elevated

uranium levels more commonly than have been reported from government surveillance

programs.374,375,1376 While some differences may relate to the populations being evaluated, the lower rate

of uranium detection in government programs has spurred discussion and disagreement concerning the

most sensitive and most appropriate testing method to use.374,1469,1626 Unfortunately, regardless of the

methods used or the uranium levels detected, evaluations of this type have provided no direct insights into

health effects of detected levels of DU or uranium. Similarly, identification of chromosome abnormalities

in Gulf War veterans does not provide useful insights into DU’s health effects without data on symptoms

or other health parameters and without suitable comparison groups.

Research studies evaluating the health of Gulf War veterans in relation to DU exposure.

In 2006, the ombudsman for Canadian National Defence and Canadian Forces issued a special report

related to health concerns raised by members of a Canadian combat engineer regiment that had been

camped next to the U.S. compound at Camp Doha when it caught fire in July 1991. The report described

the heroism of members of the unit who entered the compound during the fire to assist in controlling the

damage, and the unit’s medical staff who worked into the night treating hundreds of injured U.S. troops

under extremely hazardous conditions.1101 The ombudsman indicated that soldiers from the unit have

reported significant health problems since their return—severe headaches, respiratory problems, seizures,

tumors—and that these concerns were poorly addressed by Canadian officials. The report was not

intended to document the extent, nature, or causes of the veterans’ health concerns, focusing instead on

how members of the unit had been treated. Yet it provides a compelling illustration not only of health
96  Effects of Gulf War Experiences and Exposures

problems reported by Canadian Gulf War veterans, but also of the lack of systematic information on the

extent to which those problems may have resulted from DU exposure.

Symptom complexes and multisymptom illness. Relatively little information is available from

Gulf War epidemiologic studies concerning the relationship of symptomatic illness with DU exposure.

As summarized in Appendix A-4, three U.S. studies, one Danish study, and one Australian study have

evaluated symptom complexes in Gulf War veterans in relation to veteran-reported DU exposure. In

unadjusted analyses, two of the U.S. studies identified significant associations between DU and

symptomatic illness. In Danish Gulf War veterans, self-reported DU exposure was not significantly

associated with persistent neurological or gastrointestinal symptoms, after controlling for effects of other

exposures.1507 Depleted uranium-related information from most of these studies is problematic, however,

due to limitations in how veterans were asked about exposure. Over and above usual problems related to

accurate recall of self-reported exposures during the Gulf War, Gulf War military personnel were

frequently not aware of what DU was, when it was used, or if they had come into contact with it. As a

result, results from studies that simply asked veterans whether or not they were exposed to DU during

deployment are highly questionable.

As with several other Gulf War-related exposures, exposure to DU, would have been most common

among personnel who served in battlefield areas. Two studies have reported that Gulf War illness and

other health outcomes are most prevalent among veterans who reported being in Iraq or Kuwait during the

war, as opposed to those who remained in areas more distant from battlefields.692,1476

Other health outcomes in relation to DU exposure. There is little information from Gulf War

epidemiologic studies concerning associations between DU exposure and health outcomes other than Gulf

War illness. A 2005 study of British Gulf War veterans reported that those who had reported DU

exposure in earlier surveys had nearly twice the rate of disease-related deaths, overall, as other veterans.

The observed excess was based on a relatively small number of deaths, however, and fell short of being

statistically significant (MRR = 1.99, 95% C.I. = 0.98 – 4.04).944 Evaluation of this same cohort between

1991 and 2002 had not identified any indication of excess cancer rates among Gulf War veterans who

reported DU exposure.943

As previously described, media and conference reports have suggested that children born in Iraq in the

1990s, in regions where high concentrations of DU munitions were fired, have experienced excess rates

of birth defects since the Gulf War. Several studies have also indicated that a limited number of birth

defects have occurred at excess rates in children born to Gulf War veterans.57,361,747 Although many have

speculated that DU exposure causes elevated rates of birth defects, no research information is available

that directly addresses this question. Specifically, no studies that have evaluated birth outcomes and birth

defects among Gulf War veterans and their children have assessed whether there is any connection

between reproductive outcomes and DU exposure in the Gulf War.

VA longitudinal study of Gulf War veterans involved in friendly fire Incidents. Just one

research project has directly evaluated the health of Gulf War veterans with known exposure to DU. In

1993 and 1994, VA and DOD initiated a program to monitor health parameters among U.S. personnel in

friendly fire incidents involving DU munitions. Follow up evaluations have been conducted every 2-3

years since that time.1472 In total, about 70 of the 100 individuals identified as eligible for the program

have been evaluated at least once, with between 29 and 50 individuals participating in any given

evaluation year. About one-fourth of study participants continue to carry embedded shrapnel

fragments.992 A variety of parameters have been assessed in veterans participating in the program. In the

1997 evaluation, 29 veterans involved in friendly fire incidents were compared to 38 Gulf War veterans

with no identified DU exposure.997 Later evaluations did not include an unexposed comparison group, but
Depleted Uranium and the Health of Gulf War Veterans  97

Table 4. Baltimore VA Longitudinal Evaluation of Gulf War Veterans in Friendly Fire Incidents:

Summary of Findings in Veterans with High (vs. Low) Levels of Excreted Uranium

Sources: McDiarmid 992-998

Abbreviations: sign. = statistically significant (p<0.05), ns = borderline statistical significance (0.05<p<0.10), corr = correlated,

HPRT = hypoxanthine-guanine phosphoribosyl transferase

instead compared health measures between subgroups of DU-exposed veterans with lower (< 0.10 ug/g

creatine) vs. higher (> 0.10 ug/g creatine) urinary levels of uranium. A number of differences between

these subgroups have been identified, which are summarized in Table 4.

The most prominent finding from this series of evaluations is that veterans with embedded shrapnel have

continued to excrete elevated levels of uranium throughout the follow up period, levels that have been

fairly consistent over time.628,998 This indicates that these veterans have had a continuous systemic

exposure to uranium as it is mobilized from the fragments and/or a storage depot in the body, and that

excretion has not significantly lowered the body burden of circulating uranium over time.

The significance of identified differences between veterans with higher vs. lower excreted uranium levels

shown in Table 4 is unclear. A number of differences in specific measures have been inconsistent from

year to year. It is not known whether this is because these differences were artifactual or transient, or

because different individuals were in the high and low uranium subgroups in different years. For

Measure Findings (by evaluation year)

Urine uranium 1994, 1997, 1998, 1999, 2001, 2003, 2005: Elevated levels detected in veterans with embedded shrapnel

Renal function 1999: Serum calcium sign. higher, urine creatinine ns lower

2001: Serum creatinine sign. lower; urine total protein and retinol binding protein ns higher

2003: Serum phosphorous sign. higher; retinol binding protein ns higher

2005: Serum uric acid ns lower

Neurocognitive

function

1997: Poorer accuracy on automated performance tests sign. corr with higher uranium levels

2001: Poorer accuracy on automated performance tests ns corr with higher uranium levels

2003: Poorer accuracy on automated performance tests ns corr with higher uranium levels

Serum measures

Hematological 1994: White cells, neutrophils sign. higher; lymphocytes, monocytes sign. lower

1997: Eosinophils ns higher

1999: Neutrophils, monocytes sign. higher; lymphocytes sign. lower

2001: CD4+ T cells, monocytes sign. higher; CD8+ T cells sign. lower; hematocrit and hemoglobin sign. lower

Endocrine 1997: Prolactin sign. higher

2001: Prolactin ns lower; free thyroxine sign. lower

Other 1999: Lactate dehydrogenase sign. lower

2001: Lactate dehydrogenase sign. lower

2003: Glutamic oxaloacetic transaminase ns lower

Genotoxicity

measures

1997: Sister chromatid exchanges ns lower

1999: Sister chromatid exchanges sign. higher

2001: Chromosomal aberrations sign. higher; HPRT mutations ns higher; sister chromatid exchanges ns lower

2003: HPRT mutations ns higher

2005: ln mutation frequencies sign. higher; total number chromosomal abnormalities ns higher

Sperm measures 1997: Sperm concentration sign. higher

1999: Sperm count sign. higher, sperm concentration ns higher

2001: Sperm count and concentration ns higher

2003: Sperm count and concentration ns higher
98  Effects of Gulf War Experiences and Exposures

example, prolactin levels were significantly higher in the high uranium subgroup in 1997, but

significantly higher in the low uranium subgroup in 2001, with levels outside the normal range. From one

perspective, this might be interpreted to indicate that the findings are contradictory and not likely to be

important. Conversely, it might indicate that, overall, prolactin perturbations in this small cohort of DUexposed veterans may reflect time-related changes associated with circulating uranium levels. In general,

study investigators have characterized identified differences as having no clinical significance.

One of the more consistent findings over time relates to indications of poorer accuracy on automated

neurocognitive performance tests in 1997, 2001, and 2003 that correlated with urinary uranium levels.

Investigators indicated that these differences were primarily attributable to a subset of individuals with

embedded shrapnel who were affected by severe complications of their combat injuries. Investigators

later reported that veterans with higher urine uranium levels had worse (but not significantly lower)

scores on a summary measure of cognitive function—the Index of Cognitive Efficiency—in 2005, the

first year this summary measure was reported.994

The 2001 evaluation was the first to identify renal function differences between high and low uraniumexcreting subgroups, which investigators suggested may represent changes in proximal tubule function.992

The 2003 evaluation found indications of changes in glomerular and tubular function in both the high and

low uranium subgroups, but indicated that these were not sufficient to cause clinically significant

problems. In all years through 2003, seminal fluid sperm concentrations were higher in veterans with

higher circulating levels of uranium, but the biological significance of this finding is unknown. In

addition, indicators of genotoxicity were observed in the high uranium-excreting subgroup in 1999, 2001,

2003, and 2005.

A lack of significant differences for any given parameter is also difficult to interpret since, with the

exception of the 1997 comparison group, all veterans in the program experienced a significant DU

exposure in 1991. Further, the study’s comparisons between veterans excreting high vs. low levels of

uranium have little power to identify significant differences, given the small number in each subgroup. In

the 2003 evaluation, for example, measures were compared between 13 DU-exposed veterans in the high

uranium-excreting subgroup and 19 veterans in the low-excreting subgroup.995

Parameters not specifically followed or reported over the years include a 1997 finding that five of the 17

DU-exposed veterans tested had detectable uranium levels in their sperm.997 No subsequent measures of

uranium in sperm have been reported. In addition, reports on this cohort have provided little information

on chronic symptoms or symptom complexes. In 1997, the only evaluation that included a Gulf War

comparison group not involved in friendly fire incidents, 90 percent of veterans in the friendly fire cohort

and 71 percent of comparison group veterans were said to have at least one medical problem.997 Some of

the DU-exposed veterans were dealing with the aftermath of severe trauma and injuries—burns, wounds,

and loss of limbs—resulting from the friendly fire incidents in which they were involved.628,997

Investigators categorized medical problems into groups, and reported that the 38 veterans not involved in

friendly fire incidents more often reported “nervous system” and “other” problems than the 29 veterans

in the friendly fire cohort. Thereafter, no differences in “medical problems” were found between

subgroups of DU-exposed veterans excreting high vs. low levels of uranium. It is not clear whether

specific assessments were ever made to determine the frequency and severity of the symptoms commonly

associated with Gulf War service.

Longitudinal reports on this cohort have provided little or no mention of tumors, although the Committee

is aware of two veterans in the assessed group who developed cancer and a benign tumor. The discussion

section of the 1999 follow-up report briefly mentioned that the “other” category of health problems

included one veteran diagnosed with Hodgkin’s lymphoma.998 The Committee was informed that another

veteran evaluated in this cohort had developed a nonmalignant bone tumor. Both cases were confirmed

by the principal investigator of the study. Failure to mention these cases in most scientific reports on this
Depleted Uranium and the Health of Gulf War Veterans  99

cohort is puzzling.

996,1472 The study director indicated to the Committee that these cases were not

included because they were not believed to be the result of DU exposure.

Reports on this cohort are often cited to indicate that there are no likely long-term effects of DU exposure,

yet the limited types of information provided and the small number of veterans evaluated leave important

questions unanswered. Most prominently, the study provides no information on possible associations

between DU exposure and the chronic symptom complexes associated with Gulf War illness. And

investigators have not reported on the occurrence of other health outcomes not previously expected to

relate to DU exposure. Given the small size of this cohort, all health outcomes are of interest, even if they

occur as single cases. But the small size of the cohort and lack of an unexposed comparison group mean

the project cannot determine whether DU exposure is associated with common or uncommon diagnosed

conditions of concern such as cancer. As a result, although this longitudinal project has provided useful

information in relation to laboratory parameters in the small number of Gulf War veterans with embedded

shrapnel, it does not provide answers to important questions concerning health effects that may be

associated more generally with DU exposures in the Gulf War.

Taken together, results of epidemiologic studies of Gulf War veterans provide very limited information

concerning possible associations between DU and the health of Gulf War veterans. Risk assessments and

studies indicating that Gulf War veterans should have few concerns related to kidney disease or lung

cancer stemming from DU exposure are reassuring, but provide no insights into possible increases in the

development of chronic symptom complexes or other unexpected health outcomes. The lack of clear

information related to questions of primary concern for Gulf War veterans underscores the need for

additional, focused research studies more capable of providing direct answers to these questions.

Summary. The health of Gulf War veterans in relation to depleted uranium. The 1990-1991

Gulf War was the first conflict in which munitions containing DU were widely used, and the possible role

of DU in causing or contributing to Gulf War-related multisymptom illness has long been the subject of

debate and controversy. About 320 tons of DU were used during the Gulf War and a substantial number

of Gulf War personnel were potentially exposed to DU at lower levels, particularly troops who came into

contact with vehicles damaged by DU munitions. The Department of Defense has indicated that at least

900 U.S. personnel were involved in incidents or activities associated with higher-level DU exposures.

Health risk assessments indicate that DU exposures at levels encountered by the majority of Gulf War

veterans are not likely to result in increased rates of kidney disease or lung cancer, but have not provided

insights directly related to questions concerning persistent symptomatic illness.

Recent animal studies indicate that DU exposure, particularly longer term exposure to soluble forms of

DU, can have adverse effects on the brain and behavior. Research in animal models has also

demonstrated mutagenic and tumorigenic effects of DU that raise concerns, particularly in connection

with sustained DU exposures. Studies of Gulf War veterans have provided limited information

concerning associations between DU and multisymptom illness and other health outcomes of interest.

The extensive use of DU in current Middle East conflicts, in the absence of a widespread “Gulf War

illness”-type problem in returning veterans, suggests that DU is not likely a primary cause of Gulf War

illness for most Gulf War veterans. Questions remain, however, concerning long-term effects of DU in

relation to other health outcomes, particularly among individuals with higher level DU exposures. These

questions indicate the need for epidemiologic research to more comprehensively assess effects of DU

exposure in Gulf War veterans.
100  Effects of Gulf War Experiences and Exposures

Recommendations

Preliminary evidence from animal studies that DU accumulates in the brain and can cause adverse

physiological and behavioral effects is of interest and potentially of great importance. However, the

Committee finds that specifically with respect to the health of Gulf War veterans, the primary issues of

concern are whether DU is a cause or contributor to Gulf War multisymptom illness, cancer, or mortality.

Therefore, prior to making recommendations related to animal/toxicological studies that evaluate

biological effects of DU, additional research is needed to determine whether rates of Gulf War illness, or

other health outcomes, are associated with DU exposure in an expanded cohort of personnel exposed to

DU during the Gulf War.

To address priority questions concerning health effects related to DU exposures in the Gulf War, the

Committee recommends the following research:

 Conduct an epidemiologic investigation to evaluate health outcomes in Gulf War veterans who had the

greatest exposure to DU during deployment and an unexposed comparison group. The exposed cohort

should include Gulf War veterans exposed to DU via inhalation, ingestion, dermal contact, or

embedded fragments as a result of friendly fire incidents, veterans who served in units tasked with

processing Iraqi or Coalition vehicles struck by DU munitions, and in relation to the Camp Doha fire

and subsequent cleanup activities. Evaluated health outcomes should include detailed information on

symptoms, Gulf War illness, functional status, diagnosed medical conditions, and reproductive

outcomes.

 In current and future studies of Gulf War veterans, assess possible DU exposure by querying veterans

in detail about experiences most likely to have resulted in DU exposures, including veterans’

involvement in friendly fire incidents and the extent of their exposure to vehicles destroyed by U.S.

munitions.

 Continue monitoring cancer rates and mortality in Gulf War veterans, including assessment of cancer

and mortality rates among subsets of veterans identified as being exposed to DU and veterans who

served in areas where the highest concentrations of DU munitions were fired.
Vaccines and Gulf War Illness  101

Vaccines and Gulf War Illness

Vaccines given to troops for the Gulf War have been among the most prominent, and controversial,

suspected causes of Gulf War illness. Most military personnel who served in the Gulf War received

multiple vaccinations in preparation for deployment, and many received additional shots in theater. Two

of the vaccines used during the war were intended to protect troops from serious disease, and possible

death, in the event of exposure to biological weapons—anthrax and botulinum toxin—that Iraq was

believed to possess. Since the war, reported adverse reactions to the anthrax vaccine, and quality control

issues related to its production, have given it a particularly high profile as a possible cause of Gulf War

illness. There is relatively little scientific research, however, that has provided clear information on the

potential for the anthrax vaccine, or other vaccinations received by Gulf War veterans, to produce chronic

symptoms similar to those of Gulf War illness. Receipt of multiple vaccines over a brief time period,

prior to and during deployment, has also been suspected as a possible contributor to Gulf War illness.

But relatively little research has specifically assessed the development of chronic symptoms following

receipt of numerous vaccines, particularly the specific shots received by Gulf War personnel.

The Committee has reviewed diverse types of evidence relating to multiple questions concerning the

potential for vaccines—individually or collectively—to have contributed to Gulf War illness. The

Committee’s 2004 report, in a preliminary assessment of the issue, pointed out that several epidemiologic

studies had identified associations between Gulf War illness and vaccines received for deployment. The

Committee recommended both prospective and retrospective assessments of individuals who received the

type of anthrax vaccine used during the Gulf War to determine the degree to which recipients developed

symptom complexes like those affecting Gulf War veterans.

Vaccines Given to Gulf War Military Personnel

Routine and predeployment immunizations. Vaccines are an important component of military

force health protection and readiness in both peacetime and in war. Vaccines routinely administered to

military personnel at the time of the Gulf War are shown in Table 1. New recruits are given a series of

vaccinations to protect them from infectious diseases that are common in the U.S., and also from diseases

of greater concern for military populations. At the time of the Gulf War, new recruits received as many

as 17 antigens during the first two weeks of basic training.1523

Throughout their military service, personnel continue to receive vaccines and boosters to maintain

immunity to pathogens of concern. Additional vaccines are given to specific occupational groups, such as

medical personnel, as protection against risks associated with their job duties. Still other vaccines are

routinely given for overseas deployment, as dictated by circumstances specific to the region.1523 Policies

regarding specific vaccines and schedules are established by each service branch. The Department of

Defense reports that these policies are developed in compliance with U.S. Public Health Service

guidelines and in accordance with the U.S. Center for Disease Control and Prevention’s (CDC) Advisory

Committee on Immunization Practices, in consultation with the Armed Forces Epidemiological Board and

Armed Forces Medical Intelligence Center.1622

The specific vaccines received by individual U.S. troops before and during the Gulf War varied,

depending on shots they had previously received, required boosters, branch of service, and their military

occupation. In addition to the requirement for all personnel to update required vaccines and boosters,

U.S. Central Command (CENTCOM) recommended additional vaccines for deployment to the Gulf War

theater, including meningococcal, typhoid, and yellow fever vaccines, and immune globulin to protect

against hepatitis A.1622 Smallpox, plague, cholera, and rabies shots were not generally recommended.
102  Effects of Gulf War Experiences and Exposures

Table 1. Vaccines Routinely Given to U.S. Military Personnel at the Time of the Gulf War

Vaccine

Personnel Directed

to Receive Vaccine Schedule

Adenovirus all recruits 1 oral dose

Influenza all recruits and active duty annual shot

Measles all recruits 1 shot

Meningococcal all recruits, active duty as required 1

st shot, then booster every 3-5 years

Plague all Marines; Army and Navy special

forces, others in at-risk occupations or

deploying to high risk areas

5 shots over 12 months, then booster

every 1-2 years

Polio all recruits 1 oral dose

Rabies special forces, at-risk occupations 3 shot series

Rubella all recruits 1 shot

Smallpox vaccine or booster to new recruits

through the late 1980s

1 dose

Tetanus-diphtheria all recruits, active duty, and reserve booster every 10 years

Typhoid Army and Air Force alert forces and for

deployment to high risk areas

2 doses in 2 months, then booster every

3 years

Yellow fever all Navy and Marine Corps, Army and

Air Force alert forces and for deployment

to high risk areas

1

st shot, then booster every 10 years

Sources: Takafuji,1523 U.S. Department of Defense1622

Vaccines administered during the war, and the proportions of U.S. and U.K. veterans who reported

receiving those vaccines, are listed in Table 2. The Iowa survey indicated that nearly all Gulf War

veterans reported getting at least one vaccine for deployment: 70 percent reported receiving more than

five vaccines, and 30 percent received more than 10.692

CENTCOM’s Gulf War-specific vaccine recommendations were modified by the different service

branches, most often by the Army. For example, CENTCOM recommended the meningococcal vaccine

be given to individuals that hadn’t received it for at least five years and were likely to have prolonged

contact with local populations. The Army modified this to recommend meningococcal shots for all

deploying personnel.1622 DOD has reported that there were shortages of the meningococcal vaccine,

immune globulin, and influenza vaccine prior to the war, and that some troops may have received some of

these shots in theater.1622

Vaccines against biological warfare agents. Prior to the war, intelligence reports indicated that

Iraq had weaponized two biological agents, anthrax and botulinum toxin, and military officials believed

they posed a possible threat to U.S. troops. Vaccines against both agents were available. The U.S.

anthrax vaccine had been licensed since 1970, and had primarily been used by occupational groups at risk

for anthrax, for example, veterinarians and those working with animal hides. A pentavalent botulinum

toxoid (BT) was developed in the 1950s and, although not licensed, had investigational new drug (IND)

status with the U.S. Food and Drug Administration (FDA). In light of the potential risk posed by these
Vaccines and Gulf War Illness  103

Table 2. Vaccines Given to U.S. Military Personnel Specifically for Gulf War Deployment

Proportion of Veterans Reporting

They Received the Vaccine

Vaccine/

Prophylactic

Measure

U.S. Personnel

Recommended

to Receive Vaccine

Recommended

Schedule

for Gulf War

U.S.

National

Survey751

U.S.

Navy

Seabees527

U.K.

National

Survey1698

Anthrax fixed units, rear deployed 2 shots, 2 weeks apart 41% 30% 57%

Botulinum toxoid fixed units, forward deployed 2 shots, 2 weeks apart;

3

rd shot 10 weeks later

12% 8%

Immune globulin all troops, dose varied by branch and

length of deployment

1 dose (some received

2

nd dose)

60% 41%

Meningococcal all Army; personnel in other branches

who had not received it in 5 years and

would have close contact with locals

1 shot 14% 2%

Typhoid all Army; personnel in other branches

who had not received it in 3 years

2 initial doses or 1 booster 59% 50% 12%

Yellow fever all Marines, Navy, Air Force; Army

special forces

1 shot 14%

Sources: U.S. Department of Defense,

1622 and studies indicated

two agents, the Assistant Secretary of Defense for Health Affairs, in September 1990, recommended

instituting a program of immunization against anthrax and botulinum toxin, with the support of the

Surgeons General of all branches of the armed forces.1622,1635

The immunization protocol for the U.S. anthrax vaccine required a series of six injections over a period of

18 months, with annual boosters thereafter. Adequate supplies of anthrax vaccine were not available to

protect all deploying troops with the six-shot regimen, however.1635 Nor was there enough time to fully

immunize troops in the time frame expected for the war to get underway. At the time of the Gulf War,

the U.S. anthrax vaccine was exclusively produced by the Michigan Department of Public Health

(MDPH). Attempts were made in the fall of 1990 to identify additional sources of the vaccine. According

to DOD, these attempts were unsuccessful,1675 and only MDPH-produced anthrax and BT were ultimately

used during the war.1622 CENTCOM developed a policy for using available supplies, and plans for

additional distribution as more vaccine became available.

Department of Defense reports indicate that 310,680 doses of anthrax vaccine were delivered in theater

and that approximately 150,000 troops received one or more anthrax shots. The U.S. Gulf War biological

warfare vaccine program was terminated in March of 1991, when CENTCOM indicated that individuals

who had begun anthrax or BT vaccine series need not complete them.1622

Policies for distribution of biological warfare vaccines to U.S. troops were established in December,

1990, after available supplies were ascertained. A report from DOD indicates that CENTCOM based its

policy for use of the anthrax vaccine on the expectation that, since anthrax takes several days to develop,

it would most likely be used against troops who were not forward deployed.1622 The policy directed that

anthrax vaccine be given to troops in fixed ground units in areas specified by CENTCOM, listed in Table

3. It was not to be given to transient or shipboard personnel, with the exception of pathologists and

laboratory workers.1636 The majority of Gulf War troops vaccinated against anthrax received one or two
104  Effects of Gulf War Experiences and Exposures

shots in theater, in January and February 1991.1622 In addition, some Army special operations forces are

reported to have received anthrax vaccine prior to their deployment in August of 1990, with a second shot

given in October or November of 1990.1623

GD oversaw the immunization of more than 14,000 troops against anthrax in one 72-hour

marathon completed just a few days shy of the U.N.’s January 15th deadline for Iraq to pull out

of Kuwait. The Army gave the 129th a special commendation for this achievement. But what

really sticks out in GD’s mind are the extra precautions he and his ‘shot teams’ took in giving

troops the injections—precautions that, even today, strike him as peculiar. ‘Each soldier had

to read a classified sheet of instructions, stating that he, or she, was receiving a secret shot,

and that this was for reasons of national security. You don’t want to tell the enemy you’re

getting protection against one of his weapons.’

...‘Our battalion commander also told us there wasn’t enough anthrax vaccine to go around.

Only combat support troops were getting the shot; we were supposed to keep quiet about it so

the front line guys didn’t get upset about not getting the vaccine. It was a morale issue.’

--Report on Gulf War Army Reservist 977

Which individual Gulf War veterans actually received the anthrax vaccine is not known, however.

According to DOD, units were directed to keep a low profile when administering both anthrax and

botulinum vaccines, for operational security purposes. Shots were not to be given in open areas and no

media or photographs were allowed.1636 Personnel were commonly not told what the shots were, or told

not to discuss with others that they had received them. Although vaccines administered by the military

are typically entered into individuals’ shot records, receipt of anthrax and botulinum vaccines during the

Gulf War were often not recorded, or entered with notations like “Vac A” and “Vac A-2” for the first and

second doses of anthrax vaccine and “Vac B” for the botulinum vaccine. Units sometimes used rosters to

indicate who had received the shots. The DOD Office of the Special Assistant for Gulf War Illnesses

(OSAGWI) reported that it collected a large number of such rosters, but that some did not provide clear

information.1622

Military planners also believed that Iraq had developed the deadly botulinum toxin as a bioweapon and

that it posed a possible danger for troops in theater. The investigational botulinum toxoid (BT) vaccine

had been available for decades and had been used by some high-risk occupational groups, but limited

supplies were available. Due to the perceived threat, DOD petitioned FDA for permission to administer

BT to troops in theater, without informed consent. On December 21, 1990, an interim ruling was jointly

issued by FDA and the Secretary of Health and Human Services, allowing BT to be given to troops in the

Gulf War without informed consent. This interim ruling applied in the limited military situation in which

there was an imminent threat of combat, informed consent was not feasible, and withholding the

treatment (vaccine) would not be in the best interest of personnel.1275

According to DOD, CENTCOM policy for BT distribution in theater was based on the assumption that,

because serious illness develops rapidly after exposure to botulinum toxin, this weapon would most likely

be used against forward deployed troops.1622 As shown in Table 3, personnel in the VII Army Corps and

the 1st Marines Expeditionary Force were designated to receive BT. The recommended protocol in the

Gulf War called for two shots to be given, 14 days apart, with a third dose given 10 weeks later.1637 Due

to limited supplies, the vaccine was to be administered on a voluntary basis. Although several thousand

troops are reported to have declined the vaccine, it appears that troops were not always aware that the

vaccine was voluntary. In all, DOD estimates that 137,850 BT doses were delivered in theater, and that

8,000 individuals received at least one BT shot.246,1622 Like the anthrax vaccine, administration of BT was

directed to be carried out under a low profile, and little information is now available concerning which

individuals received it.
Vaccines and Gulf War Illness  105

Table 3. U.S. Troops Designated by CENTCOM to Receive

Biological Warfare Vaccines in January 1991

Anthrax Vaccine Botulinum Toxoid

personnel in Riyadh Army VII Corps

personnel in Dharan-Damman areas 1

st Marine Expeditionary Force

personnel at King Khalid Military City

personnel at Logistic Bases A,B,C,D,E

personnel at Army VII Corps HQ

personnel at Army XVIII Airborne Corps HQ

personnel in Bahrain

1

st Cavalry Division

Source: U.S. Department of Defense1622

Abbreviations: CENTCOM = U.S. Central Command, HQ = headquarters

Vaccines received by Coalition forces. Other countries in the allied Coalition adopted different

policies with respect to vaccines and measures taken against the threat of biowarfare agents.1679 British

troops were routinely immunized against yellow fever, tetanus, typhoid, and polio. Some troops also

received the cholera vaccine, and medical personnel were given hepatitis B shots or “jabs.”666 The U.K.

also provided vaccines against biological agents in the Gulf War, in a program also carried out under a

veil of secrecy.1567,1622 The anthrax vaccine used in the U.K. differed from the U.S. vaccine, and was

available in sufficient quantities to provide to all troops. Pertussis vaccine was given as an adjuvant, to

boost the immune response to the anthrax vaccine. Although British troops were not required to take the

anthrax shots, it was administered without explicit informed consent.1087,1567 The British Ministry of

Defence estimated that up to 75 percent of Gulf War personnel received at least one dose of the

anthrax/pertussis vaccine combination, with rates falling off for subsequent shots in the series.1567 British

troops did not receive BT, but were given plague vaccine.

Among other Coalition troops, some Canadian and Australian personnel are reported to have received

anthrax and plague vaccines on a limited basis.75,511 No other Coalition troops are believed to have

received vaccines against bioweapons on a widespread basis.

Health Effects of Vaccines Given to Gulf War Troops

One sick veteran who testified, Air Policeman JG of the Air Force, with orders to ship out to

the Gulf War from Germany, had taken the vaccines and PB tabs and become sick. His

orders were canceled at the last moment. ‘I signed up for the VA Health Registry in 1994.

They sent me to the VA hospital for an exam. The doctor asked me what was wrong and to

describe the symptoms. I was ... referred to the mental health clinic for stress-related

problems. Seems awful funny to me that my illness is stress and I was not even in theater.’

--1997 Congressional report, testimony of Air Force veteran1684

The central question related to vaccines for Gulf War veterans is whether any of the vaccines they

received, or some combination of those vaccines, contributed to the development of Gulf War illness or

other chronic health problems. Although Gulf War personnel received many vaccines, attention has

focused overwhelmingly on the anthrax vaccine. Questions have also been raised about possible adverse
106  Effects of Gulf War Experiences and Exposures

effects from receiving multiple vaccines in a short time period, as opposed to reactions to any single

vaccine. There have also been concerns related to reports of health problems among individuals who

received vaccines in preparation for Gulf War deployment, but did not actually deploy.69,1476

All vaccines are known to produce, in some individuals, transient, local reactions such as redness or

swelling at the injection site. Less commonly, vaccines can produce systemic and/or prolonged effects.

Very serious reactions can also occur, usually in a very small number of individuals who have an atypical

reaction to some component of a vaccine. In the U.S., the Vaccine Adverse Effect Reporting System

(VAERS) was established in 1990 as a nationwide reporting system for adverse reactions to vaccines.

Co-administered by FDA and CDC, it provides a passive surveillance system that is useful for flagging

unexpected events. The VAERS cannot be used to accurately determine rates of adverse events, since it

depends on reports submitted by healthcare providers, vaccine manufacturers, and patients. Since 1995,

the Department of Defense has required that all adverse reactions to military vaccinations be reported to

VAERS. This includes any event requiring hospitalization or that causes the recipient to miss more than

24 hours from duty.1010,1622

Federal agencies have commissioned multiple reports to evaluate available evidence on health effects

potentially related to vaccines received by Gulf War veterans. The U.S. Army commissioned the 1996

Institute of Medicine (IOM) report Interactions of Drugs, Biologics, and Chemicals in U.S. Military

Forces.

677 The IOM committee indicated there was little information describing health effects of the

many combinations of multiple vaccines, drugs, and chemicals to which military personnel are exposed.

The panel recommended a strategy for categorizing known and unknown interactions, and a graded

approach for monitoring and studying their effects.677 In 2000, Volume One of the IOM Gulf War and

Health series of reports reviewed research information on effects of the anthrax vaccine, botulinum

toxoid, and multiple vaccinations. The report concluded that, while evidence clearly indicated that

vaccines are associated with transient adverse effects, there was insufficient evidence to determine

whether the vaccines considered, or multiple vaccinations, are associated with long-term adverse health

effects.679 The Department of Defense also commissioned the RAND Corporation to conduct a review of

scientific information related to vaccines administered to Gulf War veterans, a report that has not yet been

published.

Anthrax Vaccine

The anthrax vaccine has been the focus of intense controversy and debate on multiple fronts. Concerns

have been raised about the vaccine’s efficacy against inhalational anthrax, quality control issues in its

production, short and long-term side effects, vaccine components and adjuvants, and military policies

requiring mandatory vaccination. These issues have been addressed by government investigations and

reports, expert panel reviews, scientific studies, court cases, and editorial

commentaries.514,680,773,1046,1096,1112,1406,1674,1684,1690 With current concerns about the use of biological

weapons against both military and civilian targets, it is vitally important that the full scope of issues

regarding the safety and efficacy of the anthrax vaccine be fully considered in the public arena.

In keeping with its charge, however, the Committee is concerned primarily with evidence related to

associations between the anthrax vaccine given to Gulf War personnel and the development of Gulf War

illness or other chronic health problems. This limited our primary focus to questions about the safety of

the anthrax vaccine, and more precisely, about the potential for the anthrax vaccine administered to Gulf

War veterans to produce persistent health effects. Such questions are complicated by indications that the

anthrax vaccine has not been a constant or uniform entity. Most obviously, the vaccine given to U.S. Gulf

War troops differed substantially from that given to British personnel. But the U.S. vaccine also differed,

in some ways, from the vaccine licensed for use in 1970 and perhaps also from the vaccine distributed to

U.S. military personnel today.
Vaccines and Gulf War Illness  107

Although media stories describing Gulf War veterans’ unexplained health problems began to appear soon

after the war, concern about a possible role for anthrax vaccine did not become prominent until six years

later. In 1997, a series of stories in Insight magazine reported that Gulf War veterans were made ill by

unlicensed adjuvants added to vaccines they received for the war.1299 Vaccine concerns were heightened

by reports that multiple safety violations had been identified in the production facilities of the

government’s sole anthrax vaccine supplier. Adding to the controversy, in December 1997, DOD

announced plans to implement a program of mandatory anthrax vaccination of all U.S. military personnel.

In March 1998, DOD initiated the Anthrax Vaccine Immunization Program (AVIP), a massive effort to

vaccinate all personnel against anthrax using the six-shot, 18 month protocol. This program has been

controversial since its inception, associated with high profile media reports of serious illness, even death,

following receipt of the anthrax vaccine.416,417,1247 Some personnel refused to be vaccinated and some

refusers were punished—fined, dishonorably discharged, or court marshaled.418,623,1069 Reservists and

National Guardsmen were reported to be leaving the military or changing their duty status to avoid taking

the vaccine.231,1680 The issue has been fought in court cases for nearly a decade, resulting in the vaccine

moving back and forth between mandatory and voluntary status.382,1773 An often cited reason for

questioning the safety of the anthrax vaccine has been its putative role as a cause of Gulf War illness. But

a detailed consideration of available evidence that supports or refutes this assertion has not generally been

provided in the debate.

Characteristics of the anthrax vaccine used in the Gulf War. The anthrax vaccine licensed for

use in the U.S. was developed in the 1950s. The U.S. vaccine, referred to as anthrax vaccine adsorbed

(AVA), is a cell-free filtrate of an unencapsulated strain of anthrax, adsorbed onto aluminum hydroxide.

Its immunogenic component is protective antigen (PA), one of three proteins produced by the anthrax

bacillus that contribute to its toxic effects. Aluminum hydroxide acts as an adjuvant to boost the body’s

immune response to the vaccine. Although disputed by nonmilitary observers,977 the Department of

Defense has consistently maintained that all anthrax vaccine used in the Gulf War was manufactured and

supplied by the Michigan Department of Public Health (MDPH), which had been producing AVA since

1970. In 1995, the vaccine manufacturing division of MDPH became known as the Michigan Biological

Products Institute (MBPI). MBPI was sold in 1998 to the private company, Bioport. Bioport is currently

a subsidiary of Emergent Biosolutions, which continues to manufacture AVA for the U.S. military under

the trade name BioThrax.

It has been necessary for the Committee to distinguish the large amount of information now available on

the anthrax vaccine—pro and con—from the more limited amount of information specifically relevant to

anthrax vaccine and the health of Gulf War veterans. An important first question, which the Committee

was not able to fully answer, concerns the extent to which research on adverse effects of the U.S. anthrax

vaccine, largely conducted prior to 1972 and again after 1998, can be applied to the anthrax vaccine given

to Gulf War veterans. There are many unknowns surrounding the anthrax vaccine provided at the time of

the Gulf War. This includes a number of indications that AVA has not been an unvarying product with a

risk profile that can be assumed to be the same before, during, and after the Gulf War.

The anthrax vaccine used during the Gulf War was the general type developed and tested in the 1950s,

but modifications were made in vaccine components and production methods over the years, including

major changes made between the 1950s efficacy trial and vaccine licensure in 1970.1009,1678 Specific

changes in the manufacturing process were also made by MDPH in 1990, just prior to the Gulf War, to

meet the military’s increased demand. At that time, MDPH changed from glass to stainless steel

fermenters and substituted nylon filters for the ceramic filters previously used.680,1678 The changes sped

up processing time and increased production volume for a given lot, allowing more vaccine to be

produced in a shorter time period.1678 No information is available from testing done by MDPH at the time

of these changes, however, to determine possible effects on the vaccine. An investigation by the General
108  Effects of Gulf War Experiences and Exposures

Accounting Office (GAO, now the Government Accountability Office) suggested that the filter changes

could result in higher levels of proteins in the vaccines, and that MDPH did not test for anthrax proteins

edema factor (EF) or lethal factor (LF). The GAO also reported that results of an unpublished Army

study, conducted in October 1990, found as much as a 100-fold increase in the level of PA in the vaccine

after the filter change.1678

It is likely that some of the vaccine lots distributed in the Gulf War were manufactured prior to the 1990

production changes, and some after, raising the possibility of differences among lots given to Gulf War

military personnel. Earlier studies, for example, had indicated that AVA lots produced in the 1980s

contained detectable amounts of LF and EF.513,915 The type of filters used in the Michigan production

plant were again changed in 1997, to a polyvinylidene filter.1678 Therefore, vaccine lots produced in the

late 1980s and after the 1990 filter changes might both have differed from vaccine produced after the

1997 filter changes and also from lots produced after extensive changes were made in the Michigan

production facility in 1998 and 1999.

Several reports have indicated that acute reaction rates to the Michigan-produced anthrax vaccine did vary

between lots. For example, data collected by CDC between 1967 and 1972 in support of AVA licensure

identified significant lot-to-lot variation in rates of acute reactogenicity.680,1009 Similarly, adverse

reactions reported by 1,583 workers who received anthrax vaccine at Fort Detrick between 1973 and 1999

also varied significantly by lot.1213 Of the 32 anthrax vaccine lots used over the 26 year period, highest

injection site reaction rates were reported for lots numbered 10, FAV001, FAV004, FAV006 and

FAV008. This is of particular interest, since anthrax vaccine lots FAV001, FAV004, and FAV006 were

also given to Gulf War troops during the war, and lot FAV008 was manufactured at about the same time

as lots given to Gulf War troops.589,1622

There are other distinctions potentially applicable to Gulf War-era anthrax vaccine. The vaccine is

temperature sensitive, and must be kept between two and eight degrees Celsius.138 Reports have

described the challenges involved in maintaining a high-quality system for packaging and transporting the

vaccine to ensure it is maintained at proper temperatures.453,1676 After the 1991 Gulf War cease fire, for

example, DOD reports that all unused anthrax vaccine stocks were stored at an Army medical supply

facility in Dhahran, Saudi Arabia. Refrigeration malfunctions at the facility in April and May 1991

prompted Army officials to recommend that the vaccine be disposed of, rather than returned to the

U.S.1622 In 1999, DOD had to destroy a shipment of 20,000 vials of anthrax vaccine delivered to a U.S.

base in Germany because of vaccine degradation caused in shipment. Since that time, an improved

system for packaging and transporting AVA was jointly developed by DOD and Bioport.1676 But during

the Gulf War, it is possible that some vaccine was affected by problems during shipment, storage, or

distribution under the difficult circumstances of wartime, mass inoculations, and the harsh desert

environment.

Although there are many sources of possible variability in the anthrax vaccine used in the Gulf War, there

is little reliable information to indicate whether or how the anthrax vaccine given to Gulf War veterans

was actually affected by any of these circumstances. So the question of whether effects of AVA received

in the Gulf War can reliably be deduced from studies of vaccine produced in the years before the war, or

in more recent years, remains open. If the anthrax vaccine given to Gulf War troops varied in important

ways from AVA produced in recent years, adverse effects data from recent studies would tell us little

about adverse effects of anthrax vaccine given to Gulf War veterans. If there were problems with specific

shipments or lots of the vaccine used during the war, Gulf War veterans or other subgroups who received

those lots might be affected by problems not typical of vaccine recipients overall, problems that could go

undetected when all Gulf War veterans are assessed as a single group.

Quality control issues related to vaccine production at the Michigan facility. U.S. FDA

regulations require any vaccine lot approved for distribution to pass specific tests that demonstrate the
Vaccines and Gulf War Illness  109

lot’s purity, potency, sterility, and safety. The anthrax vaccine has a three year shelf life, but the

manufacturer may request three year extensions of the expiration date, after retesting and demonstrating

the lot’s potency.1676 As mentioned, FDA identified multiple violations and problems in MBPI/Bioport’s

production facility in the late 1990s. But little quality control information is available on anthrax vaccine

produced by MDPH at the time of the Gulf War. There were no FDA inspections of the MDPH anthrax

vaccine production facility prior to 1993. Department of Defense inspections, however, identified

multiple problems in the MDPH anthrax vaccine production process in 1992, including a lack of stability

studies.1674

In 1993 and 1995, FDA inspections at MBPI revealed a number of problems and violations in product

lines unrelated to anthrax vaccine.680 Additional problems were noted between 1996 and 1998, some of

which did relate to anthrax vaccine production and testing. For example, 1998 FDA inspections

identified significant violations related to stability testing, potency testing, assigning expiration dates, and

justification for redating expired anthrax vaccine lots that resulted in MBPI quarantining several lots.

FDA issued warnings during this period, and a 1997 notice to revoke MBPI’s license. 680,1665

MBPI voluntarily ceased vaccine production in January 1998 to undergo extensive plant renovations that

had been previously planned. The facility transferred ownership to Bioport in September 1998. After

renovations were completed, the production facility and newly produced vaccine were required to

undergo detailed testing and FDA review before full production could resume, and before newlymanufactured vaccine was released for distribution. All plans, processes, and facilities related to

production of the anthrax vaccine received final FDA approval in January, 2002.680

Production changes in the U.S. anthrax vaccine before and at the time of the Gulf War, lot-to-lot variation

documented before and after the Gulf War, production violations after the Gulf War, and extensive

improvements in the manufacturing process since 1998 all contribute to the Committee’s observation that

health effects potentially related to AVA given to Gulf War veterans may not be reflected by vaccine

studies conducted prior to 1972 and, again, after 1998. However, any identified patterns of health

problems that relate to AVA more generally, over different periods of time, may be informative about the

potential for anthrax vaccine to have contributed to ill health in Gulf War veterans. Therefore, the

Committee reviewed available research concerning acute reactogenicity and longer-term health effects of

the anthrax vaccine.

Short and long-term health effects of AVA. Unwanted side effects of vaccines can be due to

antigens used in the vaccine or to other vaccine components such as adjuvants, preservatives, or

contaminants. Since the military implemented its anthrax vaccination program, a growing number of

studies and monitoring efforts have provided data on acute adverse reactions associated with the anthrax

vaccine. There has also been more information available related to longer-term health outcomes in AVA

recipients. Thus far, however, longer-term studies have focused primarily on large health services

datasets that provide information on hospitalizations, clinic visits, and disability for diagnosed conditions.

While these represent an important step forward in understanding possible longer-term health effects of

the anthrax vaccine, such studies provide few insights concerning symptom rates and undiagnosed

multisymptom conditions.

Until recent years, the only controlled clinical trial of AVA was a study conducted between 1955 and

1959 that compared rates of anthrax among 1,249 vaccinated and unvaccinated workers in four goat hair

mills.162 Investigators reported that 35 percent of vaccine recipients had acute, local reactions to the

vaccine over the course of the vaccination series, with less than three percent characterized as severe.

The U.S. Centers for Disease Control and Prevention (CDC) also provided unpublished data in support of

licensure of the anthrax vaccine in 1970. Those data, described in a 2002 IOM report, indicate that

among the nearly 7,000 people vaccinated, eight percent had mild reactions and 0.2 percent had severe
110  Effects of Gulf War Experiences and Exposures

Table 4. Studies Identifying Rates of Acute Adverse Reactions to the U.S. Anthrax Vaccine

Injection Site Reactions Systemic Reactions

Study Follow up

%

All

%

Women

%

Men

%

All

%

Women

%

Men

Clinical trial of 1,249

mill workers, 1955-1959162

Active,

48 hours

any

red < 5 cm

red > 5 cm

35%

30%

5%

any 0.2%

CDC surveillance of 6,895

AVA recipients 1967-

1972138,680

Active,

48 hours

any

mild

moderate

severe

10%

9%

1%

<0.2%

any <0.06%

Reanalysis of CDC data

on 1,749 AVA recipients

1967-19721009

Active,

48 hours

any

mild

moderate

severe

28%

24%

3%

0.2%

48%* 16%* any

fever

headache

0.6%

0.3%

0.2%

1,583 Fort Detrick lab

workers who received AVA

1973-19991213

Passive,

“short term”

any

induration

erythema

tenderness

3.6%

2.8%

2.5%

1.7%

6.4%

6.3%

3.6%

2.0%

1.7%

1.3%

any

headache

fever

1%

0.4%

0.1%

0.7%

0.2%

0.3%

<0.1%

Fort Bragg booster study,

452 men received AVA

and BT boosters 1992-

19941214

Active,

1 month

any 26% any

myalgia

rash

headache

45%

31%

17%

17%

Fort Detrick dosing study,

101 volunteers received 1-

3 doses AVA subQ

19981214,1215

Active,

1 month

tenderness

nodule

erythema

70%

38%

36%

84%

63%

63%

63%

24%

22%

headache

malaise

myalgia

11%

8%

7%

9%

10%

3%

GAO survey of 311 Air

Guard and reservists in

2000 who received AVA1680

Active,

duration not

specified

any

burning

knot

red > 2.5 in

76%

60%

55%

19%

any

joint pain

fatigue

fever

24%

16%

12%

8%

2,824 Army personnel in

Korea, 1998-1999612

Active,

symptoms

recorded at

next dose

any*

knot

red > 5 cm

68%

58%

11%

40%

28%

4%

pain

malaise

fever

19%

15%

2%

10%

6%

1%

Tripler Army Medical

Center, 601 healthcare

personnel 1998-20001754

Active,

1-2 weeks

lump*

soreness

red > 5 cm

90%

80%

41%

64%

66%

17%

myalgia

fatigue

headache

47%

36%

33%

41%

22%

17%

48 Fort Lewis ROTC

cadets, received standard

dose AVA in 2000543

Active,

“few days”

sore arm*

lump

swelling

83%

42%

42%

fever

tiredness

headache

8%

0%

0%

Abbreviations: AVA=anthrax vaccine adsorbed; BT = botulinum toxoid; subQ = subcutaneous

Note: *reaction rates after initial dose
Vaccines and Gulf War Illness  111

reactions.680 Recently, CDC investigators reanalyzed a subset of those data, using original reporting

forms for 1,749 individuals, and found that local, mostly mild reactions had occurred with 28 percent of

the doses, and that women were nearly three times as likely as men to have had adverse reactions.1009

The Committee reviewed these, and more recent studies to evaluate rates of acute reactions to the anthrax

vaccine, as summarized in Table 4. Although such studies rarely provide information on vaccine

reactions that persisted longer than a few days, acute reactions may be relevant to chronic health problems

affecting Gulf War veterans. A direct connection is suggested by two Gulf War studies indicating that

veterans who experienced acute reactions to deployment-related vaccines were more likely to be in poor

health years after the war.1374,1698

As shown in Table 4, reported rates of both local and systemic reactions were markedly higher among

vaccine recipients evaluated after 1998 than groups evaluated in the 1950s-1970s. The only exception is

the study of laboratory workers at Fort Detrick, which relied on passive surveillance rather than actively

querying individuals about vaccine reactions, and included some individuals who received anthrax

vaccine produced in the 1960s or 1970s. Studies of AVA recipients have consistently reported that

significantly higher proportions of women than men have localized reactions to AVA. Several studies

have also reported higher rates of systemic reactions in women.612,1213,1754

Overall, local reaction rates in post-1998 vaccine studies were extremely high, generally affecting 70-80

percent of recipients. Systemic reactions were also much higher than in early studies. Pre-1972 reports

had indicated that fewer than one percent of AVA recipients experienced systemic reactions. Post 1998

studies, however, typically reported that 10-40 percent of vaccine recipients experienced systemic

reactions. It is not clear why adverse reactions have been reported at dramatically higher rates in recent

studies. It could be that the current AVA is more reactogenic than formulations used in the 1960s and

1970s. Alternatively, the differences may relate to how data were collected, that is, the recent use of

interviews or questionnaires that proactively query vaccine recipients about specific problems, rather than

a passive process that requires individuals to come forward to identify complaints.

The 2002 IOM report on AVA provides data from a commissioned report summarizing rates of adverse

reactions identified in clinical trials of other vaccines, for comparison to adverse reactions reported for

AVA.680 The IOM report concluded that rates of acute adverse reactions to AVA appeared comparable to

other vaccines. As shown in Table 4, however, recently published studies indicate that AVA is associated

with extremely high rates of acute, local reactions, higher than is typical of other vaccines.

Earlier committee reports often observed that no studies had provided information on long-term health

outcomes in relation to receipt of AVA or other vaccines. But in recent years, military studies have begun

to address this issue, largely through research involving the use of large military health services datasets.

Studies providing information on longer-term health outcomes in relation to receipt of anthrax vaccine are

summarized in Table 5. Studies that specifically evaluated the health of Gulf War veterans in relation to

receipt of the anthrax vaccine are discussed in a later section.

As shown in Table 5, data linkage studies that evaluated hospitalizations, outpatient visits, and disability

claims for diagnosed conditions six weeks to four years after vaccination have found few differences

between anthrax vaccine recipients and nonrecipients. In considering results of these large data linkage

studies, however, it is important to keep in mind potentially important biases. These include: (1) the

generally better fitness level of “combat ready” personnel most likely to have received the anthrax

vaccine and likelihood that those with identified disabilities would not have received AVA, (2) the

inclusion of only military hospitalizations, and (3) follow-up periods that were insufficient to detect

conditions associated with long latency.680,1370,1514,1760 No studies have actively assessed rates of

symptoms or multisymptom illness months or years after receipt of the anthrax vaccine.
112  Effects of Gulf War Experiences and Exposures

Table 5. Studies Assessing Longer-term Health Outcomes

Following Receipt of U.S. Anthrax Vaccine

Study Follow up Outcomes

Long-term follow up of 155 Fort Detrick workers

who received multiple vaccines 1943-1969,

including multiple doses of AVA, compared to 265

community controls1212

Up to 43 years No differences in diagnosed medical conditions. Significantly more

AVA recipients reported fatigue and had abnormal lab values for

several measures, including a higher proportion (12% vs. 4%) with

monoclonal gammopathies.

Comparison of outpatient visits among 4,045 AVA

recipients at Langley AFB to 1,132 unvaccinated

personnel deployed to southwest Asia 1998-

19991263

6 month period

after return from

deployment

No differences in total number of outpatient diagnoses or any

specific diagnoses in vaccinated vs. unvaccinated.

1998 military hospitalizations among 159,386

active duty AVA recipients compared to

nonrecipients1355

0-42 days after

vaccination

Vaccinated personnel sign. less likely to be hospitalized overall,

and for multiple diagnostic categories.

Retrospective medical chart review of 403

Canadian military personnel who received AVA in

1998, compared to 445 who did not655

8 month period

after vaccine

received

Overall, groups similar in total number of symptoms and diagnoses;

minor increases in symptoms and diagnoses post-deployment in

both groups.

Comparison of general health status and

healthcare visits among 301 AVA recipients and

639 unvaccinated personnel at Tripler Army base

in 20001754

Up to 2 years

following receipt

of 1st vaccine

Most outcomes similar in vaccinated and unvaccinated. Vaccinated

women were 4 times as likely to report general health as fair or

poor (6.6% vs.1.5%); sign. fewer mental health visits in vaccinated.

CDC study of postal and government workers

who received antibiotics only (n=948) or

antibiotics with AVA (n=165) following possible

exposure to anthrax in 2001973,1541

2 months active,

then passive

43-46% of AVA recipients reported at least one adverse event,

similar for those who did/did not receive AVA. Four conditions sign.

lower in AVA group. No serious adverse events reported by AVA

recipients.

Case control study of AVA as a risk factor in

1,131 cases of optic neuritis, using DMSS data

1998-20031180

6-18 weeks after

vaccination

No association between optic neuritis and receiving AVA or number

of doses of AVA.

Comparison of DMSS data on outpatient visits

and hospitalizations for 843 diagnoses among 2

million individuals in “prevaccination” and

“postvaccination” cohorts; 23% received AVA

during 3 year observation period865

1 day-21 months

after vaccination

Overall, fewer hospitalizations and outpatient visits in postvaccination cohort. Higher number of postvaccination

hospitalizations for 17 diagnoses and outpatient visits for 34

diagnoses—fewer than expected by chance, partially explained by

confounding.

Comparison of disability claims for AVA recipients

and nonrecipients among 716,833 Army

personnel; 22% received AVA1514

1 day-4 years

after vaccination

Overall, rate of disability evaluations similar for vaccinated and

unvaccinated. No sign. differences related to neurological or

musculoskeletal conditions. Older AVA lots associated with slightly

higher disability than newer lots.

Post-vaccination military hospitalizations among

170,723 active duty AVA recipients deployed

1998-2001, compared to pre-vaccination

hospitalizations1760

0-42 days after

vaccination

Overall, vaccinated personnel sign. less likely to be hospitalized

than unvaccinated for any cause; no increases in any diagnostic

categories.

Health status and hospitalizations among 67,796

military personnel enrolled in the Millennium

Cohort Study1427

Time after

receipt of AVA

not specified

AVA recipients and nonrecipients were similar on all SF36

measures and rates of hospitalization for any cause.

Abbreviations: AVA = anthrax vaccine adsorbed, DMSS = Defense Medical Surveillance System, sign. = statistically significantly
Vaccines and Gulf War Illness  113

One data linkage study utilized the Defense Medical Surveillance System (DMSS) to evaluate

hospitalizations and outpatient visits 1998-2000 in military medical facilities worldwide in personnel who

received AVA, compared with a “prevaccination cohort” of personnel who had not yet been

vaccinated.865 Overall hospitalization and clinic visit rates were higher in the prevaccination cohort,

reflecting generally better health among personnel who receive immunizations and deploy overseas. Of

the 843 diagnoses evaluated, significantly higher post-vaccination hospitalization rates were identified for

17 conditions, fewer than the number expected by chance.680 Some differences were explainable by

confounding, for example, higher rates of malaria identified after vaccination, reflecting AVA received

prior to deployment to regions where personnel were at increased risk for malaria. None of the 40

diagnoses reported to VAERS after receipt of AVA were associated with significantly higher

hospitalization rates. However, the post vaccination cohort had a nonsignificant increase in

hospitalization for multiple sclerosis (RR=1.3) Unpublished data provided to the IOM anthrax vaccine

committee indicated that this elevation was limited to women AVA recipients, an observation the panel

considered a preliminary “signal” that warranted continued monitoring.680

The military’s current policy is not to give the vaccine to pregnant women, based on early indications of a

possible increase in birth defects among women who received AVA in the first trimester of

pregnancy.138,221,680 A large study has recently been reported by the U.S. Naval Health Research Center

that used computerized records to identify all birth defects identified in the first year of life among over

115,000 live births to women service members between 1998 and 2004. Women who received AVA in

the first trimester of pregnancy had a significant 20 percent greater risk for having children with birth

defects, compared to those who had not received the vaccine.1335 Atrial septal defects were the only

specific birth defect category significantly associated with first trimester receipt of the vaccine. Smaller

studies have found no association between receipt of AVA and number of pregnancies, birth outcomes, or

male fertility measures.217,1785

Individual cases and VAERS reports. Several published case reports have described medical

conditions that developed in individuals after they received the anthrax vaccine. These have included

immediate and delayed hypersensitivity reactions,533,971,1521,1544 rheumatoid arthritis,1711 optic neuritis,797

lymphocytic vasculitis,1085 and oral pemphigus vulgaris, an autoimmune condition associated with oral

blisters and ulcers.1080

As previously described, the military requires that all serious adverse reactions to vaccines, specifically

those requiring hospitalization or those resulting in lost duty for more than 24 hours, be reported to

VAERS. It appears that vaccine reactions are sometimes not reported to VAERS, however, for reasons

that include reticence of military personnel to identify health problems and lack of familiarity with the

reporting process.1680 Among the 600 healthcare personnel evaluated in the Tripler Army survey after

receiving the anthrax vaccine, five events were reported to VAERS. This included one female with MRI

indications of demyelinating disease within one week of her fourth shot who was eventually diagnosed

with multiple sclerosis.1754 Two studies have provided summary analyses of VAERS data in relation to

AVA, and found more adverse reactions involving joint symptoms and gastrointestinal problems than

have been reported for other vaccines.477,478

Determining whether the anthrax vaccine is the primary cause of conditions that develop in temporal

proximity to receipt of the vaccine can be difficult, however.571,1392 At the request of the Army Surgeon

General, the Department of Health and Human Services appointed an advisory panel of civilian

physicians and scientists, the Anthrax Vaccine Expert Committee (AVEC), to advise on the likelihood

that individual adverse events reported to VAERS were caused by the anthrax vaccine.1391 Over the first

four years of the AVIP program, after 500,000 military personnel had received the anthrax vaccine, the

AVEC reported that 1,841 reports involving 3,991 adverse events had been submitted to VAERS.1390 The

most commonly reported problems involved extended areas of inflammation and redness at the injection

site, rash elsewhere on the body, malaise/fatigue, arthralgia, and headache. Forty-four reports described
114  Effects of Gulf War Experiences and Exposures

an arthralgia-related multisymptom illness, defined as including arthralgia and two or more of the

following: malaise/fatigue, paresthesia, memory loss, sleep disorder, and altered mentation. One hundred

forty-seven events were classified as serious or medically important. These included five cases of an

anaphylactic-type reaction, four cases of Guillain-Barré syndrome, three cases of multiple sclerosis, two

cases each of seizure, diabetes, and Hashimoto’s thyroiditis, and one case each of lupus, rheumatoid

arthritis, and fibromyalgia. Of the 147 serious/medically important events, 26 were identified as possibly,

probably, or certainly the result of the vaccine. Others were identified as unlikely, unrelated, or

unclassifiable. Of the six deaths reported, four were identified as unrelated to the vaccine, and two were

unclassifiable. The AVEC concluded that the evidence indicates that AVA was not associated with an

unusually high rate of serious adverse events and identified no pattern of problems with specific lots.

All cases of serious medical conditions that develop after receipt of the anthrax vaccine, are, of course, of

great concern. Individuals who develop disease as a result of vaccines received for military service are

entitled to have their condition acknowledged and their health needs addressed by DOD and/or VA. But

there is no indication from research studies conducted thus far that anthrax vaccine is associated with an

increased risk of any specific chronic medical condition—diagnosed or undiagnosed. Given the

limitations of studies conducted to date, however, it cannot be said with certainty whether or not AVA is

associated with excess rates of undiagnosed multisymptom conditions or with serious diagnosed diseases

of longer latency periods that would not be detected in short-term studies of military hospitalizations and

clinic visits. Therefore, it is still important that individuals who received AVA be monitored for an

extended period to carefully ascertain rates of both multisymptom illness and diagnosed diseases.

Ongoing anthrax vaccine research. Government officials have generally considered the U.S.

anthrax vaccine to be both safe and effective.459,514 But the extended dosing schedule required, and

concerns about the vaccine’s reactogenicity have prompted efforts to develop improved anthrax vaccines,

as well as alternate dosing methods and schedules for the current vaccine.679,914,968,1213 Multiple projects

have been funded by the military, as well as by other agencies in connection with Project Bioshield.

Studies to ascertain safety and immunogenicity of a next-generation recombinant PA anthrax vaccine

continue, despite recent contract and production problems.1334 The U.S. Centers for Disease Control is

currently sponsoring a multifaceted program to evaluate AVA effectiveness, adverse effects, and optimal

dosing/scheduling. The program includes a human trial to determine reactogenicity and immunogenicity

resulting from current and alternate dosing methods, a primate trial to determine vaccine immunogenicity,

and laboratory studies to determine biological processes associated with the development of anthrax.

Additional objectives include long-term follow-up of previously immunized populations.681

Other Vaccines Given to Gulf War Troops

Although the anthrax vaccine has been the primary vaccine-related issue raised in connection with Gulf

War illness, Gulf War veterans received many other immunizations prior to and during deployment.

There is little or no documented evidence regarding associations between any of these vaccines and longterm health outcomes, including symptom complexes like those affecting Gulf War veterans.

Botulinum toxoid (BT). Seven different toxins are produced by strains of the bacterium Clostridium

botulinum. These extremely toxic substances affect peripheral nerves at extremely low doses, causing

death by paralysis and respiratory failure. Animal studies have assessed the effectiveness of different

individual and combination toxoid vaccines, but as is generally the case, provide limited information on

adverse reactions and no information on long-term effects. The pentavalent BT vaccine used in the Gulf

War contains aluminum phosphate as an adjuvant. It requires three injections, given over 12 weeks, with

annual boosters thereafter. This vaccine has still not been licensed, and is still designated by FDA as

investigational. In studies of the efficacy of this and other pentavalent BT vaccines conducted in the

1960s, investigators reported there were few problems with acute, local reactions and no problems with
Vaccines and Gulf War Illness  115

systemic or severe reactions.439,440 The IOM report on vaccines also describes an unpublished study,

conducted by the Army, of two BT vaccine formulations given to 36 individuals.679 Both formulations,

containing different levels of formaldehyde, produced similar rates of local reactions (15-18%), and no

severe reactions. CDC monitoring data for BT recipients reportedly found that seven percent of the

nearly 17,000 doses administered prior to 1997 were associated with a moderate local reaction and 0.4

percent with a severe reaction. These events were described as being of limited duration.679

The agreement that allowed BT to be given to personnel in the Gulf War stipulated that records be kept of

who received the vaccine and that side effects be monitored, but neither were effectively carried out.462 A

1995 IOM report provided results of a postcard survey of 123 Marines at Camp Pendleton who had

received BT during the Gulf War. Of the 121 Marines who responded, 12 percent reported they had had a

mild local reaction to the vaccine, 14 percent reported pain that temporarily limited the use of the

vaccinated arm, and 2.5 percent reported some type of systemic reaction. No reactions were associated

with serious problems or limited duty.675

Additional vaccines given to military personnel. As shown in Tables 1 and 2, Gulf War veterans

received many different types of vaccines before and during deployment. Little concern has been raised

about vaccines other than anthrax and BT, however. Most vaccines administered at the time of the Gulf

War had been in use for many years, by both military and civilian populations. For example, yellow fever

vaccine has been widely used by the military and by civilians in endemic areas for decades, and is

considered to have an acceptable safety profile.445,1060 Reactions to this vaccine are generally mild

(headache, low-grade fever, and myalgia) and can affect up to 25 percent of recipients.

964 In recent years,

neurological conditions have been reported to VAERS in relation to receipt of the yellow fever vaccine,

including four cases of encephalitis, four cases of Guillain-Barré syndrome, and three cases of

demyelinating disease reported between 2001 and 2006.964

Other vaccines used in the war are also associated with transient, local effects, and with rare cases of

serious systemic and/or chronic effects.550 Similarly, immune globulin injections, used to prevent

hepatitis A in the Gulf War, can produce transient local effects and, infrequently, more serious effects.219

Although widely considered to be safe, little research information is available concerning long term

effects of these vaccines, individually or in combination.

Vaccine Adjuvants

The presence of anti-squalene antibodies in ill people and the absence of the antibodies in

healthy people is the first hard laboratory evidence that Gulf War illness is what some might

refer to as a ‘real disease.’ It is also the first evidence that an abnormal immunological

response is under way in Gulf War illness patients.

-- Dr. Robert Garry, statement for 2002 Congressional hearing 474

Adjuvants are substances added to vaccines to enhance the immune response triggered by the vaccine.

Although only aluminum-based adjuvants are licensed for use in the U.S., many types of adjuvants have

been developed and tested. Different adjuvants produce different types and strengths of immune

stimulation, and have different adverse reaction profiles.548,963 In 1997, a series of magazine articles

reported that Gulf War illness had been linked to autoimmune abnormalities caused by the use of an

unlicensed adjuvant containing squalene in a vaccine given to military personnel.1299 The reporter

described evidence provided by Dr. Pamela Asa, a Tennessee immunologist in private practice, who had

tested the blood of a number of ill veterans and found high levels of antibodies to squalene. These reports

spurred a major controversy, and the squalene theory of Gulf War illness became the subject of

government inquiries, scientific articles, panel reviews, and a high profile book published by an

investigative journalist.679,977,1675,1690
116  Effects of Gulf War Experiences and Exposures

The squalene controversy has been multifaceted, raising such diverse questions as whether the

government illegally used an experimental vaccine adjuvant during the Gulf War, whether squalene

adjuvants cause the types of symptoms seen in Gulf War veterans, and whether the tests used to detect

squalene antibodies are reliable. The Committee reviewed available evidence concerning these and other

questions. For the Committee’s purposes, however, a single question is primary, that is, whether there is

evidence that symptomatic Gulf War veterans have abnormally high levels of circulating squalene

antibodies. Despite the attention given to the squalene issue over the past decade by scientists and

government agencies, no clear answer to this question has emerged.

Squalene antibodies in ill veterans. Although Dr. Asa is reported to first have broached the subject

of adjuvant-induced illness in Gulf War veterans with military officials in 1994,977,1675 the first study that

addressed the issue was published in 2000. In the study, Dr. Asa and colleagues at Tulane University

tested for IgG antibodies to squalene in two Gulf War veteran groups, using an assay developed at

Tulane. In the first group, blinded analyses were conducted on sera from 38 sick and 12 healthy Gulf

War veterans. Symptomatic Gulf War veterans in the study all met the CDC definition of chronic

multisymptom illness, but more than a third also had serious diagnosed conditions such as ALS, lupus,

and multiple sclerosis.69 Results indicated that 36 of the 38 sick veterans (95%) tested positive for

squalene antibodies, but none of the 12 healthy veterans tested positive. An additional six symptomatic

Gulf War era veterans who had received vaccines for deployment, but had not actually deployed, also

tested positive.

The second set of analyses were not blinded. The samples tested included 86 Gulf War veterans of

undetermined health status and 48 blood donors from the general population. Sixty-nine percent of the

Gulf War veterans tested positive for squalene antibodies, but only five percent of the community blood

donors were positive. By comparison, few patients from separate groups of lupus patients and breast

implant recipients tested positive for squalene antibodies.69

In a second paper, Dr. Asa and her Tulane collaborators reported elevated levels of squalene antibodies

among military personnel who had received the anthrax vaccine after 1997, as part of DOD’s anthrax

vaccine immunization program (AVIP). About half of the 25 vaccine recipients in the sample were

symptomatic, although case status was not explicitly defined. Thirty-two percent of vaccine recipients

tested positive for squalene antibodies, compared to only 16 percent of matched, nonmilitary controls.

Further analyses indicated that all individuals with squalene antibodies had received anthrax vaccine from

one of five specific lots. Among the 17 individuals who received vaccine from those lots, 76 percent

were symptomatic and 47 percent had squalene antibodies. None of the eight veterans vaccinated with

other lots were symptomatic or had squalene antibodies.70

These studies were reported to have been done with no external funding and, in a number of ways, were

not optimally designed.1572 Samples were small, self-selected, and poorly defined. For example, some

Gulf War multisymptom illness cases in the first study had concurrent autoimmune diseases, while some

controls had fibromyalgia or chronic fatigue; some findings came from unblinded analyses of sera

obtained from poorly characterized patients. Still, study results were intriguing and raised a hypothesis

that could be further evaluated in more definitive studies. Identification of an objective test that

distinguished a sizable proportion of symptomatic from healthy Gulf War veterans was potentially of

great importance as a diagnostic tool, and for providing possible insights concerning pathophysiological

processes and even treatments for ill veterans.

Squalene antibody research at Walter Reed Army Institute of Research (WRAIR). After its

publication, the Asa/Tulane squalene antibody research was criticized by government scientists and

panels.45,679,1572 Critics questioned the idea that squalene, when injected, acted as an antigen, and whether

the assay used had actually detected antibodies to squalene. Within months, however, investigators at

Walter Reed Army Institute of Research (WRAIR) published research showing that squalene can act as
Vaccines and Gulf War Illness  117

an antigen and that antibodies could be detected in a model system.981 A WRAIR high throughput

squalene antibody assay was developed by 2002,979 and subsequently used to evaluate squalene antibodies

in mice and humans. Human blood samples from three populations were evaluated: (1) retired laboratory

workers from Fort Detrick who had received multiple vaccines, including AVA, over many years, (2)

similarly aged community controls who had never received AVA, and (3) samples from an Army blood

center at Fort Knox, which primarily contained serum from young recruits.980

Squalene antibodies were detected in all of the groups tested. IgM antibodies were found in about one

third of both the Fort Detrick and community cohorts (37%, 32% respectively), but in significantly fewer

blood center samples (19%). IgG antibodies were found less frequently in the Fort Detrick and

community samples (7% and 15%, respectively), and were not detected at all in the Army blood center

samples. Investigators suggested that the prevalence of squalene antibodies increases with age, since the

mean age of Fort Detrick volunteers was 68, and the blood center samples were predominantly from

individuals 18-21 years of age. This was supported by studies in mice demonstrating a significant

increase in circulating squalene antibodies with age.980

The WRAIR studies have been extremely useful, developing a well-validated assay and demonstrating

that squalene antibodies are detectable in human serum at rates that may increase with age. However, this

research did not address the core issue raised by the Asa/Tulane studies concerning Gulf War illness.

That is, the WRAIR studies did not measure IgG squalene antibodies in individuals who received

vaccines postulated to contain squalene. Nor did they compare squalene antibody levels in symptomatic

versus healthy Gulf War veterans. It is important to note, also, that the WRAIR and Asa/Tulane studies

provided comparable results concerning “background” rates of squalene IgG antibodies in humans. The

WRAIR study identified IgG antibodies in 7-15 percent of individuals in the Fort Detrick and community

samples, similar to the 5-16 percent range identified in control populations in the two Asa studies.

Did anthrax vaccine used in the Gulf War contain a squalene adjuvant? Both DOD and NIH

have sponsored multiple animal studies and human trials of vaccines with experimental adjuvants

containing squalene and squalane, a hydrogenated variant of squalene. This includes DOD-sponsored

animal studies of anthrax vaccine formulations with squalene-containing adjuvants begun in 1987, and

two small DOD-sponsored human trials of a malaria vaccine that were underway before the Gulf War.1675

It has been argued that, given the deadly threat posed by anthrax, the addition of a potent adjuvant to

AVA at the time of the Gulf War might have been considered a responsible decision, to enhance the

immunogenicity provided by the vaccine in the limited time available in the run up to the war. Facing

similar time constraints, British officials opted to use the pertussis vaccine to adjuvanate the U.K. anthrax

vaccine. But U.S. government reports have consistently maintained that DOD officials decided against

using novel adjuvants with the anthrax vaccine because of restrictions and delays required for FDA

licensure of an altered vaccine formulation.1622,1675

Still, given the concern surrounding the issue, several investigations were undertaken to determine

whether or not there was squalene in the U.S. anthrax vaccine. The Department of Defense

commissioned Stanford Research Institute International (SRI) to develop an assay capable of detecting

squalene in anthrax vaccine. The initial assay could detect squalene at levels of 140 parts per billion,

equal to 70 ng. of squalene per 0.5 ml. AVA dose. SRI then tested samples from 17 lots of AVA,

including the five lots identified in the 2002 Asa study as being associated with excess levels of squalene

antibodies. No squalene was found in any of the lots tested.1459

In 2000, however, U.S. Food and Drug Administration (FDA) officials announced that, using a more

sensitive assay, they had detected “trace” amounts of squalene, ranging from 10 to 83 parts per billion, in

each of five lots of anthrax vaccine tested, and also in lots of tetanus and diphtheria vaccines.984 The FDA

report verified that manufacturing records did not indicate that squalene had been added to the anthrax
118  Effects of Gulf War Experiences and Exposures

vaccine formulation, and concluded that the low levels detected were likely related to natural occurrence

or low-level contamination.1665 Subsequently, SRI developed a more sensitive assay, capable of

identifying squalene at the level of 1 ng. per 0.5 ml. dose of vaccine, and tested samples from 38 lots of

AVA, including seven lots reported to have been used during the Gulf War. All lots tested had been

produced by MDPH or Bioport, with expiration dates between 1982 and 2001. No squalene was detected

in 43 of the 44 lots tested, but an extremely low level was detected in three samples from lot FAV008 (1-

9 ng. per ml.).1458 In contrast to the FDA findings, none of the suspect lots identified in the Asa/Tulane

studies were found to contain squalene.

Reports indicate that, when squalene-containing adjuvants are used as part of a vaccine formulation,

squalene is present at a concentration of 0.2 – 5.0 percent, or 1-25 mg. in a 0.5 ml. dose of vaccine.1458,1665

This is more than a million times the level of squalene detected in anthrax vaccines by FDA and SRI

testing. Whatever the source of the detected squalene, the FDA and SRI studies support the government’s

assertion that squalene-containing adjuvants were not added to the tested vaccine lots at levels generally

used for adjuvants. Some have speculated that even these very minute levels of squalene, less than the

level normally found in human blood, might be capable of stimulating reactions,977 but no studies have

evaluated this contention.

Health effects of squalene. Squalene is an oily substance that naturally occurs in plants and animals.

It is found in a variety of foods, lotions, and cosmetics. It is also used as a food supplement and has been

postulated to provide therapeutic benefits.225,787 In humans, squalene is synthesized by the liver as a

precursor to cholesterol, and circulates in the blood. Many substances that are ingested or found in the

blood, however, cannot be safely injected. Squalene, when injected, stimulates a nonspecific immune

response, making it a useful component of vaccine adjuvants.41,1218 The original theory relating anthrax

vaccine and squalene adjuvant to Gulf War illness suggested that veterans’ symptoms were autoimmune

in nature, that is, they were associated with autoantibodies stimulated by receipt of the vaccine.

Associations between autoimmune conditions and vaccines have long been postulated, including vaccines

against diptheria, tetanus, polio, and hepatitis B.1148,1404 In animal models, squalene has been used to

induce antibodies and precipitate diseases that simulate human autoimmune conditions, including

lupus847,1356 rheumatoid arthritis,213,618 and multiple sclerosis.114

No squalene-containing adjuvants are licensed for use in the U.S., but a number have been evaluated in

clinical studies. These include trials of vaccines for influenza, herpes simplex, and HIV.92,518,867,972,1675

MF59, an oil-in-water microemulsion, is the most widely used squalene-containing adjuvant. An

influenza vaccine containing MF59 has been licensed for use in European countries since 1997 and is

considered to have a good safety record.1217

A recent collaborative study between Italian and U.S. investigators suggests that receipt of squalenecontaining adjuvants may not stimulate elevated levels of squalene antibodies in humans.328 Using an

ELISA squalene antibody assay, investigators identified low-levels of squalene IgG antibodies in 79

percent of a sample of U.S. adults, and 26 percent of European adults who had not received vaccines

containing squalene. IgG antibodies to squalene were also detected at low levels in 94-100 percent of

European adults 65 years of age and over who participated in influenza vaccine trials, whether or not the

vaccine received in the trial contained MF59. Investigators concluded that low levels of circulating

squalene antibodies are commonly found in adults, and that squalene antibody levels are not affected by

receipt of vaccines containing squalene. Although interesting, these findings raise more questions than

they answer. No clear explanation is offered, for example, for the substantial differences in rates of

squalene antibody positivity in the three cohorts evaluated. Nor is there any explanation for why results

differed so dramatically from the two previous U.S. studies, which found IgG antibodies in fewer than 20

percent of adults studied.69,980
Vaccines and Gulf War Illness  119

Conclusions of special committees. Previous government committees and scientific panels have

focused on different aspects of the squalene issue. The theory was sometimes dismissed without detailed

consideration, based on DOD assertions that squalene was not added to the anthrax vaccine.1227,1690 Little

published research was available to earlier panels, so conclusions were usually based on commonsense

observations. The Presidential Special Oversight Board pointed out, for example, that low levels of

squalene had been found in diphtheria and tetanus vaccines, but no “Gulf War syndrome” issues had been

raised in relation to these vaccines.1232 An Institute of Medicine panel pointed out shortcomings in the

Asa/Tulane squalene antibody studies, and concluded they did not provide persuasive evidence that

squalene antibodies had been detected.679 The World Health Organization issued a statement on the

safety of squalene-containing adjuvants, citing the safety record of the 22 million doses of the Italian

influenza vaccine distributed since 1997.1812

Other adjuvants in Gulf War vaccines. Adjuvant issues relating to the anthrax vaccine have also

made headlines in the U.K. The British MOD acknowledged, in 1997, that pertussis vaccine had been

used to adjuvanate the anthrax vaccine given to British Gulf War troops, a decision that has also been

controversial.203,1551,1756 MOD officials have maintained that no vaccines containing squalene were given

to British troops. Tests conducted by an independent laboratory in 2001, sponsored by MOD, found no

squalene in 11 lots of the U.K. anthrax vaccine, nor in other types of vaccines given to British troops

during the Gulf War.1568

The U.S. Department of Defense has consistently maintained that all adjuvants in vaccines used during

the Gulf War were aluminum-based and FDA approved. Immunizations given to Gulf War veterans that

contained aluminum adjuvants included anthrax, BT, and tetanus-diptheria vaccines.1622 Aluminum

adjuvants have been used in vaccines for over 60 years, and are considered to have a good safety

record.711,909 Vaccines containing aluminum adjuvants have been extensively studied in humans and

animals for both effectiveness and adverse effects, but very little research has specifically looked at

neurological effects of vaccine adjuvants, an area of particular interest in relation to Gulf War illness.

A recent Canadian study evaluated long-term effects of both squalene and aluminum hydroxide adjuvants

on behavior and central nervous system tissues in a mouse model.1202 Using dosages comparable to those

used in human vaccines, animals received two injections, two weeks apart, of one of the adjuvants, both

adjuvants combined, or placebo. They were then evaluated using a variety of neurobehavioral tests over a

six month period, followed by histochemical analyses of brain and spinal cord tissues. Anti-squalene

antibodies were found in 20% of animals injected with placebo, 27% of those injected with aluminum,

40% of those injected with squalene, but only 10% of those injected with both adjuvants. Overall, the

aluminum adjuvant produced more adverse effects than placebo, squalene, or the combined adjuvants.

After six months, mice injected with the aluminum adjuvant exhibited significant declines in muscle

strength and endurance, and increased indicators of anxiety, compared to placebo. Aluminum adjuvant

was also associated with indicators of increased central nervous system inflammation and motor neuron

loss, as reflected by a significant increase (350%) in the number of reactive astrocytes in the lumbar

spinal cord and neuronal apoptosis in the motor cortex and spinal cord. Investigators concluded that their

findings were consistent with an association between aluminum adjuvants and neurological deficits,

including ALS. By contrast, squalene adjuvant was associated with fewer changes in brain and behavior,

none of which were statistically significant.

Vaccines containing aluminum hydroxide adjuvant have also been associated with the development of

macrophagic myofasciitis.486 This recently-identified condition is characterized by macrophage

infiltration of muscle tissue after receipt of vaccines.239,485 Patients develop arthromyalgias and fatigue,

among other symptoms, with one report indicating that about half of macrophagic myofasciitis patients

meet criteria for chronic fatigue syndrome.76
120  Effects of Gulf War Experiences and Exposures

Although squalene has been the primary adjuvant issue raised in relation to Gulf War veterans, no studies

have specifically linked receipt of squalene-containing adjuvants to biological processes or chronic

symptoms that parallel those affecting Gulf War veterans. In contrast, there are preliminary indicators,

from both human and animal studies, that aluminum hydroxide adjuvant may be associated with

neurological damage and chronic symptoms potentially relevant to the health of Gulf War veterans.

Primary Gulf War squalene antibody question unanswered. Eleven years after the squalene

controversy was first publicly raised, studies have addressed several related questions. Two laboratories

have assessed levels of squalene in selected lots of the U.S. anthrax vaccine, both yielding results that

support government assertions that a squalene-containing adjuvant was not added to those lots.

Additional studies have provided insights on detection of antibodies to squalene in humans and animals,

but have provided little indication that receipt of squalene-containing adjuvants results in chronic

production of squalene antibodies.

The observation from the Asa/Tulane studies that is most relevant to the health of Gulf War veterans,

however, has not been further evaluated. Their initial study, reported in 2000, indicated that symptomatic

Gulf War veterans had detectable levels of IgG antibodies to squalene, but that healthy veterans did not.

This raised a testable hypothesis concerning an objective measure of an immunological abnormality that

distinguished ill from healthy veterans. The Asa/Tulane studies may have correctly identified excess

rates of squalene antibodies in ill veterans, whether or not they were caused by vaccines, by vaccine

contamination, or by clandestine use of an unapproved adjuvant. It is important to determine whether the

observed association between squalene antibodies and Gulf War illness is supported, or refuted, by more

definitive research.

Health Effects of Receiving Multiple Vaccines

Most studies conducted to establish vaccine safety in humans evaluate vaccines individually. Studies that

evaluate receipt of more than one vaccine at the same time are generally concerned with changes in

vaccine effectiveness, but may also report on short term adverse effects. The Committee identified little

research that provides information on long-term effects of specific vaccine combinations, or numerous

vaccines received in a brief time span.512,675 Receipt of multiple vaccines together is fairly common,

however. Multiple immunizations are routinely given to infants and young children. Adults traveling

overseas also commonly receive multiple immunizations. Studies have assessed short term side effects

related to receipt of vaccine combinations in childhood and have generally reported little or no increase in

short-term reactogenicity.236,1453,1540 In civilians traveling to foreign countries, receipt of multiple

vaccines has also been reported as being well-tolerated, although the number who experience acute side

effects increases with the number of vaccines received.156,426 For many years, multiple vaccinations have

also been given to new military recruits and to troops preparing for overseas deployment.1523 Surprisingly

little information is available, either from studies or from monitoring programs, that quantifies short or

long-term adverse effects resulting from specific combinations of vaccines, or a large number of vaccines

received concurrently.

Some insights regarding effects of multiple vaccines received over a prolonged period of time have been

provided by a series of follow-up evaluations of laboratory workers at Fort Detrick, Maryland. These

workers received multiple immunizations as participants in vaccine studies conducted for the U.S.

biological weapons development and countermeasures program between 1943 and 1969.1211 The first

three assessments were conducted in 1958, 1965, and 1974. No abnormal excess of diagnosed diseases

affected the workers, but several indicators of a chronic inflammatory process were identified. These

included increased rates of leukocytosis and lymphocytosis, alterations in ratios of alpha and beta

globulins, and higher mean serum levels of hexosamine.1189,1190,1770
Vaccines and Gulf War Illness  121

The most recent assessment, reported in 2004, evaluated 155 former workers who participated in a Fort

Detrick laboratory alumni gathering in 1996, and 265 age and gender-matched controls.1212 Fort Detrick

participants were evaluated an average of 43 years after their first program immunization. Individuals

had received different types and numbers of vaccines—a median of 154 each—during their years in the

program. For example, 142 of the 155 Fort Detrick workers had received multiple doses of anthrax

vaccine, an average of 23 doses per subject. Results indicated no differences in clinically diagnosed

diseases between workers and community controls. Fort Detrick workers reported their overall health

status to be slightly worse, however, and a higher proportion reported being fatigued. Several serum

parameters also differed between the groups. Most significantly, unspecified monoclonal proteins were

detected at elevated rates in the Fort Detrick workers. These gammopathies were not further characterized

and were not associated with identifiable disease, but have been linked in other studies with the

development of serious conditions, including multiple myeloma.851,852

The Fort Detrick studies provide an interesting look at the long-term health of selected individuals many

years after receiving a large number of vaccines. Overall, the studies indicate that receipt of repeated

doses of multiple vaccines over an extended period of time was not associated with identifiable disease,

but may produce persistent immune alterations in a subset of individuals. For several reasons, however,

these studies have limited relevance for understanding effects of multiple vaccines received for Gulf War

deployment. Of the over 3,000 original participants in the Fort Detrick program, those evaluated in

follow-up studies were a select group of volunteers. They would not have included, for example,

individuals who did not tolerate multiple vaccinations and withdrew from the program, those who had

died, or those not healthy enough to attend a social gathering many years after retirement.1211,1212 Unlike

the Fort Detrick program, Gulf War veterans received multiple vaccines over a brief period of time,

vaccines that differed from those given to Fort Detrick workers in the 1940s, 1950s, and 1960s.

Animal studies of effects of vaccines combined with other Gulf War exposures. As part of

its Gulf War research effort, the British Ministry of Defence (MOD) sponsored a series of studies that

evaluated effects of multiple vaccines given to U.K. military personnel in the Gulf War, combined with

pyridostigmine bromide (PB), in several animal models. A number of abnormalities resulting from these

exposures were identified, which differed according to the study design and animal model used.

Relatively high-dose combinations of anthrax and pertussis vaccines produced observable illness and

weight loss in mice, with milder effects associated with more dilute vaccines. Toxicity effects in the

mouse model were attributed mainly to the pertussis vaccine.1285 A separate study found that PB, given at

levels comparable to those used in the Gulf War, had no effect on humoral immunity in mice.535 A

second series of experiments evaluated effects of 10 vaccines, given at various doses, alone and with PB,

in a guinea pig model. After 72 days, all animals appeared generally healthy. The only observable effect

was slight weight loss in the animals who received the highest-dose vaccine regimen.

The most comprehensive series of studies evaluated diverse health parameters in the marmoset, a small

primate, following receipt of vaccines and/or PB. Evaluations included effects on general health,

cognitive function, muscle function, sleep patterns, electroencephalograms (EEGs), immune function, and

adrenal function. Animals received one-fifth the human dose of all 10 vaccines, along with boosters, over

a 51 day period, and were infused for 28 days with PB at the dose required to reduce serum cholinesterase

levels by 30 percent. Outcomes were monitored over a 21 month period. The marmosets exhibited no

obvious behavioral or health changes over that time, and no differences in weight or muscle function.

Animals that received PB and/or vaccines, however, had significantly higher error rates on two of the

eight measures of cognitive function (new learning and compound reversal) that lessened over the period

of observation.1486 Animals treated with PB exhibited significantly reduced EEG alpha wave activity

early in the study, and reduced beta 2 waves at various times over the observation period. Pyridostigmine

bromide was also associated with reduced levels of rapid eye movement (REM) sleep and fewer REM

periods. In contrast, animals who received multiple vaccines, had fewer waking periods early in the
122  Effects of Gulf War Experiences and Exposures

observation period, with improved sleep efficiency and more REM periods.1789 Urinary cortisol levels did

not vary by treatment group and there were no indicators of compromised immunity following treatment

with multiple vaccines and/or PB.632

Overall, the U.K. studies found no interactive or synergistic effects between PB and receipt of multiple

vaccines on any of the parameters studied. Individually, receipt of multiple vaccines, as well as PB,

produced a limited number of significant neurobehavioral effects. Both also produced significant, but

different, effects on sleep patterns. But neither PB nor multiple vaccines had detectable effects on muscle

function, peripheral immune response, or cortisol levels.

Results from the marmoset studies have parallel observations in Gulf War veterans—both in what was

found and in what was not found. A large British epidemiologic study reported no significant interaction

between PB and receipt of multiple vaccinations in relation to Gulf War illness.1698 Gulf War veterans

have also been reported to be similar to controls with respect to resting cortisol levels,502 and in vitro tests

of cellular and humoral immunity.422 Gulf War veterans commonly report sleep and cognitive

difficulties, and studies have identified several domains of measurable cognitive impairment in subsets of

symptomatic veterans.1709,1779

As will be described in a separate section, the Committee has reviewed evidence suggesting that immune

alterations related to veterans’ persistent symptoms might more likely be found in the brain than in the

peripheral circulation. A study conducted by investigators at Boston University School of Medicine

provides a preliminary indication that combined exposure to vaccines, stress, and PB may affect brain

processes associated with central immune activation and inflammation.917,1752 Immune stimulation by

KLH, used as a vaccine analog in the Boston study, significantly enhanced and prolonged the production

of stress-activated kinases regionally in the mouse brain. This effect was further enhanced and prolonged

by PB. Investigators suggested that vaccines and PB may act synergistically to dysregulate processes

normally associated with immune activation and inflammation in the brain, processes that mediate

neuronal damage following exposure to stress and toxic chemicals.

Studies Evaluating the Health of Gulf War Veterans in Relation to Vaccines

Association of Gulf War illness with individual vaccines. As detailed in Appendix A-12a, Gulf

War studies have frequently reported significant associations between Gulf War illness and receipt of

individual vaccines (e.g., BT, meningococcal, anthrax, plague, typhoid) using analyses that did not take

into account effects of other exposures in theater. This includes novel findings from a large study of

British Gulf War veterans that tetanus and cholera vaccines were not associated with Gulf War illness if

veterans received them before deployment, but were problematic for veterans who received them during

deployment.641 It is not possible to reliably interpret these findings, however, in light of confounding

potentially introduced by concurrent exposures, as previously described.

Only two Gulf War studies have assessed effects of individual vaccines while adjusting for the effects of

other exposures in theater. The large U.S. study of Navy Seabees queried veterans about their receipt of

five vaccines and immune globulin. All were significantly associated with Gulf War illness in unadjusted

analyses. After controlling for effects of other exposures, however, only meningococcal vaccine was

associated with Gulf War illness, presenting a significant, but only slightly elevated risk (OR = 1.3).527 In

the Fort Devens cohort, receipt of the anthrax vaccine was a significant risk factor for Gulf War illness

after adjusting for other exposures in theater. The increased risk for anthrax vaccine was also modest

(OR = 1.5) and the study did not assess contributions of other vaccines.1804

Health effects of anthrax vaccine in Gulf War veterans. Although it has often been suggested that

anthrax vaccine is a cause of Gulf War illness there is relatively little reliable evidence to support this
Vaccines and Gulf War Illness  123

view. No efforts were made during the Gulf War to monitor short or long-term health problems following

receipt of AVA. Epidemiologic studies have generally not identified the anthrax vaccine to be a

prominent risk factor for Gulf War illness. As indicated, anthrax vaccine has been associated with

increased rates of symptoms, Gulf War illness, and poor health status in several studies, using analyses

that did not take into account effects of other exposures in theater.161,511,1371,1374,1698 The magnitude of risk

identified for the anthrax vaccine in these studies, however, was similar to that for most other vaccines,

and lower than for other types of exposures in theater. But more informative research on this issue is

extremely limited. Only two studies have evaluated the association of anthrax vaccine with Gulf War

illness, adjusting for effects of other exposures. Anthrax vaccine was identified as a significant, albeit

modest, risk factor in one of those studies.1804

There has been some concern that, since many Gulf War veterans might not have known if they received

the anthrax vaccine, inaccurate reporting could markedly affect studies evaluating effects of the anthrax

vaccine. Two studies have compared health outcomes in Gulf War veterans with self-reported versus

documented receipt of the vaccine. In a large study of U.K. Gulf War veterans, associations between

anthrax vaccine and health outcomes were similar in individuals who did and did not have their vaccine

records, as well as for anthrax vaccine received prior to and after deployment.641,1698 In all subgroups,

receipt of the anthrax vaccine was associated with a 1.3 to 1.5 times greater risk of Gulf War illness, with

no adjustments made for other types of exposures in theater.

The U.S. DOD has identified over 7,000 Gulf War veterans who are known to have received the anthrax

vaccine, based on available documents. Investigators from the Washington, DC, VAMC identified 352 of

those individuals among the 11,441 Gulf War veterans previously interviewed for the U.S. national

survey of Gulf War veterans.957 Gulf War veterans documented to have received the anthrax vaccine

reported a number of medical conditions and symptoms at higher rates than veterans who said they did

not receive the anthrax vaccine. These included significantly higher rates of dermatitis, gastritis, diarrhea,

joint pain, fatigue, mood changes, sleep abnormalities, and indigestion. A still greater number of

symptoms and health problems were significantly associated with self-reported, but undocumented,

receipt of the anthrax vaccine. These results indicate that, while the anthrax vaccine is potentially

associated with excess symptoms in Gulf War veterans, self-reported data introduced a bias that led to an

overestimate of the vaccine’s adverse effects.

Gulf War illness and receipt of multiple vaccines. An additional vaccine-related question of

importance is whether receipt of multiple vaccinations together, rather than any single vaccine alone,

contributed to the development of Gulf War illness. This issue has been of particular interest in the U.K

and has been investigated in studies of British and Australian Gulf War veterans, but not U.S. veterans.

In 1997, Professors Rook and Zumla of University College in London hypothesized that receipt of

multiple vaccines for the Gulf War could have precipitated an immunological shift that resulted in an

unbalanced production of Th2-type cytokines (associated with humoral immunity) relative to Th1-type

cytokines (associated with cell-mediated immunity).1306 They suggested that this shift may have resulted

from the many TH2-inducing vaccines given to Gulf War personnel, exacerbated by stress and perhaps

also by pesticide exposures. This idea, referred to as the Rook hypothesis, provided a testable theory for

explaining veterans’ diverse symptoms.

In 1999, investigators from King’s College in London reported that Gulf War veterans who received the

largest number of vaccines for the war had significantly worse health, on multiple measures, than veterans

who received fewer vaccines.1698 Additional analyses among the 923 study veterans with vaccination

records appeared, initially, to indicate that receipt of multiple vaccines before deployment was not

problematic. However, veterans who received five or more vaccines during deployment had a

significantly elevated rate of Gulf War illness (OR = 5).641 Commentators identified possible

explanations for this difference, pointing out, for example, that the types of vaccines received in theater
124  Effects of Gulf War Experiences and Exposures

differed from those administered prior to deployment.153,638,679 The study investigators suggested that the

difference was attributable to receiving multiple vaccines in conjunction with the stress of deployment.641

Further analyses, however, indicated that receiving multiple vaccines in theater was not more problematic

than multiple vaccines received before deployment. In response to suggestions from scientific colleagues,

the King’s College investigators revised their analytic approach and found no significant differences

between effects of multiple vaccines administered before and during deployment.638 Their final

conclusion, then, was that their data supported an overall association between multiple vaccines and ill

health in Gulf War veterans that was not specific to post-deployment vaccines.638 A study of Australian

Gulf War veterans also reported higher symptom rates among those who received the largest number of

immunizations for the Gulf War.789 Results of both the King’s College and Australian studies are difficult

to interpret, however, since neither study assessed effects of multiple vaccines, adjusted for other types of

exposures in theater.

A second British study provides a more informative look at this issue. Controlling for effects of multiple

exposures during deployment, investigators at the University of Manchester reported that the number of

inoculations received by British Gulf War veterans was significantly correlated with overall symptom

severity, and with symptoms of peripheral neuropathy.241 The Manchester study also indicated that there

were no differences between effects of vaccines received prior to and during deployment. No specific

information was provided, however, on types of vaccines or vaccine combinations linked to veterans’ ill

health.

There are two components of the original Rook hypothesis. The first is that receipt of multiple

vaccinations contributed to veterans’ persistent symptoms after the war. This has not been evaluated in

U.S. veterans, but is supported by one well-analyzed study of British veterans, with suggestive evidence

provided by two additional studies. The other component of the Rook hypothesis is that veterans’ ill

health resulted from a Th1-Th2 shift in cytokine production. Several studies have tested this directly by

assessing Th1 and Th2-related immune parameters in Gulf War veterans.1420,1835 As will be described in

more detail in a later section of the report, findings have not supported a bias towards production of Th2-

type cytokines in ill Gulf War veterans. It is not possible to know if such a shift occurred, temporarily, at

the time of the war, but a Th1-Th2 shift is not evident in veterans evaluated years after their return from

theater.1182

Other health effects of vaccines received during the Gulf War. Very few other Gulf Warrelated health outcomes have been assessed in relation to vaccines. Two studies have identified

significant associations between acute adverse reactions to vaccines received for deployment and poor

health outcomes after the war.1374,1698 Military hospitalization records indicate that there were 58

hospitalizations in theater for adverse reactions to vaccines. The largest number of cases attributed to one

vaccine was tetanus. One hospital admission, for seizures, was attributed to receipt of the anthrax

vaccine.1622 A report on U.S. military personnel who participated in DOD’s Gulf War registry program,

the CCEP, indicated that veterans who reported receiving BT, but not anthrax, had a significantly higher

rate of hospitalization after the war.1435 In studies of British Gulf War veterans, cancer rates were not

associated with receiving biological warfare vaccines (anthrax, pertussis, plague).943 Self-reported receipt

of the anthrax vaccine was associated with a small, nonsignificant, increase in overall mortality among

British veterans (mortality rate ratio = 1.2).944

Vaccines and the health of veterans who did not serve in the Gulf War. Epidemiologic

studies have generally assessed Gulf War-related health outcomes by comparing the health of Gulf War

veterans to personnel who served in the military during the war, but did not deploy to the Gulf War

theater. A potential problem of using nondeployed Gulf War era veterans as a comparison group is that

they may have received some or all of the vaccines given to Gulf War veterans. There are several reports
Vaccines and Gulf War Illness  125

of military personnel with symptoms that resemble Gulf War illness who received vaccines in preparation

for service in the Gulf War, but did not actually deploy.69,918,1684

Very little research has assessed health problems in relation to vaccines received by Gulf War-era

veterans who did not serve in the Gulf War. The Kansas study asked nondeployed Gulf War-era veterans

if they had received any vaccines during the time of the Gulf War. Nondeployed veterans who reported

getting vaccines during that time had significantly higher rates of symptoms in several domains (chronic

somatic pain, neurological, and gastrointestinal problems) and a nearly four-fold higher rate of Gulf War

illness than nondeployed veterans who did not receive vaccines. Veterans who served in theater, by

comparison, had Gulf War illness symptoms at 11 times the rate of nondeployed veterans who did not

receive vaccines.1476 These findings provide support for the idea that military vaccines contributed to the

development of chronic symptoms in Gulf War era veterans. But the findings are preliminary and are

nonspecific, that is, no information is provided on the types or number of vaccines received by

nondeployed personnel.

Findings from the King’s College study of U.K. veterans may also have relevance to this issue. The study

compared the health of U.K. Gulf War veterans with Bosnia veterans, and asked both groups about

vaccines they had received. Few Bosnia veterans reported receiving biological warfare vaccines: anthrax,

pertussis, or plague. The total number of vaccines received was significantly associated with

multisymptom illness in Gulf War veterans, but not in Bosnia veterans.1698 Information provided did not

allow for a clear interpretation of these findings, however. They could indicate that the multiple vaccine

effect observed in British Gulf War veterans is related to specific vaccines given to Gulf War, but not

Bosnia, personnel. Alternatively, they could indicate that the multiple vaccine effect resulted from

confounding by other risk factors associated with Gulf War service. For example, the large Manchester

study of British Gulf War veterans found that the number of vaccines received by Gulf War veterans was

significantly correlated with other exposures in theater, such as the number of days PB was used.241

Accuracy of self-reported vaccine data. Most Gulf War studies have assessed veterans’ health in

relation to vaccines based on veterans’ own reports of immunizations they received for the war. Selfreported information on the number and types of vaccines received for Gulf War deployment is

potentially more problematic than for some other self-reported exposures. In addition to usual problems

related to accurate recall, veterans might not have known what vaccines they received at the time they

received them, as has been reported for anthrax and BT vaccines. Several studies have provided useful

insights related to the accuracy of vaccine reporting by veterans. Department of Veterans Affairs

investigators were able to evaluate the accuracy of veterans’ self-reported receipt of the anthrax vaccine

in 352 veterans interviewed for the U.S. national Gulf War survey. When questioned, three-fourths of the

352 veterans with DOD-documented receipt of the anthrax vaccine reported that they had, in fact,

received it. Only 10 percent reported they did not receive the anthrax vaccine and 16 percent didn’t

know.957

Two studies of U.K. Gulf War veterans found that veterans who used their shot records in reporting

immunizations tended to report more vaccines than veterans who did not have shot records.241,1698 But

misreporting and underreporting of vaccines appears to have had little effect on health findings related to

vaccines. Both large national studies of British Gulf War veterans found that associations between

vaccines and health outcomes were similar in veterans who did have vaccine records compared to

veterans who did not have their records.241,1698

Summary. Vaccines and Gulf War illness. Gulf War veterans received multiple immunizations for

deployment. These included the anthrax vaccine, which was given to a large number of military

personnel for the first time during the Gulf War. Diverse issues have been raised in relation to the anthrax

vaccine’s potential for causing adverse health effects. Due to changes in production methods and quality

control measures between 1990 and 2001, it is not known if the safety profile of the anthrax vaccine in
126  Effects of Gulf War Experiences and Exposures

current use is the same as that of the vaccine given to Gulf War personnel. Recent studies have indicated

that the current anthrax vaccine is associated with high rates of acute adverse reactions, particularly in

women. No information is available on rates of persistent symptoms or multisymptom illness following

receipt of the anthrax vaccine. Studies have not identified excess hospitalizations or outpatient visits for

diagnosed diseases in the weeks and months following receipt of the vaccine. Limitations in the types of

information provided by these studies, however, indicate a continued need for long-term follow up, to

determine whether excess rates of diagnosed or undiagnosed conditions occur in anthrax vaccine

recipients.

An excess of circulating antibodies to the natural substance squalene was reported in symptomatic Gulf

War veterans in 2000, and investigators suggested this could have been caused by an unapproved vaccine

adjuvant in the anthrax vaccine. Testing of potentially suspect vaccine lots by two laboratories identified

only trace amounts of squalene, far below levels usually used for vaccine adjuvants. The observed

association between Gulf War illness and elevated levels of squalene antibodies was not contingent on

anthrax vaccine being the source of this abnormality, however, and has not yet been independently

evaluated.

Gulf War epidemiologic studies have not identified any individual vaccine, including the anthrax vaccine,

to be a prominent risk factor for Gulf War illness. Several studies have provided indications that

personnel who received a larger number of vaccines for deployment have had higher rates of persistent

symptoms since the war. Few Gulf War studies have adequately analyzed data collected in relation to

vaccines received for deployment, however, to determine whether individual vaccines or combinations of

vaccines are independent risk factors for persistent health problems in Gulf War veterans.
Vaccines and Gulf War Illness  127

Recommendations

Diverse concerns have been raised in relation to vaccines received for the Gulf War, but relatively little

reliable information has implicated individual vaccines as prominent risk factors for Gulf War illness.

Several issues related to vaccines received by Gulf War veterans have not been adequately addressed by

existing research. These include the need for more thorough evaluation of vaccines as risk factors for

chronic health problems in epidemiologic studies, a definitive study to conclusively evaluate the

previously-observed association between squalene antibodies and Gulf War illness, and the need for

longer-term evaluation of symptoms and diagnosed diseases following receipt of the anthrax vaccine.

The Committee therefore recommends the following research:

 In previously-conducted and future epidemiologic studies of Gulf War veterans, analyze

associations between Gulf War illness and individual vaccines, combinations of vaccines, and total

number of vaccines received using methods that control for potential confounding by other Gulf

War-related exposures.

 Commission a case-control study to provide clear answers concerning possible associations

between Gulf War illness and squalene antibodies. The study should, at minimum, analyze blinded

samples from well-characterized symptomatic and healthy Gulf War veterans for the presence of

squalene antibodies using each of the assays developed for this purpose. It should also assess

whether there is an identifiable link between levels of squalene antibodies in ill Gulf War veterans

and receipt of the anthrax vaccine or vaccines more generally. The project should be organized and

overseen by qualified investigators not affiliated with the federal government or civilian scientists

whose initial work raised the squalene issue in relation to Gulf War illness.

 Evaluate the association of anthrax vaccine adsorbed (AVA) with chronic symptoms, Gulf War

illness, and diagnosed diseases in personnel known to have received the anthrax vaccine during the

Gulf War. These health outcomes should also be assessed at least five years after vaccination in

deployment and era subgroups of personnel in the Millenium Cohort study as well as other groups

vaccinated in association with the military’s anthrax vaccine immunization program and federal

anthrax vaccine trials.
128  Effects of Gulf War Experiences and Exposures

Cholinergic and Related Neurotoxicants: Pyridostigmine Bromide,

Pesticides, and Nerve Agents

Vesser [Acting Special Assistant to the Secretary of Defense for Gulf War illnesses LTG Dale

Vesser] remarked that although Saddam Hussein didn’t use nuclear, biological, or chemical

agents against coalition forces during the war, ‘it never dawned on us ... that we may have

done it to ourselves.’

... ‘We know that at least 40,000 American troops may have been overexposed to

pesticides,’ Vesser said, adding that more than 250,000 American troops took the small, white

pyridostigmine bromide pills. .... Both of these substances may cause symptoms that are

consistent with the symptoms that some Gulf War veterans have.’

--Armed Forces Press Service, 2001491

Many classes of chemicals are neurotoxicants, that is, exposure to these compounds can have adverse

biological and physical effects on the nervous system. Three types of neurotoxicant exposures

encountered by Gulf War military personnel during deployment are chemically related. They include

chemical nerve agents, many of the pesticides used during the Gulf War, and pyridostigmine bromide

(PB), the drug given to troops as a protective measure in the event of nerve gas attack. In its 2004 report,

the Committee provided an overview of information concerning veterans’ exposures to these toxicants,

what was known about their health effects, and what had been learned from studies of Gulf War veterans.

The report concluded that available evidence supported a probable link between Gulf War illness and

exposure to these compounds.

Chemical nerve agents, PB, and many of the pesticides to which Gulf War veterans were exposed belong

to a class of chemicals known as acetylcholinesterase (AChE) inhibitors. They share a common toxic

mechanism of action, that is, they inactivate the enzyme AChE, which is essential for breaking down the

nerve signaling chemical (or neurotransmitter) acetylcholine. Inhibition of AChE leads to the buildup of

acetylcholine in the brain and peripheral nerve endings, and over stimulation of cholinergic nerve

receptors. Acetylcholinesterase-inhibiting medications and pesticides can be used safely at recommended

levels. Adverse effects can occur with excessive exposure, and are also seen at lower doses in individuals

who are particularly sensitive to these compounds.

The acute symptoms of excess exposure to AChE inhibitors relate to the different types of cholinergic

receptors affected by acetylcholine buildup. Excess cholinergic stimulation of muscarinic receptors of the

parasympathetic autonomic nervous system results in increased salivation and respiratory secretions,

nausea, abdominal cramping, diarrhea, and excess sweating. Effects on autonomic nicotinic receptors

include increased heart rate and blood pressure. Excess stimulation of nicotinic receptors in skeletal

muscles leads to muscle twitching, cramps, weakness, tremors, and paralysis. Excess stimulation of

acetylcholine receptors in the brain produces fatigue, mental confusion, headache, poor concentration and

general weakness and, at higher exposures, convulsions and coma.387 At sufficient doses, exposure to

AChE inhibiting chemicals can result in respiratory arrest and death.

This section of the report provides information on what is known about Gulf War veterans’ exposure to

these chemicals, what is known about their health effects overall, and what has been learned about their

effects from studies of Gulf War veterans. It also includes information on additional pesticides of

concern that are not AChE inhibitors and information from research on effects of exposure to

combinations of PB, pesticides, and nerve agents.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  129

Exposure to Cholinergic and Related Neurotoxicants During Gulf War Deployment

My unit arrived in the Gulf the day before the air war started. We first spent about a month in

Dhahran in Saudi Arabia. Our chemical alarms went off several times during that month, and

we had to go to MOPP-level four, which meant we had to put on chemical suits, masks,

gloves, and boots. While we were still in Dhahran, we started taking pyridostigmine bromide

pills, which were supposed to protect us against exposures to nerve gas. About three days

after I started taking the pills, my eyes were jittery, my vision was jumping, and I was seeing

double, and I was nauseated. By the fourth day, I was vomiting a little blood, so I went to

sick-call. They told me to cut the dose in half and said there was nothing to worry about. At

least I no longer vomited blood after I reduced the dosage. Many other people in the unit

reported having similar vision problems.

--SSgt PB, Gulf War veteran716

Military personnel serving in the 1990-1991 Gulf War were exposed to a variety of substances that have

the potential to adversely affect the central nervous system. These include multiple types of

anticholinesterase compounds—pyridostigmine bromide (PB) pills, pesticides, and for some veterans,

low-level exposure to chemical nerve agents. But not all personnel were exposed to the same compounds

at the same dosages and in the same combinations. Although records are not available that document

individual exposures to these compounds, government investigations have provided considerable

information on the extent and patterns of use of PB and pesticides, and have modeled nerve agent

exposures in relation to the largest verified nerve agent release incident.

Table 1. Veteran-Reported Exposures to Neurotoxicants During Gulf War Deployment

U.S. National

Survey751

U.S. Army

Veterans1804

U.S. Navy

Seabees524

U.K. National

Survey1698

Took pyridostigmine bromide pills 49 % 66 % 33 % 82 %

Used personal pesticides 48 % 46 % 35 % 69 %

Exposed to nerve gas/chemical agents 10 % 19 % 3 % 9 %

Population-based surveys of Gulf War veterans have also provided consistent information on veteranreported exposures during deployment. Table 1 summarizes responses to survey questions from studies

of Gulf War veterans in the U.S. and U.K. concerning their use of PB and pesticides, and whether they

thought they were exposed to chemical weapons. About half of all U.S. Gulf War veterans, and a higher

proportion of U.K. Gulf War veterans, report using PB and pesticides during deployment. Nearly two out

of three Gulf War veterans in the U.S. national survey reported that they had heard chemical alarms sound

or put on their MOPP gear (mission oriented protective posture, protective garments worn in a possible

chemical event) during deployment,751 but only 10 percent believed that they were exposed to nerve

agents or other chemical weapons in theater. Overall, Army veterans report greater exposure to PB,

pesticides, and nerve agents than Navy veterans. A large survey of British Gulf War veterans also found

that PB and pesticide use were reported by more U.K. Army personnel than those in the Royal Air Force

or Navy.241
130  Effects of Gulf War Experiences and Exposures

Pyridostigmine bromide (PB) use in the Gulf War

Pyridostigmine bromide (PB) is a compound that reversibly binds to, and temporarily inactivates, AChE.

It is the active ingredient in the nerve agent pyridostigmine pretreatment (NAPP) pills that were

distributed to military personnel in the Gulf War as part of a three drug regimen to protect troops from

poisoning by nerve agents. The small white PB pills were intended for use before a nerve gas attack, to

establish blood levels adequate to temporarily bind about 30 percent of circulating AChE. If exposed to

nerve agents, soldiers were to inject themselves (or their buddy) with two antidotes, atropine and 2-

pralidoxime chloride (2-PAM), using prepackaged autoinjectors. These measures were intended to

protect cholinergic receptors from excess acetylcholine buildup, and “rescue” AChE in order to restabilize

cholinergic nerve transmission after the attack. Orders for initiating PB pretreatment were issued by unit

commanders. The NAPPs were contained in blister packs of 21 pills, 30 mg. each. Each pack provided

the number of pills needed for one week at the recommended dosage of one 30 mg. pill every eight

hours.951,1604

The 1990-1991 Gulf War was the first time the U.S. military had used PB on a widespread basis as a

nerve agent pretreatment. In 1990, PB was not licensed for this purpose by the U.S. Food and Drug

Administration (FDA) but had been approved, since 1955, for treatment of myasthenia gravis. As a nerve

agent protective measure, PB was considered an investigational new drug (IND). At the request of DOD,

FDA granted a temporary waiver, in December 1990, that allowed use of PB in theater, in situations

involving combat or the threat of combat, without the usual IND requirement for informed consent.1275

The waiver was granted in light of the threat posed by Iraqi chemical weapons and the long history of PB

safety in the treatment of myasthenia gravis.781,951,1275,1604,1667 A number of problems occurred in

implementation of the use of PB under this agreement, however, which prominently included insufficient

information provided to troops in theater, and failure to keep adequate records of PB distribution and

use.462,1275,1604,1667

Pyridostigmine bromide has now been approved by FDA for use as a pretreatment measure against

exposure to the nerve agent soman.1664 Research in animal models indicates that PB pretreatment

enhances the effectiveness of the two antidotes that are used after exposure to soman, which permanently

inactivates AChE within minutes. Pyridostigmine is not useful as a pretreatment in the event of sarin

exposure, since sarin’s effects on AChE can be mitigated by the post exposure antidotes over a period of

several hours.504,830,951,1793,1810 There have been no reports indicating that soman was present in theater

during the 1990-1991 Gulf War, however. Available documents suggest that during the war, PB

pretreatment was directed in anticipation of nerve agent exposure more generally, rather than specifically

in relation to soman.781,1588,1604,1690

Epidemiologic studies indicate that about half of U.S. Gulf War veterans report using PB during

deployment,692,751 with greatest use among Army personnel.458,1804 The DOD Office of the Special

Assistant for Gulf War Illnesses (OSAGWI) commissioned the RAND National Defense Research

Institute to undertake an in-depth evaluation of pesticide and PB use patterns by ground troops during the

Gulf War.458 Investigators conducted detailed interviews of over 2,000 Gulf War veterans. Results

indicated that slightly more than half of Army and Navy/Marine Corps personnel serving on the ground

used PB, but only 23 percent of Air Force personnel used PB. Among individuals who used PB, the

number of pills taken was highly variable, with an average of 26 pills used in a given month. Most

individuals reported taking three or fewer pills per day for 30 days or less, but a small percentage reported

taking substantially more.458 Overall, troops living in the open desert took PB at twice the rate of troops

in tent cities, who in turn took PB at twice the rate of personnel living in buildings.458 Results from the

population-based Iowa study also suggested that active duty personnel took more pills, overall, than

reservists.692
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  131

Pesticide use and exposures in the Gulf War

On a nightly basis, we would spray our uniforms with pesticides. There was a chemical spray

that they gave us to spray our uniforms. We had to hang them outside so that the excess

spray would dissipate in the air, I guess. We weren’t supposed to put them on immediately

after spraying them. The sand fleas were a problem. We used to put flea collars around the

legs of our cots or we would put flea powder on the floor around our cots to try to keep the

sand fleas away from us while we were sleeping. We slept with nets over us to keep the flies

off. The flies were ungodly.

--SSgt TS, Gulf War veteran716

The desert environment was home to large numbers of flying and biting insects, and other pests, which

posed a risk of disease to troops in theater. Control of disease-carrying pests is an important part of force

protection and readiness during military deployments. Troops serving in the region in earlier campaigns

had been affected by high rates of pest-borne diseases475,596,1632 and the U.S. military implemented

extensive measures to limit this problem in the Gulf War. Individuals were issued pesticide creams,

liquids, and sprays, to use on their skin, their uniforms, and their bedding, and pest strips, bait, and sprays

to use in their living quarters. Military preventive medicine specialists and field sanitation teams also

conducted extensive operations to control pests in areas where people lived, ate, and worked with

environmental fogging and surface spraying. These efforts were largely successful, as demonstrated by

the low rate of vector-transmitted infections identified during the war.664,1632

Similar to other exposures in the Gulf War, no records were kept in relation to pesticide use or exposure

for different areas, units, or individuals. After the war, when concerns were raised about the possible

contribution of pesticides to veterans’ unexplained illness, DOD undertook a number of assessments to

determine the types of pesticides to which Gulf War veterans were exposed, the amounts used in theater,

and patterns of pesticide use among individuals in the general military population and by pest control

personnel.

In its final Environmental Exposure Report on pesticide use in the Gulf War, issued in 2003, DOD

reported that U.S. personnel serving in the Gulf War used or had available for use, at least 64 pesticides

and related products, containing 37 active ingredients.1632 Of these, 15 were identified as “pesticides of

potential concern” based on what was known about the use and toxic effects of these compounds. The 15

pesticides are listed in Table 2, and include seven organophosphates, three carbamates, two pyrethroids,

one organochlorine, and two forms of the insect repellant DEET.

The most commonly used personal repellants were DEET, which was primarily to be used on the skin,

and permethrin, which was to be sprayed onto uniforms. Some personnel are known to have acquired

personal use pesticides in addition to those supplied by the military, including the commercial product

OFF, citronella products, and flea collars. Military environmental pesticide control measures included

surface spraying and environmental fogging using the organophosphates chlorpyrifos, diazinon, and

malathion, in varying concentrations, as well as the carbamates propoxur and bendiocarb. The

organochlorine lindane powder was used by military police and other personnel for delousing in the

processing of the more than 87,000 enemy prisoners captured in the war. Lindane was also issued to

troops for their personal use, primarily to Army personnel.1632 In addition, environmental pest control

was commonly provided by local pest control services in host nations, either under contract with the

military, or supplied by health departments of local Saudi Arabian municipalities. Relatively little

information is available concerning the types of compounds used or the frequency and patterns of

spraying done by local pesticide services.1632

Gulf War epidemiologic studies queried veterans about pesticide use in theater in diverse ways that

ranged from a simple question about whether or not the veteran had used “pesticides” during deployment,

to more detailed questions about specific types used and the extent of their use. The U.S. national survey
132  Effects of Gulf War Experiences and Exposures

Table 2. Pesticides and Insect Repellants Identified as Pesticides of Potential Concern

by the Deployment Health Support Directorate

Compound Use Chemical Class Purpose Application

Pesticides and Repellants Used by the General Military Population

DEET, 33% cream, stick Personal use

repellant

Dialkylamide Repel flies and

mosquitoes

By hand to skin

DEET, 75% liquid Personal use

repellant

Dialkylamide Repel flies and

mosquitoes

By hand to skin, uniform,

netting

Permethrin, 0.5% spray Personal use

repellant

Pyrethroid Repel flies and

mosquitoes

Sprayed on uniforms

d-Phenothrin, 0.2%

aerosol

Area use

repellant

Pyrethroid Knock down, kill flies

and mosquitoes

Sprayed in tents, other

enclosed areas

Methomyl 1% crystals Fly bait Carbamate Attract and kill flies Placed in pans outside

latrines, tents

Azamethiphos, 1%

crystals

Fly bait Organophosphate Attract and kill flies Placed in pans outside

latrines, tents

Dichlorvos, 20%

pest strip

Pest strip Organophosphate Attract and kill

mosquitoes

Hung in tents, working

areas, dumpsters

Pesticides Used by Pesticide Applicators

Chlorpyrifos, 45% liquid Sprayed

liquid

Organophosphate Kill flies, mosquitoes,

flying insects

Sprayed in corners,

cracks, crevices

Diazinon, 48% liquid Sprayed

liquid

Organophosphate Kill flies, mosquitoes,

flying insects

Sprayed in corners,

cracks, crevices

Malathion, 57% liquid Sprayed

liquid

Organophosphate Kill flies, mosquitoes,

flying insects

Sprayed in corners,

cracks, crevices

Propoxur, 14.7% liquid Sprayed

liquid

Carbamate Kill flies, mosquitoes,

flying insects

Sprayed in corners,

cracks, crevices

Bendiocarb, 19% liquid Sprayed

powder

Carbamate Kill flies, mosquitoes,

flying insects

Sprayed in corners,

cracks, crevices

Chlorpyrifos, 19% liquid Fog Organophosphate Kill flies, mosquitoes Large area fogging

Malathion, 91% liquid Fog Organophosphate Kill flies, mosquitoes Large area fogging

Delousing Pesticide

Lindane, 1% powder Delouser Organochlorine Kill lice, other insects Dusted on prisoners,

also for personal use

Source: DOD Environmental Exposure Report: Pesticides (2003)1632

indicated that about half of all Gulf War veterans reported using personal pesticides,751 with additional

studies suggesting that pesticide use was more common in Army than Navy personnel.524,1782 The Iowa

study also indicated that reservists reported pesticide use more commonly (63%) than active duty

personnel (44%).692
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  133

The RAND investigation of pesticide use among ground troops during the Gulf War reported

considerable diversity in patterns of pesticide use in theater. Survey respondents were often unable to

recall the specific chemicals used during deployment, but could identify the form of pesticides used (e.g.,

spray, liquid, powder) and how it was used (e.g., on clothing, skin, in tent), from which investigators

imputed the most likely compound.458 Personnel living in the desert used more pesticide sprays and

liquids than those who lived in buildings. Officers reported less use of pesticide lotions and flea collars

than enlisted personnel, and senior enlisted personnel reported greatest use of pesticide sprays and

powders.

Overall, 62 percent of ground troops interviewed reported some form of pesticide use. Forty-four percent

used pesticide sprays, a median of 30 times per month, and 26 percent used pesticide lotions a median of

20 times per month. Investigators estimated that the most commonly used compound was DEET, used by

half of all personnel, a median of 30 times per month. Permethrin was used by fewer personnel458,1632 but

was used an average of almost 30 times per month. This raises concerns, since the permethrin label

indicated that uniforms were to be sprayed only once every six weeks, or after six launderings. In

contrast, DOD reports indicate that guidance issued to some Army personnel directed them to “apply a

light coat of permethrin every four or five days.”1632

The RAND investigation indicates that overuse of pesticides was most apparent for permethrin, dphenothrin, lindane, and flea collars, although fewer individuals used these than the more commonly used

DEET. No-pest strips were also frequently used in greater density than recommended, particularly in

eating areas and latrines. Some pesticide overuse was extreme. About 13 percent of veterans reported

using pesticide sprays more than 50 times per month, and about five percent reported using pesticide

liquids or lotions more than 100 times in a given month, or more than three times per day.458

It also seems reasonable that people in environments with large numbers of insects, such as

in the Persian Gulf, would be tempted to use whatever means was available to remove the

pests, including using products in ways that were not recommended.

--RAND National Defense Research Institute, Pesticide Use During the Gulf War458

RAND investigators reported that personnel who reported frequent use of one type of personal pesticide

were also more likely to report frequent use of multiple pesticides, suggesting exposure to a “cocktail of

pesticides.” 458 Use of personal pesticides was also significantly correlated with the number of PB pills

taken in a given month. Over one in four veterans serving on the ground reported they had applied

pesticides from 51 to over 120 times in a given month, and had also used an average of 15-19 PB pills in

the same month.458 By comparison, ground troops who reported no use of pesticides took, on average,

only six PB pills in a given month.

The DOD final environmental exposure report on pesticides in the Gulf War included a health risk

assessment that relied on information from the RAND survey, as well as interviews conducted with

preventive medicine personnel knowledgeable about field pesticide use. The report concluded that “at

least 41,000 Gulf War service members may have been overexposed to pesticides” and that

“overexposure to pesticides, particularly organophosphates and carbamates, may have contributed to the

unexplained illnesses reported by some Gulf War veterans.” The figure of 41,000 was provided as a

minimum figure, and did not consider effects of “overexposure” potentially resulting from combinations

of organophosphate and carbamate pesticides with concurrent exposures to DEET, permethrin, PB, or

low-level nerve agents or pesticide exposures resulting from pest control services provide by host

nations.1632
134  Effects of Gulf War Experiences and Exposures

Although comprehensive information on pesticide use in current deployments to Iraq and Afghanistan has

not yet been reported, it appears that improved pesticide use and oversight have been among the

important lessons learned from the 1991 Gulf War.36 In 1993, the Deputy Undersecretary of Defense

issued three pest management “Measures of Merit” that established objectives for improved pest

management planning, a 50 percent reduction in the amount of pesticides used on military installations,

and improved training and certification of pesticide applicators.442 The military has now established

improved standards and practices that include expanded use of trained preventive medicine field teams

that monitor environmental hazards, training and printed materials for military personnel on the need for

proper use of pesticides and insect repellants, as well as some changes in the specific pesticide products

used.1074,1583,1632

There are multiple indications that pesticide usage in Operation Iraqi Freedom has differed from that in

the 1990-1991 Gulf War. DEET formulations currently provided by the military contain 20-33 percent

DEET; the 75 percent DEET liquid issued during the Gulf War is no longer in use.62 Lindane, the

organochlorine issued for delousing prisoners and for personal use during the Gulf War is no longer used

for either purpose by the military.63 In addition, troops in current deployments have had access to

uniforms that were pretreated with permethrin, and permethrin treatment kits that reduce risks associated

with uniform spraying, and sometimes over spraying, as occurred in the Gulf War.62,1771

Reports indicate that Iraq War troops were more educated about pesticides,36 but sometimes did not have

sufficient access to repellants, at least in the first years of the war.399,1771 A survey of 870 service

members at camps in Kuwait in 2004 indicated that most personnel had received medical briefings on

why and how insect repellants were to be properly used. However, only 36 percent had been issued any

DEET product and 48 percent had received permethrin products.1771 A substantially larger number of

cutaneous leishmaniasis cases have occurred among Iraq War troops, compared to the 1991 Gulf War,399

which a National Defense University report suggests may be related to reduced used of pesticides.1537

Therefore it appears that pesticide usage by troops in Operation Iraqi Freedom is decreased, or from

another perspective, improved and more judicious, compared to pesticide usage in the 1991 Gulf War.

This can be attributed to a number of factors, including improved pest management policies, improved

education of pesticide applicators and the general military population, expanded placement of preventive

medicine field sanitation teams, differences in living conditions, discontinued use of lindane and 75

percent DEET, and, in some cases, inadequate supplies of repellant products.

Exposure to chemical weapons in the Gulf War

In late January 1991, while assigned to an area between Rafha and Naryian about six miles

south of the Iraqi border, BM recorded in his journal and on videotape that chemical ‘false

alarms’ were going off almost every day. At first, according to BM, the alarms were explained

as being caused by vapors coming off the sand. Later, since the alarms kept going off and

troops no longer believed they were being caused by vapors, BM said he was informed by

both his battalion commander and the battalion NBC NCO that the alarms were sounding

because of ‘minute’ quantities of nerve agent in the air, released by the coalition bombing of

Iraqi chemical weapons facilities. The troops were assured that there was no danger.

--1994 Senate Committee report on Gulf War veteran, 18th Airborne Corps1688

Among the many challenging issues related to understanding levels and effects of hazardous exposures in

the Gulf War, those surrounding troop exposures to chemical weapons in theater are the most complex

and controversial. Multiple accounts of chemical alerts during the war, positive readings on chemical

detection tests, and incidents involving unusual vapors and unexplained symptoms were reported in the
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  135

media and documented in Congressional reports. Seventeen years after the war, after numerous

government and special committee investigations, research studies, and reports, significant questions

remain about the extent to which military personnel were exposed to low levels of chemical warfare

agents during the Gulf War.

For the first five years after Desert Storm, DOD maintained that no troops had been exposed to chemical

agents. The Iraqis were known to have chemical weapons and to have used them against Iranians and

their own citizens in the 1980s. The Department of Defense consistently affirmed, however, that Iraq had

not used chemical weapons offensively in the Gulf War and that none had been positioned in areas of Iraq

that were penetrated by Coalition forces. In preparing for the Gulf War air offensive, U.S. military

planners had identified multiple Iraqi targets where chemical weapons were believed to be manufactured

or stored.1748 Most of these chemical targets had been successfully destroyed during the air campaign.320

But DOD indicated that any chemical agents released with the bombing of Iraqi targets had occurred a

great distance from Coalition troop locations, too far away to have affected U.S. or allied personnel.

In June of 1996, DOD announced that U.S. troops had potentially been exposed to low levels of nerve

agents after the cease fire in March of 1991, when Army personnel detonated large caches of munitions

stored at a massive compound near Khamisiyah, in southeastern Iraq. This announcement proved to be a

turning point in the federal response to Gulf War health issues. It triggered an expanded effort to analyze

and address Gulf War health issues overall, stimulated multiple investigations into chemical weapons

exposures in theater, and led to a military research program aimed at better understanding effects of lowdose exposure to chemical warfare agents.1102

Chemical warfare agent exposure and detection in the Gulf War theater. Understanding the

likely extent of chemical agent exposures in the Gulf War has been complicated by a number of factors.

These include long-time official denials that chemical releases and exposures had occurred in theater, the

postwar disappearance of the U.S. Central Command’s records of reported chemical events during the

Gulf War, the limited capabilities of chemical monitoring equipment in theater, controversy surrounding

government conclusions about chemical releases at Khamisiyah and other locations, and the limited

degree to which military personnel could have known if they had been exposed to low levels of chemical

agents.

There are multiple scenarios in which chemical agent exposures could potentially have occurred. These

include Iraqi offensive use of chemical weapons, downwind drift of chemical agents released by Coalition

aerial bombing of Iraqi targets, local exposure and downwind drift following ground destruction of

chemical munitions, and exposure of individuals who entered bunkers or other areas contaminated by

chemical weapons. The Department of Defense has maintained that there was no offensive use of

chemical weapons in theater, and has only verified that troops were exposed to nerve agents in one case,

as a result of the ground destruction of chemical weapons at Khamisiyah. Multiple reports of chemical

detections and other incidents that potentially involved chemical exposures have long fueled speculation,

however, that additional exposures may have occurred, exposures that were either not identified or not

verified by DOD.388,1560,1683,1685,1688

In the years since the war, an extensive number of reports from DOD, the U.S. Central Intelligence

Agency (CIA), the United Nations, and other sources have provided information on the types and

amounts of chemical agents stored, deployed, and destroyed in different locations in the Gulf War theater.

Previous advisory panels, government agencies, and Congressional committees have been tasked with

reviewing available information on these issues. Their reports have identified a variety of different issues

and produced different, sometimes contradictory, findings.1231,1232,1595,1683,1688,1690 Detailed analysis of the

many intelligence reports, modeling protocols, incident reports, and investigations related to possible

chemical releases and exposures in theater was beyond the scope of the present report. Instead, the
136  Effects of Gulf War Experiences and Exposures

Committee broadly reviewed information provided by government investigations and issues raised by

earlier panels to determine what has been learned about chemical agent exposures during the Gulf War.

It is important to note that there have been no reports during or after the war of high-level chemical

exposure incidents in which large numbers of personnel experienced clear signs and symptoms of

chemical agent poisoning. Available information indicates that the major unanswered questions about

exposure to chemical weapons during the Gulf War relate to: (1) whether more limited or lower level

chemical agent exposures occurred in theater that were undetected, unreported, or unverified by the

government, and (2) if modeled plume estimates for the Khamisiyah demolitions usefully reflect chemical

exposures that resulted from releases at that site.

Limitations and problems in detecting chemical warfare agents. At the most fundamental

level, identifying chemical agent exposures during the Gulf War depended on reliable detection of those

agents. Concerns about the inability of chemical monitoring systems used in the Gulf War to detect lower

levels of chemical agents in the field were raised in 1994 by the Senate Banking Committee, and again in

1996 and 1997 by the Presidential Advisory Committee on Gulf War Veterans’ Illnesses.1227,1231,1690

During the Gulf War, the U.S. military used a multilevel system for detecting and verifying chemical

agents. With an initial detection, an alarm alerted personnel to the possible presence of a chemical agent

and troops donned protective gear until results from a second type of test either verified a positive

detection or permitted an “all clear” notification. The primary early warning system for airborne

chemical agents was the M8A1 chemical alarm. These alarms could be placed upwind from the unit’s

position to monitor for VX and G series nerve agents, including sarin. The M8A1 could only detect nerve

agents at levels that can also cause symptoms, and could not detect blister agents such as mustard gas at

any level.1231,1595,1605,1690 Handheld chemical agent monitors (CAMs) could detect airborne vapors of both

nerve and blister agents but were not primarily used as an open air warning device. They were more

commonly used to determine if personnel or surfaces had been contaminated, by assessing and roughly

quantifying vapors emanating from liquid agent.961,1595 Liquid chemical agent hazards could also be

detected by M8 and M9 papers, issued to individual service members, and by a specialized kit (M272)

used by NBC (nuclear, biological, chemical) personnel to identify chemical agents in water.1595

The most widely used system for verifying airborne chemical agents was the M256A1 Chemical Agent

Detector Kit. Testing was conducted by trained NBC personnel and involved a sequence of steps that

required 20-25 minutes to complete.1595,1613 Although not useful as an early warning monitor, the

M256A1 kits were more sensitive to nerve agents than the alarms, and less prone to false positives.

The U.S. military also fielded 60 armored FOX NBC Reconnaissance vehicles, provided by Germany

during Operation Desert Shield.1606 The Fox vehicles were considered the most technologically advanced

chemical equipment used by the U.S. in the Gulf War. This mobile unit could conduct chemical and

radiation reconnaissance in different settings, with capabilities to sample for, detect, and verify chemical

agents. Fox vehicles were equipped with the M43A1 chemical agent detector and an MM-1 mobile mass

spectrometer. They were designed primarily to identify ground contaminated areas and were most

sensitive and specific for detecting liquid chemical agents. The Fox was not considered a suitable first

warning device when used in air sampling mode, since a relatively high concentration of nerve or blister

agent vapor was required for detection.1231,1595,1606,1628,1690 The MM-1 spectrometer provided detailed

chemical agent verification capability, but identified only the compound present at the highest

concentration.1228,1628 If, for example, nerve agent was present, but at a lower concentration than a

compound in oil fire smoke, only the oil fire compound would be identified.

The multilevel chemical agent detection system used by the military during the Gulf War was intended to

detect chemical agents at levels that could cause acute harm to troops in the field, and provide warning to

allow them to take protective action. This was consistent with the understanding at the time that subacute
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  137

Table 3. Chemical Agent Vapor Detection Capabilities of Equipment Used in the Gulf War,

and Current Chemical Weapons Air Exposure Guidelines and Standards

Sarin Mustard

Vapor Detection Capabilities of Chemical Detection Equipment Used by the U.S. Military in the Gulf War

M8A1 chemical alarms 0.1 – 0.2 mg/m3no capability

Portable chemical agent monitors < 0.1 mg/m3< 0.1 mg/m3

M256A1 detector kits 0.005 mg/m32 mg/m3

Fox vehicle M43A1 alarm 0.2 mg/m3no capability

Fox vehicle MM-1 mass spectrometer monitor 62 – 100 mg/m3

Chemical Weapons Air Standards and Guidelines Currently Used by the U.S. Military

Air exposure limits:

Immediate danger to life and health (1 time exposure)

Short term exposure limit (occasional 15 minute exposure)

0.1 mg/m3

0.0001 mg/m3

0.7 mg/m3

0.003 mg/m3

Acute exposure guideline levels (1 time exposure)

Level 1 (potential for noticeable effects, minor discomfort)

- 10 minutes

- 1 hour

Level 2 (more obvious effects, potential impact on function)

- 10 minutes

- 1 hour

Level 3 (potentially life threatening)

- 10 minutes

- 1 hour

0.0069 mg/m3

0.0028 mg/m3

0.087 mg/m3

0.035 mg/m3

0.38 mg/m3

0.13 mg/m3

0.400 mg/m3

0.067 mg/m3

0.600 mg/m3

0.100 mg/m3

3.900 mg/m3

2.100 mg/m3

Chemical Agent Detection Capabilities Sources: Defense Science Board Task Force on Persian Gulf War Health Effects,1597

National Research Council,1007 U.S. Department of Defense1605,1606,1613

Air Standards and Guidelines Source: U.S. Army Center for Health Promotion and Preventive Medicine1581,1582

exposure to chemical agents did not pose a serious health threat. In recent years, growing concern about

possible adverse effects of lower level exposures have prompted federal agencies, including DOD, to

revise chemical agent exposure standards and adopt guidelines that are more conservative than those in

place during the Gulf War, that is, standards that consider lower exposure levels to be potentially

problematic.1574,1755 The Department of Defense has also replaced the M8A1 alarms with next generation

alarms that have expanded capabilities and are less prone to false alarm.1605

Information on detection capabilities of equipment used by the U.S. in the Gulf War for airborne sarin

and mustard is provided in Table 3. The table also provides current toxicity standards and guidelines used

by the military for exposure to these agents. Because the toxicity of chemical agents varies with the

concentration and duration of exposure,86 limits are provided for immediate and short term exposures, and

guidelines identify levels at which mild, more serious, and life threatening health effects may acutely

occur.1581,1582 As shown, the M8A1 alarms could have detected sarin at levels that pose an immediate

danger to life and health with a one time exposure. The alarms would not have detected sarin present at

levels capable of producing limited symptoms after only 10 minutes exposure, identified as a Level 1

exposure in the table. The M8A1 alarms also might not have detected a Level 2 exposure, associated with
138  Effects of Gulf War Experiences and Exposures

more significant symptoms and signs with 10 minutes exposure. The M256A1 detection kits could

potentially have identified chemical agents at considerably lower levels, but would not likely have been

used in the absence of an initial warning alarm.

Overall, monitoring capabilities for chemical agent vapors were insufficient to detect levels that could

cause limited symptoms with relatively brief exposures, or more pronounced problems with sustained

exposures. And, as previously indicated, the M8A1/M43A1 alarm systems would not have detected

nerve agents at levels too low to cause any symptoms, or blister agents at any level.

From the Saudi berm north, the air was heavy with oil smoke. This smoke deposited an oily

residue on the alarms’ paddles which tripped the alarms. On the average, the alarms

activated every 20 to 30 minutes. ... The M8A1s were useless in the smoky, dusty desert

environment.

--March 1991 memo, 2nd Light Armored Infantry Battalion1381

Another major concern related to chemical detections were problems caused by the repeated sounding of

alarms deemed to be false. Department of Defense reports indicate that M8A1 alarms were widely used in

theater, and that false alarms were triggered by factors such as fuel vapors and engine exhaust, oily

smoke, blowing sand, and low batteries on the units.961,1605 Surveys of Gulf War veterans consistently

report that most ground troops heard chemical alarms one or more times during deployment, indicating

that a very large number of alarms sounded in theater. But overall, it is not known how many chemical

alarms sounded over the course of the war, in what areas they occurred, or how many were followed up

with additional testing. Repeated false alarms in some locations led some units to ignore or disable their

alarms.1228,1684 Such problems might have led some personnel to believe they were exposed to chemical

agents when they had not been, or others to believe they had not been exposed when they might have

been.

Chemical incidents during the war that were communicated to Central Command (CENTCOM) forward

headquarters in Riyadh, Saudi Arabia, were recorded in logs maintained by NBC desk officers. In 1996,

DOD announced that the NBC logs on which chemical incidents had been recorded during Operations

Desert Shield and Desert Storm were missing. The Pentagon’s Office of the Inspector General (IG)

investigated the logs’ disappearance and issued its report in 1997. The IG report indicated that the NBC

logs had initially been generated in hard copy, entered into computer files, and backed up on portable

disks by the NBC desk in Riyadh.1602 After the war, hard copies, laptop computers, and disks containing

the logs were shipped to CENTCOM Headquarters in Tampa, Florida, and stored in safes. It was never

determined with certainty what happened to them, but the IG report found it likely that, contrary to DOD

policy, they had inadvertently been disposed of when the NBC office was relocated in 1994. Duplicate

disks had also been sent to Aberdeen Proving Ground after the war, but were also not locatable.

The loss of the NBC logs made it impossible to ascertain what chemical incidents had been reported to

CENTCOM and what determinations had been made. It also raised a great deal of public skepticism

concerning the reliability of DOD reporting on chemical exposures in theater. The IG report indicated

that copies of 32 of the approximately 150 pages of the missing NBC logs had been provided to assist the

Defense Science Board Task Force on Persian Gulf War Health Effects in 1993, whose 1994 report

contained information compiled from those pages. The graph in Figure 1 is taken from the 1994 report,

and depicts an unspecified group of chemical reports logged by CENTCOM between January 1 and

March 7, 1991. The largest number were recorded in the early days after the air war began, and again in

the days surrounding the ground war.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  139

Figure 1. Logged Chemical or Biological Reports Processed:

Compiled from CENTCOM Logs

Source: Defense Science Board Task Force on Persian Gulf War Health Effects1595

As previously described, verification of a chemical agent detection required that an initial detection be

retested and confirmed by a second type of test that used different technology. The Presidential Advisory

Committee pointed out that verification of chemical detections using the Fox vehicle was often not

possible on the battlefield, as described below:

Doctrine required that following an initial alarm for CW [chemical warfare] agent(s), the Fox

vehicle’s full spectrum capability should be engaged. To complete the full spectrum analysis,

however, required that U.S. military personnel stop the Fox vehicle, return to the site where

the MM-1 alarmed, and then perform a 20-minute process. Fox vehicle personnel recognized

the danger that stopping in the midst of battle would pose to themselves and their fellow

service members, and so they did not. As a consequence, full spectrum analyses rarely were

performed during the Gulf War. Yet doctrine is clear it is impossible to confirm a detection

without a full spectrum. Because doctrine did not accommodate the actual conditions of use,

a post-incident evaluation of an incident that lacks a full spectrum cannot be validated.

--Presidential Advisory Committee on Gulf War Veterans’ Illnesses, 19971231

The Department of Defense has consistently maintained that no U.S. chemical agent detections during the

Gulf War were verified as positive. This is commonly interpreted to mean that all alarms that sounded in

theater were false alarms, and that troops were not exposed to chemical agents, except in relation to the

Khamisiyah demolitions. But there are limitations in what can and cannot be determined from chemical

alarm detections. It can only be said that DOD has not verified any U.S. chemical detections based on its

own criteria which, at a minimum, required evidence of positive detections using two types of tests.1230

As indicated, blister agents and lower level exposures to nerve agents would not have been detected by

M8A1 alarms or the M43A1 alarm used on Fox vehicles. And detections that did trigger alarms were not

always followed up with additional testing.

It is relevant to note that at least one chemical alarm sounded on March 4, 1991, during the first munitions

demolitions at Khamisiyah. Initial follow up tests with M256A1 kits were inconclusive or negative, and

repeat tests were negative, leading NBC personnel to conclude that the alarm had been false, and that no

chemical agents were present. Therefore, no additional actions were taken and no chemical incident

report was submitted up the chain of command.1638 Years later, DOD confirmed that there were multiple

definite releases at the site and that about 100,000 troops may have been exposed to low levels of nerve
140  Effects of Gulf War Experiences and Exposures

agent as a result. But based on routine field criteria, even at close proximity to the chemical agent release,

the alarm was determined to be a false alarm, and the detection not credible.

Exposure to nerve agents in relation to the Khamisiyah demolitions. In early March of 1991,

just days after the U.S. declared a cease fire, U.S. soldiers began operations to destroy enemy munitions at

a large weapons compound near Khamisiyah, about 100 km. from the Kuwaiti border in southeastern

Iraq. The Khamisiyah Ammunition Supply Point was a massive Iraqi weapons storage area, covering

nearly 40 square km., which included approximately 100 ammunition storage bunkers, 88 ammunition

storage warehouses, and many additional buildings.1630 It is now known that chemical agents were

located at this site and were destroyed and scattered during the demolitions operations, potentially

exposing large numbers of U.S. personnel to low levels of sarin and cyclosarin. An enormous amount has

been written about these events, including details of the demolitions operations, dissemination of

intelligence on chemical agents to units responsible for destroying munitions, and efforts to determine

who may have been exposed to chemical agents, and at what levels.1590,1630

Although attention has focused on demolition events at Khamisiyah following the cease fire, there was

considerable activity at the site during the Coalition air and ground offensives. A 2002 DOD report

indicates that during the period of active hostilities, Coalition aircraft made 40 air strikes against

Khamisiyah on six different dates between January 19 and February 25, 1991. These attacks reportedly

destroyed 45 warehouses and at least four bunkers.1630 Units of the XVIII Airborne Corps had attacked

and occupied the sector of Iraq in which Khamisiyah was located during the ground war. On February

26, 1991, the XVIII Airborne Tactical Operations Center sent a message that they may have hit chemical

munitions near a site referred to as Objective Gold, a primary target of the ground offensive that was

located about five km. from Khamisiyah.1590,1630 No further investigations have been reported concerning

possible chemical releases during the air and ground wars either at Khamisiyah or at Objective Gold. The

24th Infantry Division is reported to have pushed through the Khamisiyah weapons site on February 26,

but not to have occupied the site at that time.

Before the ground war began in February, 1991, Army Central Command had directed the XVIII

Airborne and VII Corps to destroy all enemy munitions within their respective sectors, in an effort to

eliminate Iraq’s military capabilities.1630 After the ceasefire, units in the XVIII Airborne’s 82nd Airborne

Division, along with supporting units, conducted their initial reconnaissance in and around Khamisiyah.

Troops wore protective MOPP gear and had M8A1 alarms and M256A1 test kits when they entered the

bunkers to survey the site, and chemical officers later reported that no chemical weapons had been

detected. Army directives available to the XVIII Airborne at that time indicated that Iraqi chemical

weapons could be identified by certain characteristic markings. Later information that munitions carrying

chemical agents were not clearly or consistently marked was not provided until after the

demolitions.1590,1630

After their initial survey of the site, combat engineering units set charges in preparation for the initial

large-scale demolitions on March 4, 1991. All personnel and civilians were cleared from the area. The

troops conducting the demolitions moved back, at least three miles from the site, to observe the

explosions when the charges were detonated. Reports indicate that the massive explosions were visible

for miles around, with debris flying out to great distances, some dropping in areas where demolitions

personnel were observing the explosions. M8A1 alarms were operational during this time, and at least

one is reported to have sounded from an observation location, causing unit members to go into MOPP4.

Confirmation tests using M256 detection kits were negative, and the alarm or alarms were determined to

be false. Explosions continued for hours after the detonations.1630,1638

Additional large-scale demolitions were conducted on March 10, when bunkers, warehouses, and stacks

of crated rockets in an area known as “the Pit” were destroyed. On March 20, more than 400 earth berm
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  141

bunkers located at Khamisiyah Storage Depot South were destroyed. Units from VII Corps came into the

area on March 24, and continued demolitions on remaining bunkers at Khamisiyah through early April.

The United Nations Special Commission on Iraq (UNSCOM) was created in April 1991 to identify and

destroy Iraq’s remaining chemical and biological capabilities. On May 16, 1991, Iraq declared to

UNSCOM that chemical weapons had been present at Khamisiyah before and during the Gulf War.1630

UNSCOM inspectors visited the site in October, 1991, and confirmed that both nerve and blister agents

had been in the area. Government reports later blamed confusion over different names used for the site

by the intelligence community and the military—in reports and memos transmitted before, during, and

after the war—as the reason that it did not become clear until several years later that chemical weapons

had been present at Khamisiyah.1590,1630

It was not until June 21, 1996, that DOD publicly announced that U.S. forces had destroyed bunkers

containing chemical agents at Khamisiyah.1600 In the wake of the announcement, DOD and CIA initiated

activities to investigate events at the site, to characterize the release of chemical agents, and to evaluate its

possible association with the health problems affecting Gulf War veterans.1589 In October 1996, DOD

announced it would contact the 20,000 veterans in units who had been within 50 km. of Khamisiyah to

notify them of the nerve agent release. In November, 1996, Dr. Bernard Rostker was named to head the

newly established Office of the Special Assistant to the Deputy Secretary of Defense for Gulf War

Illnesses (OSAGWI).1630

In the months and years that followed, OSAGWI mounted extensive investigations of events and

exposures during the Gulf War. This included several detailed efforts to model chemical release and

exposure scenarios resulting from the Khamisiyah demolitions, in cooperation with CIA. Modeling

efforts were complex, and involved estimates of the number and types of rockets destroyed in different

areas of Khamisiyah, the amount of agent in each rocket, the degree of purity of the agents and ratio of

sarin to cyclosarin, demolition simulations conducted at Dugway Proving Ground, and determinations of

wind speed and direction at different times over multiple days.1630,1631 The modeling approaches used

were sophisticated, but necessarily involved major assumptions and uncertainties. Alongside these

efforts, DOD developed unit location databases to determine where each unit had been located in theater

for each day in question, to assist in identifying individuals in areas potentially affected by chemical

releases at Khamisiyah.

After initially determining that 20,000 veterans had been located within 50 km. of the Khamisiyah

demolitions, DOD and CIA announced, in July 1997, results of a modeling effort developed to more

accurately characterize troop exposures between March 10 and March 13, 1991. The models for the four

day period, derived from a composite of four modeling approaches, indicated that no troops had been in

areas where exposures would have been predicted to immediately produce noticeable symptoms. This

was consistent with earlier reports from medical officers who had not observed symptoms of chemical

agent exposure at the time of the demolitions.1638 However, lower-level exposures were possible for

98,910 soldiers who had been in the modeled “low level hazard area,” where exposures below those that

cause immediate symptoms may have occurred.1630

Results of a second detailed modeling effort were released in early 2000. Overall, the 2000 models

indicated that 101,752 troops were in locations within the “potential hazard” area. This included areas

where exposures were estimated to exceed the “general population limit” threshold for a sustained four

day exposure. Exposures within this hazard area would therefore have ranged from extremely low levels

with no noticeable effects to levels that could potentially cause observable symptoms. The specific

geographical area identified by the 2000 hazard area differed markedly from the 1997 hazard area. As a

result, nearly a third of the troops identified as potentially exposed by the 1997 models were no longer in

the hazard area identified by the 2000 models, and over 30,000 additional troops were newly identified as

potentially exposed to low level nerve agents.1630
142  Effects of Gulf War Experiences and Exposures

Questions about Khamisiyah models and exposure estimates. Because of the many uncertainty

factors and assumptions used in generating both the 1997 and 2000 Khamisiyah models, it is not

surprising that both the methods used and the conclusions drawn from these efforts have been challenged.

In its 1998 report, the Senate Special Investigation Unit on Gulf War Illnesses (SIU) raised far-reaching

criticisms of the 1997 models. The committee favored an alternate approach, supported by an

independent consultant, that utilized weather data and plume diffusion modeling from the Air Force

Technical Assistance Center (AFTAC). Preliminary modeling conducted by AFTAC had described an

alternate plume that moved south and east after the detonations, extending further into Kuwait.1690

The U.S. General Accounting Office (GAO) also conducted an in-depth investigation of Khamisiyah

modeling efforts and provided its findings in a detailed report issued in June 2004.1683 The report sharply

criticized the DOD/CIA Khamisiyah models, and concluded that estimated troop exposure levels were

highly questionable because the models on which they were based were not reliable. Specific problems

were identified on many levels, beginning with the initial data on which the models were based—

information on agent quantity, purity, and concentration, and on weather and wind patterns. The report

further indicated that assumptions used to construct models were often inaccurate or contradictory and

that modeling procedures were not validated for estimating long-range environmental fallout. The GAO

report concluded that the actual extent of chemical agent exposures resulting from the Khamisiyah

demolitions could not be determined. Further, because the data required for accurate modeling were not

available, additional modeling efforts were not likely to be any more useful than DOD models had been.

It is likely that if fully developed and validated models and more realistic data for source term

were included in the modeling, particularly plume height and exposure duration, the exposure

footprints would be much larger and most likely to cover most of the areas where U.S. and

other coalition forces were deployed.

--U.S. General Accounting Office, 20031681

In addition, GAO cautioned that research findings based on the Khamisiyah models could not, with

confidence, be considered valid.1681 Use of the models to identify veterans who had been “exposed” or

“not exposed” to nerve agents was problematic for two reasons. The first related to inaccuracies specific

to the Khamisiyah models, spelled out in detail. The second related to the possibility that military

personnel had been exposed to chemical agents at other times and locations.1683 Both factors could

potentially contribute to extensive classification errors in determining which veterans had been exposed to

nerve agents. Due to the many unknown factors associated with chemical agent exposure in theater, GAO

recommended that no additional epidemiologic research be based on nerve agent exposures estimated by

the DOD Khamisiyah models.

The Department of Defense responded to issues raised by GAO, defending the modeling techniques

employed as state-of-the-art. The DOD response also pointed out a number of factual errors in GAO’s

assertions, and indicated that changes made in the 2000 models had addressed some of the concerns

raised.1683 Although DOD did not concur with GAO’s recommendation on epidemiologic research, it did

concur that no additional modeling efforts should be conducted.

The many detailed issues raised by GAO concerning the Khamisiyah models, at minimum, indicate the

need for caution in assuming that the models accurately represent nerve agent exposures resulting from

the demolitions. Additional issues related to Khamisiyah that were not raised by GAO or SIU include

questions about possible chemical releases at the site during the air and ground offensives. There is also

minimal support in DOD reports for their including only nerve agent releases from a single day, March

10, 1991, in the Khamisiyah models, although demolitions occurred there on multiple occasions over a

five week period. The GAO report also raises a second issue of importance, that is, the potential for Gulf

War personnel to have been exposed to chemical agents in other locations.1683
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  143

The possibility of other chemical agent exposures. There are numerous reports from

government and private sources, and personal stories from individual veterans, that describe incidents

suggesting possible chemical agent exposures during the war.388,521,579,961,1231,1558,1688 Many are anecdotal,

undocumented by any type of evidence. Others are associated with some level of evidence such as a

positive chemical detection, but government investigations have found the available evidence too limited

to verify the detection. Reports commonly indicate that troops believed that positive detections had been

the result of chemicals drifting south from where Coalition troops had bombed chemical facilities in Iraq.

Iraq’s chemical production and storage facilities had been high priority targets in the early days of the air

offensive.320,1284,1690

The measures we took to eliminate the enemy’s chemical and biological threat were both

active and passive. The active measures were the destruction of known storage and

production sites in the earliest stages of the strategic air campaign.

--General Norman Schwarzkopf, 1997 Senate Testimony 1690

After the war, in connection with the work done by UNSCOM, additional information became available

on locations where Iraq had produced, stored, and deployed chemical agents during the war. These sites

are shown in Figure 2. Multiple additional sites were identified where Iraq had deployed binary nerve

agent weapons, that is, weapons that contained compounds that could be converted to nerve agents by

adding a second ingredient before firing. Many suspected chemical agent release and exposure events

have since been evaluated by DOD and CIA, leading to two types of findings: (1) determinations of

whether a chemical release is likely to have occurred, and (2) determinations of whether U.S. personnel

were likely to have been exposed to chemical agents. This distinction is important, since there are a

number of sites in Iraq where CIA and DOD have reported massive releases of nerve and blister agents as

a result of Coalition bombing. For example, a 1996 CIA report indicated that during the air campaign, 17

metric tons of sarin were released at Iraq’s primary chemical weapons and storage facility, Al Muthanna,

and 15 metric tons of mustard and 2.9 metric tons of sarin were released at the Muhammadiyat munitions

storage site.1589 Both targets were in central Iraq, hundreds of kilometers from the nearest U.S. troop

locations, and CIA’s dispersion models indicated that troops would not have been exposed to chemicals

as a result of these releases. A later CIA report revised sarin release estimates dramatically downward

from the 1996 estimates, and increased estimated levels of mustard released, but continued to assert that

the chemicals had not reached U.S. troops.1591,1629

In 2002, CIA reported its findings related to 20 suspected chemical agent releases during the Gulf

War.1591 Twelve of the scenarios investigated were found to have resulted in a “definite” chemical agent

release, one as a “likely” release, six as “suspect” releases, and one as “unlikely.” Of the 20 chemical

agent releases evaluated, only Khamisiyah was found to have resulted in a “likely” chemical exposure to

U.S. troops. In addition, DOD has conducted investigations of many suspected chemical exposure events,

some of which overlap with the releases evaluated by CIA. The DOD findings are provided in 20 “Case

Narrative” reports, which sometimes encompass multiple chemical detection incidents by certain units or

in certain areas.1603 Again, only events at Khamisiyah were found to have resulted in “likely” U.S. troop

exposures to chemical agents.1630 Exposures were found to be “unlikely” for most of the remaining

events,1609,1627,1628 although a chemical agent detection by Czech chemical specialists was identified as

“valid” in one report, and several other detections were judged to be “indeterminate.”1610,1614,1617,1629

Because our Committee has not conducted detailed investigations of the many reported chemical events

during the Gulf War, we cannot offer independent judgments about whether specific exposures did or did

not occur. Our review of DOD and CIA reports does indicate, however, that conclusions related to

specific incidents are often less conclusive than might be suggested by summary findings of “likely” or

“unlikely.” For example DOD findings frequently depend on whether or not the presence of a chemical
144  Effects of Gulf War Experiences and Exposures

Figure 2. Iraqi Chemical Weapons Facilities and Declared Sites Where

Chemical Agent-Filled Munitions Were Deployed During Desert Storm

Source: U.S. Central Intelligence Agency1591

agent was verified based on two confirmed tests using different analytic methods. As a result, situations

in which two tests were done but records not retained, or where two different types of tests were not done,

or where putative exposures occurred below levels detectable by monitoring equipment would not have

been verified by post-hoc evaluations.

A compelling example is provided in a 2004 GAO report that detailed 20 positive chemical agent

detections between January 17 and 23, 1991, by U.S., Czech, French, and British units.1683 On some days

during that period, multiple detections of the same type of agent were reported by different units from

different nations, in close proximity. For example, U.S., French, and Czech units all reported detecting

sarin or an unknown nerve agent near King Khalid Military City (KKMC) in northern Saudi Arabia on

January 20, 1991. The January 17-23 period coincides with the initiation of Coalition air bombing in

Iraq. The GAO report and testimony provided to a Congressional committee also indicate that this

period coincided with a stationary weather pattern identified by meteorological satellite imagery in areas

where troops were located in northern Saudi Arabia.1683,1684
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  145

A thermal plume rose into the atmosphere over the largest Iraqi chemical warfare agent

research, production, and storage facility at Muthanna after Coalition aircraft and missile

bombardment. Seventeen metric tons of Sarin were reportedly destroyed during these

attacks, which began on January 17, 1991. These thermal and visual plumes extended

directly toward the areas where those same chemical warfare agents were detected and

confirmed by Czechoslovak chemical specialists.

--Jim Tuite, 1997 Congressional Testimony1684

Taken together, this information suggests that Coalition bombing in the early days of the air war resulted

in one or more releases from chemical weapons production or storage sites in central Iraq that, aided by

weather patterns, drifted over the Saudi border. There, chemical agents were detected by different units

over a period of several days. But both DOD and CIA have investigated many of the events described

and have concluded that this did not occur, that is, that chemical agents released with Coalition air

bombing did not drift far enough south to have been detected in northern Saudi Arabia.

The Department of Defense originally reported findings from an investigation of Czech chemical agent

detections in November, 1993.1601 At that time, the Secretary of Defense announced that Czech chemical

specialists had reported very low levels of sarin and mustard on several dates and that DOD experts had

found the detections to be credible. Czech chemical units had the most sophisticated chemical

capabilities available during the Gulf War, with detection systems that were highly sensitive for both

nerve and blister agents.1610

In 1998, an OSAGWI Case Narrative described a series of Czech nerve agent detections on January 19,

1991.1610 That morning, two separate teams of Czech chemical specialists reported near-simultaneous

detections of low-level sarin about a mile apart near Hafir Al-Batin, in northern Saudi Arabia. Thirty

minutes later, a third detection was reported by another unit about 30 miles away. In each case, the initial

detections were retested with a second type of detector and also found to be positive. An air sample

collected for further testing at a laboratory in KKMC also tested positive for sarin. The detected levels of

nerve agents were below the sensitivity thresholds of equipment used by other Coalition partners. U.S.

specialists who arrived in the area four hours later did not detect sarin using U.S. equipment. Still, DOD

concluded that the detections had been valid and credible, although the source of the sarin was not

ascertained.1610 In 2002, CIA released a report that included findings on the Czech January 19 chemical

detections. CIA officials had earlier identified these detections as credible,276,1610 but the 2002 report

concluded that the detections that day were “unlikely,” based on CIA’s inability to identify a plausible

source for sarin in the area, and newly raised questions about the reliability of the detections.1591

Although an extensive amount of information has been reported on these events, the lines of evidence that

either favor or discount the presence of chemical agent that day are less-than-definitive. It can only be

concluded that low levels of nerve agent might have been present in the northern part of Saudi Arabia on

January 19, 1991. Even if detections were accepted as valid, it is not known the extent to which U.S.

troops might have been exposed as a result.

The challenges and conflicting conclusions described with respect to this particular incident on this single

day illustrate the difficulties inherent in determining if and where military personnel might have been

exposed to low level chemical agents during the Gulf War. Other reported incidents, including additional

Czech detections, are also associated with both supporting and negative indicators.1610,1614,1627 As a result,

the extent of exposure to low level chemical agents in theater remains an open question.

Recent information concerning Iraq’s intended use of chemical weapons. In the years

following the Gulf War, several investigations suggested that Iraq had prepared to use chemical weapons

during the Gulf War, and that some limited use may have occurred.388,1560,1688 Both DOD and CIA have

consistently maintained that, based on their investigations, there is no credible evidence of Iraqi offensive
146  Effects of Gulf War Experiences and Exposures

use of chemical agents during the Gulf War.1284,1589-1591 This issue was raised again in recent years, with

findings from a comprehensive investigation, conducted by the Iraq Survey Group (ISG), of Iraq’s

weapons of mass destruction (WMD) capabilities prior to the 2003 Iraq War.693 The ISG report provides

additional information about Iraq’s deployment of chemical weapons during the 1991 Gulf War, and

evidence that Saddam Hussein had authorized their use against Coalition forces. It also documents Iraqi

attempts to use sarin against the Shia population in southern Iraq in March of 1991, to quell an uprising

after the U.S.-declared ceasefire. Iraq’s attempt to bomb the Shia with sarin was not successful, however.

This was thought to be because the sarin-filled bombs had not detonated when released from low-flying

helicopters, the only aircraft Iraq could utilize under terms of the ceasefire. As an alternative, the Iraqi

military dropped large aerial bombs filled with CS (tear gas) in the areas of Karbala and Najaf, an

estimated 200 bombs over a two week period. CS is not technically classified as a chemical warfare

agent, but is nonetheless a toxic chemical that can cause acute tearing, respiratory problems, and burning

and blistering of the skin.

The U.S. military was well familiar with Iraq’s brutal attacks in areas of Southern Iraq during this period.

A defense intelligence bulletin in early March of 1991 had warned that Iraq might resort to the use of

chemical weapons to quash the Shia rebellion.1617 Refugees, some of them seriously injured, had

streamed into U.S. controlled areas after the attacks began. U.S. forces provided humanitarian support,

and medical teams treated large numbers of wounded civilians.1617 Rev. Joel Graves, a Committee

member and Gulf War veteran, reported that on March 15, members of his unit, stationed south of Basra,

had become acutely ill in the evening and that chemical alarms had sounded nearby. The next day, his

commander informed him that mustard gas was thought to have been used in Iraqi attacks against the Shia

in Basra, and may have drifted towards U.S. troop locations with the strong southerly winds.521 A joint

staff message of March 28, 1991, indicated that Shia refugees had reported Iraqi attacks on Basra with

both mustard and white phosphorous in mid March.1599 Although the ISG report indicates that nerve

agents were unsuccessfully deployed, the events described by the Iraq Survey Group provide a sobering

indication of Saddam Hussein’s willingness to attack with chemicals, even when Iraq was occupied by

Coalition forces.

Summary. Exposure to chemical weapons in the Gulf War. During the Gulf War, military

defenses against chemical weapons emphasized detection and response to high level, acutely dangerous

exposures, to protect troops from potentially dire consequences. There are no indications that U.S. or

Coalition forces encountered large scale, high dosage exposures to chemical weapons during the Gulf

War. Since the war, however, concerns have emerged about possible effects of lower level chemical

agent exposures and their association with the health problems affecting Gulf War veterans.

Despite extensive government efforts, substantial questions remain about the extent to which Gulf War

military personnel were exposed to low-level chemical agents in theater. Uncertainties are associated

with several factors. First, it is unlikely that low levels of airborne chemical agents would generally have

been identified or documented by military personnel. Monitoring systems had little capacity to detect

chemical agents at levels that do not cause immediate symptoms. Second, although the Department of

Defense estimates that about 100,000 personnel may have been exposed to low levels of sarin and

cyclosarin nerve agents as a result of weapons demolitions at Khamisiyah, serious questions have been

raised about the accuracy of government models used to determine who was exposed, and at what levels.

Third, unanswered questions and limited information related to other reported chemical events leave open

the possibility that additional chemical exposures might have occurred during and after the Gulf War, in

locations other than those affected by the Khamisiyah demolitions.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  147

Health Effects of Cholinergic and Related Neurotoxicants

A neurotoxic response to a single large dose of a substance often predicts neither the

existence nor the type of response seen in animals repeatedly exposed to lower levels of the

same agent.

-- Biological Principles of Chemical Neurotoxicity, 20001463

Health effects of pyridostigmine bromide

Information concerning biological and health effects of PB is available from both animal research and

human studies. Pyridostigmine is a carbamate compound that temporarily, and reversibly, binds AChE.

A comprehensive review of the available literature was provided in a 1999 RAND report, which

identified several mechanisms whereby PB could plausibly contribute to veterans’ chronic symptoms.504

These included chronic dysregulation of acetylcholine and persistent damaging effects on peripheral

neuromuscular junctions. The RAND report concluded that PB could not be ruled out as a possible cause

or contributor to Gulf War illness.

Pyridostigmine research in animals. Pyridostigmine normally does not cross the blood brain

barrier in significant amounts, due to a positively charged quaternary ammonium group. This confers an

important advantage for using PB as a nerve agent pretreatment over other reversible AChE inhibitors,

since direct effects on the central nervous system would be expected to be minimal. The importance of

brain penetration in determining some effects of PB is demonstrated by recent research from the Lovelace

Respiratory Research Institute, which evaluated effects of anticholinesterase compounds on the immune

response and hypothalamic-pituitary-adrenal (HPA) function. Pyridostigmine administered

subcutaneously had no effect on antibody response or corticosteroid levels. But when injected directly

into the brain, PB significantly inhibited antibody response and reduced circulating corticosteroid levels

in the same way as physostigmine, an anticholinesterase drug that readily crosses the blood brain

barrier.868

Animal studies conducted since the 1980s have demonstrated that PB can adversely affect peripheral

nerve function and structure,25,364,651 and can also have central and behavioral effects, especially when

given at higher doses.144,366,648,916,1401,1443,1793,1807 Research in animal models has also described acute

adverse effects on gastrointestinal function with relatively low doses of PB,816 and autonomic, immune,

respiratory, and cardiovascular effects at moderate-to-high doses.129,771,1188,1379,1439,1814

Although multiple studies have evaluated biological effects of PB in animal models in recent years, most

have focused on effects of PB in combination with other Gulf War-related exposures and with stress.

These have included assessments of PB in combination with low-level sarin, pesticides and insect

repellants, caffeine, and vaccines, as will be described in a later section.

Effects of low-level pyridostigmine on brain and behavior. It has long been observed that PB can

produce significant, acute effects on the brain and behavior when given in high doses.144,366,916,1401 In

recent years, multiple studies have also identified significant central nervous system effects resulting from

low-dose exposure to PB. Dutch investigators have reported that primates exhibited significant EEG

abnormalities after receiving low dose PB for four days.1706 Five studies conducted in rodent models

since 2000 have reported that low-to-moderate doses of PB, administered by gavage on a schedule of

repeated exposures over time, produced significant deficits on a variety of tests of learning and

behavior.10,11,14,1704,1705 Animals exposed to PB in these studies are described as exhibiting no overt signs

of cholinergic toxicity or ill health.

A consistent feature of the behavioral studies is that repeat, low and moderate dose exposure to PB, over a

period of days to weeks, produced central effects not reported from studies using single, brief exposures,
148  Effects of Gulf War Experiences and Exposures

even at higher doses. Additional effects of repeated PB dosing on the central nervous system have been

demonstrated by researchers from Purdue University and the East Orange, New Jersey VAMC. Purdue

investigators reported that repeated, low-to-moderate doses of PB, administered over a four day period

produced only a limited decrease in brain AChE activity, but yielded extensive neuronal apoptosis in the

cortex, striatum, and hippocampus of treated rats, in a dose-response pattern. The effect was sustained in

the cortex over a 30 day period following cessation of PB treatment. Investigators suggested that the

repeated dosing schedule enabled PB to cross the blood brain barrier and act directly on brain cells. 900

In addition, New Jersey researchers have reported delayed central effects of low-to-high doses of PB,

administered in drinking water over a seven day period. In exposed rats, a persistently exaggerated

acoustic startle response first appeared 15 days after PB treatment had been completed.1387 The delayed

effect was only observed in a strain of rats (WKY) with low activity of the PB-scavenging enzyme

butyrylcholinesterase (BChE).1388 Investigators suggested that individuals with low BChE activity may

have increased sensitivity to delayed, central effects of PB.

Pyridostigmine and stress. Widespread interest in the potential for PB to interact synergistically with

stress was stimulated by a 1996 Israeli study indicating that central nervous system effects of PB were

markedly enhanced, in animal models, by an intense stressor—forced swimming. Investigators suggested

that conditions of extreme stress rendered the blood brain barrier more permeable to PB.460 This initial

observation was not supported by subsequent findings from different laboratories, which found that

stressors of various types did not enhance levels of PB in the brain or lead to marked decreases in whole

brain AChE activity.519,857,1394,1414,1444,1539 Several studies did report, however, that PB exposure alone

reduced brain levels of AChE to a limited degree, independent of whether animals had been stressed or

not.85,900,1414

Recent studies have reported findings of other types that do suggest interactive effects between PB and

stress, however. Investigators at Wright State University found that PB, alone, had no effect on heart rate

or blood pressure in mice. But in combination with a relatively mild stressor (intermittent shaker stress),

PB produced significant autonomic alterations, specifically, increased low frequency heart rate variability

and baroreflex sensitivity.714 Researchers from the East Orange, New Jersey, VA reported that

administering an intense stressor to rats prior to PB exposure resulted in reduced AChE levels in the basal

forebrain/striatum but not in other brain areas.115 And French investigators have reported that PB, in

conjunction with stress, produced increased levels of the serotonin metabolite 5-HIAA in multiple regions

of the brain, and increased dopamine levels in the striatum/hippocampus.1528 Pyridostigmine has also

been shown to interact synergistically with physical stress in peripheral tissues. Research from Southern

Illinois University indicates that low-dose PB, when given concurrently with an exercise stressor, resulted

in significantly reduced levels of AChE and increased indicators of muscle tension and oxidative stress in

skeletal muscle, effects not seen with either PB or exercise alone.703,1442,1713

In assessing the literature on stress/PB interactions in animal models, the most important distinctions

appear to relate to the specific outcomes assessed and exposure protocols used. Overall, studies that did

not identify interactive effects between PB and stress focused on whether the combination increased

central AChE activity and permeability of the blood brain barrier. Most of these studies also assessed

acute effects, following single doses of PB at low-to-high levels. In contrast, nearly all studies that did

identify stress/PB interactions assessed effects of low-dose, repeat exposure to PB over a period of five to

14 days. In addition, these studies assessed outcomes other than changes in central AChE activity and

blood brain barrier permeability. Taken together, these studies suggest that interactive effects between

PB and stress may occur, but are not reflected by a general reduction in central AChE activity or a general

increase in blood brain barrier permeability, and are also not observable as acute effects following single

exposures. It is not possible to determine from these studies, however, whether central effects were due

to PB acting directly in the brain, or indirectly, through effects stimulated in the periphery.85,116,1528,1704
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  149

Human studies of the effects of PB. Short-term effects of PB have been evaluated in a relatively

large number of human studies in relation to its military use as a nerve agent pretreatment, its use as a

treatment for myasthenia gravis, its use in testing for growth hormone (GH) abnormalities, and other

applications. In the early 1990s, multiple studies conducted by the U.S. and Israeli militaries evaluated

health and performance effects of PB, taken over a brief time period, in small samples of healthy human

volunteers, usually military personnel. Health parameters were assessed under a variety of conditions,

including flight simulation, exercise, and heat stress. Under conditions of heat and exercise stress, PB

taken over several days produced significant reductions in heart rate, blood pressure, and handgrip

strength compared to placebo.271,1762,1763 But overall, few significant differences were identified, and there

were no indications that PB impaired work performance.53,271,410,411,476,700,1296,1762,1788 A more recent study,

in fact, identified improved reaction time on tests of memory and attention in healthy subjects taking PB,

perhaps due to effects of AChE inhibition on neuromuscular synaptic efficiency.273

Multiple studies conducted in clinical settings have documented rates and types of acute side effects

associated with PB. Milder effects include abdominal and digestive discomfort, runny nose, and excess

salivation and sweating, while more severe reactions can include diarrhea, muscle weakness and spasms,

and vomiting. Pyridostigmine also stimulates GH secretion, and this effect is used to test for GH

abnormalities in different clinical conditions.347,487 Acute side effects reported in conjunction with a

single use of PB in GH testing are similar to those seen in other clinical studies of PB. Gastrointestinal

symptoms (e.g., nausea, cramping, flatulence, diarrhea) are most common.679 Side effects appear to be

more frequent with higher PB dosages,1819 but are generally tolerable and transient.

A detailed clinical study that evaluated symptoms reported by healthy subjects who used PB over several

days, at the level recommended for use in the Gulf War, also indicated that gastrointestinal side effects

were most common. Few side effects were reported in the first day of dosing but more side effects,

overall, were reported by subjects taking PB than those taking placebo. Symptoms were generally mild

and short lived, more frequently reported by women than men, and more pronounced with higher doses of

PB.272 Several studies have also reported rates of acute side effects from PB use by military personnel

during the Gulf War. Studies indicate that use of PB during the Gulf War was associated with higher

rates of side effects than has commonly been observed in clinical settings,781,1396 and suggest that side

effects may relate to longer term illness, as will be described in a later section.

In both clinical and war zone settings, a subset of individuals who take PB develop side effects from

taking relatively low doses of PB. The factors that determine who does or does not react to PB are not

well understood, however. There are indications from two reports that symptoms associated with PB use

are not related to the degree of peripheral cholinesterase inhibition.272,1396 One case report of an Israeli

soldier who suffered severe side effects after taking PB during the Gulf War indicated that he was a rare

homozygous carrier of the atypical A allele for the butyrylcholinesterase (BChE) gene. BChE is a

circulating enzyme that serves as a scavenger that irreversibly binds cholinesterase inhibitors, thus sparing

AChE. The Israeli soldier’s BChE was found to have very poor affinity for binding PB, leading authors

to suggest that some individuals may be more genetically susceptible to adverse effects of PB.929 This

hypothesis has been further explored in relation to Gulf War illness, as will be described in a later section.

No human studies have evaluated long-term effects that might develop or persist over an extended period

after short term use of PB. Information on side effects from long-term, high-dosage use of PB is available

from studies of myasthenia gravis patients,119,627 who typically use between 300 and 1200 mg. of PB per

day over many years.52,169 Effects of PB in myasthenia gravis patients cannot be directly compared to

effects expected in healthy soldiers, however. Myasthenia gravis is associated with severely reduced

cholinergic activity, and PB treatment is used specifically to increase acetylcholine in order to bring

patients’ neuromuscular function to a more normal state. Reports indicate that the most common side

effects of PB treatment for myasthenia gravis patients include diarrhea, increased salivary secretions, and
150  Effects of Gulf War Experiences and Exposures

sweating. Symptoms are reported by 34 - 54 percent of myasthenia gravis patients, are more problematic

with higher PB dosages, but are seldom severe enough to cause discontinuation of treatment.119,627

Pyridostigmine bromide has been associated with autonomic alterations in several human studies. A

single low dose of PB has been shown to reduce cardiovascular response to physical and mental

exertion.1347,1386 Four 30 mg. doses of PB, taken at eight hour intervals over a 24 hour period, produced

significantly lower heart rate and significant increases in time domain measures of heart rate variability,

compared to placebo.1129 Research conducted by Midwest Research Institute identified more pronounced

autonomic alterations with somewhat longer PB use. After four to five days of taking either 30 mg. or 60

mg. of PB every eight hours, healthy subjects exhibited slower heart rates, significantly reduced heart rate

variability in the high frequency range, and significantly increased variability in the low frequency range

compared to subjects who had taken placebo.273 Reduced high frequency power was substantial,

averaging 21 percent at the 30 mg. dose, and was significantly correlated with the degree to which PB

inhibited AChE and BChE activity. Findings suggest a central nervous system effect of PB.

Investigators pointed out, however, that this central effect might not require PB to have crossed the blood

brain barrier, since vagal control centers are reciprocally innervated by the medullary area postrema,

which lies outside the blood brain barrier.273

Pyridostigmine bromide has been suggested to provide some clinical benefits for patients with autonomic

irregularities and patients with multisymptom illnesses. It has recently been investigated as a treatment

for neurogenic orthostatic hypotension, a condition associated with impaired autonomic regulation of

blood pressure. Initial reports suggest that PB improves standing blood pressure, without adversely

affecting supine blood pressure.472,1412 In a six month, placebo-controlled trial of 165 fibromyalgia

patients, PB was found to provide significant improvements in sleep and anxiety measures, but no

improvement in pain.723 A case series report has also described substantial symptomatic improvement in

three chronic fatigue syndrome patients treated with PB.777

Overall, diverse studies of the effects of PB in humans have indicated that PB has a low risk profile for

acute adverse side effects when taken by healthy subjects over brief time periods in clinical settings.

Little information is available concerning long-term effects of PB used by healthy subjects, although side

effects described in clinical settings are described as transient. Several studies have indicated that PB,

given to soldiers in wartime, induces a higher level of acute side effects than is typically observed in

clinical studies. Animal studies indicate that PB, even at relatively low doses, can affect the brain and that

repeated dosing schedule over an extended period of time produces central nervous system effects not

observed with single doses. Animal studies have also reported limited interactive effects between stress

and PB, although the majority of studies indicate that stress does not enhance PB passage into the brain.

Both animal and human studies have demonstrated effects of low dose PB on autonomic nervous system

function, at dosages too low to cause serious symptoms or excessive peripheral AChE inhibition. It is not

known, however, how long these effects are sustained.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  151

Health effects of pesticides and insect repellants used in the Gulf War

Overexposure to pesticides, particularly organophosphates and carbamates, may have

contributed to the unexplained illnesses reported by some Gulf War veterans.

--Environmental Exposure Report: Pesticides, U.S. Department of Defense, 20031632

Chemical pesticides and insect repellants have been in widespread use since the middle of the last

century. Many pesticides are neurotoxic by design, that is, they are developed to kill insects by attacking

their nervous systems. Thousands of compounds have been developed for use against different insects

and other pests, for application in different settings. The Department of Defense estimates that 64

different pesticide and insect repellant products, with 37 different active ingredients, were used by

military personnel during the Gulf War. The 15 pesticide products identified by DOD as being the

pesticide products of greatest concern in relation to the health of Gulf War veterans are listed in Table 2.

Although these 15 products represent a diverse mix of chemical compounds, the majority fall into two

chemical classes—organophosphates and carbamates—both of which are AChE inhibitors. The list also

includes two pyrethroid compounds, one organochlorine, and two DEET products.

Many thousands of research studies have evaluated biological effects of pesticides in animal models and

health effects in human populations. Detailed information from this large literature is compiled in

comprehensive textbooks on pesticide toxicology. New findings related to toxicological effects of

pesticides and insect repellants continue to emerge at a rapid pace. In recent years, this research has

provided important insights into health effects of lower-level and chronic pesticide exposures in human

populations, including associations with persistent symptomatic illness. The U.S. government has

launched a number of important research initiatives to better understand effects of pesticides on human

health. This includes the Agricultural Health Study, a large interagency project to characterize acute and

long term health effects in nearly 90,000 Americans who work with pesticides, and their family

members.1686 This longitudinal, multi-state project is evaluating diverse health parameters and has

produced important research findings, some of which have relevance to issues considered in this report.

In the last several years, major reports have been released internationally by government and scientific

panels concerning effects of pesticide exposures on the public health. These reports have raised

awareness of recent findings on potential associations between pesticides and a broad spectrum of human

diseases, including difficult-to-diagnose multisymptom conditions. This includes a review of the

scientific literature on health effects of pesticides from the Ontario College of Family Physicians, which

concluded that “there is a high level of consistency in results to indicate a wide range of pesticide-related

clinical and subclinical health effects” and that “exposure to all the commonly used pesticides—

phenoxyherbicides, organophosphates, carbamates, and pyrethrins—has shown positive associations with

adverse health effects.”1155 The report urges physicians to become more aware of health effects of

pesticides in order to better educate the community and treat their patients. A 2005 report on human

health affects of agricultural pesticides from the British Royal Commission on Environmental Pollution

described the complex issue of discerning chronic health effects resulting from unmeasured and varying

combinations of pesticide exposures. The Commission noted that “the clinical awareness of general

practitioners and specialists needs to be improved in order to improve the investigation of people with

chronic, ill-defined health effects.”1324

A number of reports describing toxicological issues and potential health effects specifically related to

pesticide use in the Gulf War have also been published. In addition to the detailed investigation of

pesticide use by Gulf War military personnel, DOD commissioned RAND to review scientific research

related to potential health effects of pesticide use in the Gulf War.218 The 2000 RAND report provided

information pertaining to each of the major classes of pesticides and insect repellants of greatest concern

used by military personnel in theater. It pointed out that understanding effects of pesticides on the health

of Gulf War veterans is complicated by a number of factors, including variation in individual
152  Effects of Gulf War Experiences and Exposures

vulnerability to adverse effects of neurotoxicants, differences in the degree to which pesticides used by

veterans were absorbed into their skin and circulation, and unknown effects of combinations of multiple

pesticides or pesticides in combination with other exposures in theater. The RAND report concluded that

pesticides, specifically AChE inhibitors, could be among the agents that contributed to the development

of veterans’ multisymptom illness and called for additional research to investigate the association.

The Institute of Medicine (IOM) conducted a detailed review of human studies related to health effects of

pesticide exposures as part of the Gulf War and Health series of reports.682 The report focused primarily

on effects of pesticides in relation to multiple types of cancer, with some information on effects of

pesticides on diagnosed neurological diseases and reproductive outcomes. No conclusions were provided

concerning possible associations between pesticide exposures in theater and Gulf War multisymptom

illness.

Information concerning health effects of the major classes of pesticides and insect repellants used during

the Gulf War is briefly summarized below, with attention to health issues relevant to Gulf War veterans.

Most scientific research on pesticides has evaluated effects of individual chemicals that develop over a

relatively brief time period. Human research has historically focused primarily on effects of high-level

exposures associated with pesticide poisoning. However, a growing body of research has evaluated

human health effects of lower-level exposures and exposures experienced over longer periods of time.

Nearly all studies that have evaluated effects of combinations of pesticides and repellants used in the Gulf

War have been conducted in the past 12 years, using animal models, in connection with the federal Gulf

War research effort. This research will be described in a later section that addresses effects of

combinations of Gulf War exposures.

Organophosphate pesticides. Organophosphate pesticides (OPs) constitute the largest number of

chemicals identified as pesticides of potential concern used during the Gulf War. These include

chlorpyrifos, diazinon, and malathion, used in different concentrations by pesticide applicators as area

fogs and surface sprays. They also include dichlorvos-containing pest strips, issued for personal use to

the general military population, and azamethiphos crystals used as fly bait, which was purchased

locally.1632

Organophosphate compounds are a large and diverse family of chemicals that include hundreds of

different pesticides, as well as several types of chemical warfare agents.387,932 They are among the most

extensively studied of any chemicals in toxicology. Acute effects of excess exposure to OP pesticides are

those previously described for AChE inhibiting chemicals generally, and include effects on the central

nervous system, autonomic nervous system, and skeletal muscles. There are also a growing number of

indicators that OPs can exert neurotoxic effects through mechanisms other than AChE

inhibition.216,982,1166,1436,1553 In addition, recent studies in animal models have demonstrated that repeated

exposures to OP pesticides, even at relatively low doses, can produce persistent neurochemical and

behavioral alterations that do not occur with single exposures at similar or higher

doses.29,775,823,1226,1251,1530,1531,1553

Symptoms that result from acute OP poisoning usually develop within minutes to hours and resolve in

hours to a few days, but there are exceptions. A delayed reaction to poisoning by malathion or diazinon

has been described in some individuals, a condition known as “intermediate syndrome.” This condition

develops between one and four days after OP exposure and is associated with severe muscle weakness.

Serious cases can lead to respiratory arrest but if respiration is maintained, recovery generally takes

several weeks.754

Poisoning by some OP compounds can also produce, in a minority of cases, a chronic condition known as

organophosphate induced delayed neuropathy (OPIDN). Onset of OPIDN varies with the specific

compound and dosage of exposure, but ranges from 10 days to five weeks after OP poisoning. Symptoms
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  153

usually begin with cramping muscle pain in the lower extremities, followed by numbness, parasthesia,

and progressive muscle weakness. More severe cases can also involve the upper extremities. The

condition results from inhibition not of AChE, but of a second enzyme, neuropathy target esterase (NTE),

which is not affected by all OP compounds.718,934 Only two compounds widely used in the Gulf War,

chlorpyrifos and dichlorvos, have been associated with OPIDN, and only following poisoning episodes

involving extremely high doses.

Persistent neurological and cognitive symptoms have long been described in some individuals following

recovery from acute OP poisoning, and also in relation to long term OP exposure in the absence of

poisoning.9,344,483,1313 Neurotoxicologists from the U.S. and the U.K. have proposed the existence of a

long-term OP-associated neurotoxic syndrome that develops with chronic low-level OP exposure or

persists after substantial recovery from acute OP poisoning.9,316,705 Persistent central nervous system

effects are notable in the proposed condition, as opposed to the prominent peripheral effects associated

with OPIDN. Based on his and other research teams’ investigations in animal models, Dr. Mohamed

Abou-Donia of Duke University has suggested these persistent symptoms are associated with neuronal

oxidative injury and apoptotic cell death in multiple brain regions following OP exposure.9

The issue of persistent central nervous system effects following lower-level OP exposures has been

controversial,197,387,932 as have questions related to chronic subclinical encephalopathies associated with

other neurotoxicants.31,532,1781 In IOM’s Gulf War and Health report on pesticides, the review panel

concluded there is sufficient evidence that OP poisoning is associated with long-term, measurable

neurobehavioral deficits but did not reach consensus on whether measurable deficits were associated with

OP exposures in the absence of earlier poisoning.682 Aside from questions related to measured

neurobehavioral deficits, a growing number of epidemiologic studies in diverse populations have

consistently identified elevated rates of chronic symptoms and multisymptom illness in relation to long

term, low-level pesticide exposure.

Carbamate pesticides. Carbamates are chemically distinct from OPs, but also exert neurotoxic effects

by inhibiting the enzyme AChE. There are about 25 different types of carbamate pesticides currently in

use.387 Three—bendiocarb, propoxur, and methomyl—have been identified as pesticides of potential

concern in relation to the Gulf War. Bendiocarb and propoxur were sprayed on surfaces and in cracks

and crevices by pesticide applicators to kill flies, mosquitoes, and flying insects. In addition, fly baits

containing the carbamate methomyl were issued by the military and also purchased locally, and used both

by trained pesticide personnel and by individual service members.1632

Effects of acute overexposure to carbamate pesticides are similar to those described for other

anticholinesterase compounds, and result from the buildup of acetylcholine at cholinergic nerve terminals.

Central nervous system pathology and neurobehavioral effects from higher-dose carbamates exposure

have been described in animal models. Reported cases of carbamate poisoning in humans have included

large incidents involving ingestion of contaminated food and water, and accidental exposure from aerial

crop spraying. The severity of symptoms is dependent on the specific compound and dosage received.386

Unlike OP pesticides, the chemical process by which carbamates inactivate AChE is reversible, and

AChE enzyme activity is reestablished within hours after exposure. A persistent condition similar to

OPIDN has not been described following poisoning by carbamate pesticides, but a limited number of

single case reports of prolonged neurotoxicity have been described following massive exposures.386

DEET insect repellant. DEET is the acronym used for the chemical compound n,n-diethyl-m-toluamide,

a broad spectrum insect repellant that has a long history of use worldwide. The RAND pesticide study

identified DEET as the “pesticide” product most frequently used by military personnel in the Gulf War.

As listed in Table 2, personnel were issued creams and sticks that contained 33 percent DEET, and a high

concentration liquid that contained 75 percent DEET. DEET was intended for use on areas of exposed

skin, although it appears that it may have also been used on uniforms.
154  Effects of Gulf War Experiences and Exposures

Civilian use DEET formulations typically contain 10-25 percent DEET 1464 and have a good safety record

when used as directed.774,1157,1248 DEET works as an insect repellant, that is, it reduces the number of

insect bites by discouraging insects from landing on the skin. The chemical mechanism by which this

occurs is not known, however.1076,1509 There is relatively little systematic research on effects of DEET in

humans. It appears to be a neurotoxicant, with a limited number of case reports of overexposure

associated with encephalopathy and seizures.170,390,573,1157,1438 Dermatitis has also been reported.1276

Studies indicate that in animals given extremely high doses, DEET accumulates at high levels in the

brain, adrenal glands, and lungs1297 and produces marked effects on central and peripheral nerves,

including edema in the myelin and a patchy spongiform myelinopathy.1720 Lower doses have been

associated with limited adverse effects in rodents,1365 but with tremor, hyperactivity, excess salivation,

and vomiting in dogs.1366 DEET has not been shown to inhibit AChE activity, but DEET toxicity in cats

has been associated with symptoms similar to those associated with AChE inhibition—hypersalivation,

tremors, seizures.1464 There is some indication that synergistic effects between DEET and AChE

compounds occur through pathways other than AChE inhibition.1076

DEET has been considered a useful compound for enhancing dermal absorption of other compounds

through the skin,1795 although this has been called into question by more recent studies.110 DEET applied

to the skin can accumulate and remain in deeper skin layers for an extended time period—weeks or

months.1276,1464 Studies indicate that up to 17 percent is absorbed into the circulation428,1297,1384 and can be

retained in the body for an extended period, with one study indicating that about half of absorbed DEET

is excreted over a five day period.1297 Absorption of DEET is enhanced when it is provided in ethanol

solution,1241,1384,1490 and can also be enhanced by coadministration of sunscreen.573,1314 Additional research

on synergistic effects of DEET with other Gulf War exposures is described in a later section.

Pyrethroid insecticides. Synthetic pyrethroids are a class of compounds derived from pyrethrins,

naturally occurring chemicals found in chrysanthemums. They include permethrin, a compound issued as

a spray to treat uniforms and bedding in the Gulf War, and d-phenothrin, a compound sprayed in tents and

other enclosed areas to knock down and kill flying insects. These compounds act both as insect repellants

and as insecticides.1722 Permethrin is a particularly effective long-term repellant product for fabrics

because it retains its potency for an extended period after application. The 0.5 % permethrin sprayed onto

uniforms in the Gulf War and still used by the military retains its repellant activity for six weeks, and

through six launderings.62 Absorption of pyrethroids through the skin varies by species, with the specific

formulation used, and with the area of the body to which it is applied.1407,1768 Once absorbed, pyrethroids

are widely dispersed throughout different tissues and metabolized by carboxylesterases in the liver.1316,1722

Pyrethroids are neurotoxicants and, at very high doses, can have adverse effects on both the central and

peripheral nervous systems. Their best known mechanism of action involves effects on voltage-gated

sodium channels that result in alterations in nerve cell excitability.163,1258,1722 Multiple studies have also

described additional pyrethroid targets and effects that include enhanced release of acetylcholine and

alterations in other neurotransmitter systems.351,392,400,637,1026,1255,1258,1547

Although highly toxic to insects, pyrethroids have long been considered relatively safe for mammals. In

animal studies, extremely high doses of non-cyano pyrethroids such as permethrin produce symptoms of

aggressive behavior and increased sensitivity to external stimuli, followed by extensive tremors. More

subtle neurobehavioral effects have been observed at lower doses that produce no overt signs of

toxicity.149,297,1798

In humans who have been exposed occupationally or by accident to high doses of pyrethroids, symptoms

have included nausea, facial tingling, dizziness, headache, fatigue, burning and itching of the skin, eye

irritation, and respiratory symptoms.163,237,826,827,1836 At extremely high doses, convulsions and loss of

consciousness can occur.598 Permethrin-containing products are also used as topical treatments for
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  155

scabies and head lice in humans. In clinical trials, side effects have primarily included transitory skin

reactions, and infrequent allergic reactions.1722

Organochlorine insecticide. Organochlorines are a diverse class of insecticides that include DDT,

chlordane, and dieldrin. DOD has identified one organochlorine compound, lindane, as a pesticide of

potential concern during the Gulf War. During the war, lindane powder was used as a delousing agent by

military police units and others involved in processing Iraqi prisoners of war. Two ounce bottles of

lindane powder were also issued to individual troops in theater, primarily Army personnel, for their

personal use.1632

Lindane is a neurotoxicant that blocks the action of the neurotransmitter gamma aminobutyric acid

(GABA) by altering the flow of ions through neuronal membranes.732,1093 This leads to a persistent

hyperexcitation of post synaptic membranes, primarily in the central nervous system.387 Release of other

neurotransmitters can also be affected, including alterations in levels of dopamine, serotonin, and

norepinephrine.68,290,731,1292 Animals given high doses of lindane develop behavioral changes, loss of

balance, and seizures.1738 Effects vary both with the dosage and with the dosing schedule. Behavioral

and neurochemical effects of a single exposure to lindane have been shown to differ from those of

repeated, lower-dose exposures.489,1291 Lindane is also associated with chemical kindling, the

phenomenon by which chemical exposures potentiate a persistent increase in the sensitivity of brain cells

to electrical stimuli and seizures.34,489,490,730

Human overexposure to lindane is also associated with tremors, ataxia, and seizures, and several deaths

have been attributed to lindane poisoning.318,387,1132,1360,1508 In addition, studies of brain tissues of

Parkinson’s disease patients, at autopsy, have demonstrated significantly elevated levels of lindane and

dieldrin, compared to controls.278,446

Association of chronic disease with lower-level pesticide exposure. In the past decade, a

growing number of epidemiologic studies have identified human health effects associated with pesticide

exposures at levels that do not cause acute signs and symptoms or any indication of poisoning. These

prominently include: (1) links between pesticide exposure and chronic neurodegenerative diseases, and

(2) associations between pesticide exposure and elevated rates of chronic symptoms and multisymptom

illness. In addition, a large number of toxicological studies in animal models have explored biological

processes that potentially link lower-level pesticide exposure to the development of persistent

neurological sequelae.

The extensive literature implicating pesticide exposure in the development of chronic neurological

conditions has been reviewed and summarized in several publications.179,343,705,742,1075,1259 Human

populations evaluated in these studies have often been exposed to multiple pesticides over an extended

period of time, in different combinations and at different levels, the specifics of which usually are not

precisely known. Findings from studies of this type can therefore be affected by many of the problems

described in relation to Gulf War illness research, that is, potential inaccuracies in identifying “exposed”

vs. “unexposed” groups, the lack of useful biomarkers of exposure, and individual variability in specific

exposures and vulnerability to those exposures. Given such limitations, it is important that this literature

be considered broadly, taking into account patterns of associations across multiple studies and

populations.

Pesticide exposure and chronic neurodegenerative disease. The largest number of studies have

evaluated links between Parkinson’s disease and pesticide exposure.180,343,396,899 These have included

diverse types of toxicological studies using animal models, occupational studies of farmers and

agricultural workers, and epidemiologic studies of residents living in areas of high pesticide use.575,742

The British Medical Research Council recently reviewed this literature in detail and concluded that there

is a general consistency from human population research supporting an association between Parkinson’s
156  Effects of Gulf War Experiences and Exposures

disease and exposure to pesticides generically, but insufficient evidence to implicate any specific

pesticide or combination of pesticides.180 Some epidemiologic studies have also linked chronic pesticide

exposure to increased risk for both ALS and Alzheimer’s disease, although research has been more

limited and results more mixed than those related to Parkinson’s disease.91,742,1001,1066,1348 In addition,

several studies have provided evidence of a gene-environment interaction in the risk for both ALS and

Parkinson’s disease. Both conditions have been found to occur at higher rates in individuals with genetic

variants of the paraoxonase (PON1) gene, which may cause them to be more vulnerable to adverse effects

from certain pesticides.126,1426,1840

Pesticide exposure in relation to chronic symptoms and multisymptom illness. In community and

occupational studies, chronic low-level exposure to pesticides has frequently been associated with

increased rates of symptoms and multisymptom illness similar to those affecting Gulf War veterans.742

The majority of studies have focused on effects of exposure to pesticides in general or effects of

organophosphate pesticides. Compared to unexposed controls, populations chronically exposed to

pesticides, either in relation to their occupation or where they live, have consistently been shown to report

higher rates of symptoms that include memory problems, difficulty concentrating, headache, fatigue,

difficulty sleeping, nausea, respiratory problems, and mood alterations.316,506,702,741,742,930,1283,1479

In addition to elevated symptom rates, there are a number of other parallels between ill Gulf War veterans

and populations chronically exposed to pesticides. Multiple studies have demonstrated associations

between chronic pesticide exposure and poorer performance on measures of cognition, affect, and

behavior.682,742 Most have identified reduced performance on a limited number of tests, with different

studies reporting decrements on different measures.1302,1320,1479,1484 In addition, workers chronically

exposed to organophosphate pesticides are reported to have a significantly increased risk of death due to

motor vehicle accidents compared to unexposed individuals, but no excess of disease-related mortality.

880

There is also limited evidence that PON1 polymorphisms are associated with poorer cognitive

performance, neurological alterations, and increased symptoms in individuals chronically exposed to

pesticides.182,1005 Although symptoms associated with chronic pesticide exposure include muscle

weakness and tingling in the extremities, few studies have identified objective indicators of peripheral

nerve conduction or sensory abnormalities in pesticide-exposed populations.32,805,933,1479,1493

A multisymptom condition sometimes referred to as sheep dippers syndrome has been described in a

subgroup of British sheep farmers. Since 1984, sheep farmers in the United Kingdom have been required

to periodically immerse their animals in a pesticide dip to control the spread of a serious parasitic disease.

Since use of the organochlorine pesticide dieldrin was banned in the U.K., the sheep bath has consisted

largely of OP chemicals, prominently diazinon.1471 The constellation of symptoms reported by this

subgroup of sheep farmers is similar to the multisymptom illness affecting Gulf War veterans, and

includes chronic headache, memory and concentration problems, gastrointestinal difficulties, mood

alterations, and fatigue. Farmers have also commonly indicated that their symptoms continue long after

they have quit working with sheep and are no longer exposed to sheep dip.242,1471

Research studies conducted since the mid 1990s consistently indicate that exposed sheep farmers have

significantly more symptoms than unexposed controls.112,1209,1441,1483,1522 Sheep dip-exposed farmers also

exhibit significantly poorer performance on measures of attention and information processing,1483 but only

limited abnormalities on standard neurological examinations or tests of peripheral neuropathy.112,706,1209

Symptomatic sheep farmers have also been found to have a significantly higher rate of PON1

polymorphisms that provide poorer hydrolysis of diazinon, compared to nonsymptomatic sheep

farmers.242,946,1223

Another multisymptom condition, multiple chemical sensitivity (MCS), occurs sporadically in the general

population and is often attributed by patients to exposure to neurotoxic chemicals, including

pesticides.212,1044 The syndrome is associated with diverse symptoms similar to those that affect Gulf War
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  157

veterans—cognitive impairment, sleep abnormalities, digestive difficulties, headache, fatigue, and mood

alterations—symptoms that are exacerbated by low-level exposure to chemicals. This condition has been

assessed in multiple studies of Gulf War veterans, as will be described in a later section of the report.

Patients with MCS report that minimizing their exposure to chemicals is the most useful way to limit the

severity of their symptomatic illness.488 The Committee has discussed suggestions from clinicians and

members of the public that veterans be advised to limit their exposure to pesticides and other chemicals.

Anecdotal reports have suggested that some veterans’ symptoms were triggered or worsened by exposure

to pesticides after they returned from the Gulf War.716 Clinicians have also provided testimony and case

reports indicating that chemical avoidance can be useful in improving veterans’ health.1115,1399 There is

currently no scientific research, however, to indicate whether veterans’ exposure to chemicals since their

return from the Gulf War is associated with chronic ill health, nor whether chemical avoidance provides

symptomatic relief. It is hoped that insights into this question will be provided by a recently-funded study

of a multimodal treatment for Gulf War illness that includes reduction of chemical exposures.1013

Health effects of low-level sarin exposure

The organophosphate compound sarin was developed as a chemical warfare agent by German scientists in

the 1930s. Sarin is highly toxic and when used in warfare at militarily effective doses causes serious

symptoms and death as a result of acute cholinergic toxicity. Relatively little was known about biological

effects of lower-level sarin exposures until recent years, particularly with respect to persistent or delayed

effects of low-level exposures.86 In the past decade research in these areas has expanded as a result of

several factors. These include questions raised about effects of low-level sarin exposure in the Gulf War

following DOD’s 1996 announcement that nerve agents had been released in theater, exposure of a large

number of Japanese citizens to sublethal doses of sarin in terrorist attacks during the 1990s, and increased

concern in the U.S. and elsewhere about use of chemical agents on civilian populations. Recent research

has provided important insights into effects of sublethal exposure to sarin and longer-term effects of low

dose sarin exposure, the issue most relevant to the health of Gulf War veterans.

In the late 1990s, both DOD and VA commissioned reviews of the available scientific literature to

provide information on possible health consequences of nerve agent exposure in the Gulf War. A 2000

report from the RAND National Defense Research Institute detailed the challenges of determining

whether or not Gulf War veterans had developed acute symptoms in connection with low-level chemical

agent exposures in theater.74 The RAND report pointed out that symptoms of low level exposure to nerve

agents are nonspecific and might, at the time of exposure, be attributed by a soldier to a common

headache, gastrointestinal condition, or respiratory problem. It also described research suggesting that

expected symptoms of low-level sarin in theater might have been attenuated by veterans’ use of PB, or as

a result of tolerance that developed with repeat exposures to AChE inhibitors. The RAND report

concluded that there were no indications of serious symptoms suggestive of a large dose chemical agent

exposure in Gulf War personnel. Milder symptoms associated with low dose exposures might have been

overlooked or misinterpreted, however, so could not be ruled out. The report also found that it was not

possible, based on the limited literature available at the time, to rule out the possibility that low level

exposures could produce chronic health effects, and identified research needed to investigate this issue.

In response to a Congressional directive, VA commissioned the Institute of Medicine (IOM) to conduct a

series of research reviews to assist the Secretary in making decisions about veterans’ disability

compensation, as previously described. Volume One of the resulting IOM Gulf War and Health series

was published in 2000 and included a literature review on the effects of sarin. Based on its review, the

IOM committee concluded that “there is sufficient evidence of a causal relationship between exposure to

sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to

sarin exposure and resolves in days to months”679 an effect that has been well recognized for decades.
158  Effects of Gulf War Experiences and Exposures

The IOM committee also found that evidence from human studies to determine if subsymptomatic

exposure to sarin led to long term health effects. Based on studies of nonhuman primates and humans

exposed to low levels of other OPs, the committee added that “it is reasonable to hypothesize the

occurrence of long-term adverse health effects from exposure to low levels of sarin.”679

Within several years of the IOM report’s publication, multiple studies emerged that identified effects of

low-level sarin exposure in animal models. As a result, the Secretary of Veterans Affairs asked IOM to

revisit the question of long-term effects of low-dose sarin exposure. In response, IOM published an

“Updated Literature Review of Sarin” in 2004. The conclusions of this second IOM report were

essentially unchanged from those of the first.683 Similar to the prior IOM report, the second panel did not

consider findings from toxicological research in animals or studies evaluating risk factors for

multisymptom illness in Gulf War veterans to determine the strength of evidence relating low-level sarin

exposure to health outcomes. This omission was striking, since the new animal studies had been the

reason the Secretary requested the updated report.1641

Research on the effects of low-level sarin exposure considered for the present report includes studies on

health outcomes in humans, as well as biological effects observed in animal models. Because the

Committee is charged specifically with reviewing research related to the health of Gulf War veterans, this

review focused most specifically on studies that have evaluated longer-term effects of lower-level sarin

exposures. Results from studies that have specifically evaluated health outcomes in Gulf War veterans in

relation to nerve agent exposure is considered in detail in a later section, along with similar research

related to PB and pesticide exposures in the Gulf War.

Animal research on effects of sarin exposure

Repeated exposures to levels of sarin that would not be noticed clinically resulted in delayed

development of brain alterations that could be associated with memory loss and cognitive

dysfunction.

--R. Henderson, “Response of Rats to Low Levels of Sarin”601

A large number of studies have evaluated effects of sarin in different animal models. In reviewing this

literature, several key parameters were important to differentiate in characterizing research findings. In

addition to potential effect differences in different animal species, key study parameters relate to whether

the study evaluated effects of higher doses that caused serious signs of cholinergic toxicity or death in

exposed animals, intermediate doses that caused milder effects in a subset of animals, or effects of lowerdose exposures that caused minimal or no observable signs of toxicity. In addition to dose levels, the

route of exposure (e.g., inhalation, injection, intravenous infusion) and the dosing pattern (e.g., single

doses or repeated dosing, of brief or sustained duration) appeared to make a difference in some cases. An

additional issue of importance related to how long animals were observed after exposure—hours, days,

weeks, or months—to determine the duration of identified effects or the development of delayed effects.

As will be described below, animal studies have included different combinations of these key elements,

evaluating high or medium or low dose exposures given once or multiple times by inhalation or injection,

with outcomes evaluated at time points that range from immediately after exposure to periods more than

one year later.

Acute effects of sarin exposure in animals. Acute effects of high dose sarin exposure in both

humans and animals result from cholinergic toxicity—evidenced by symptoms that include miosis,

salivation, tremors, nausea and vomiting, seizures, coma, and respiratory arrest—which vary in severity

with the level and duration of exposure.51,133,1051 Research in animal models has also demonstrated

additional acute effects of moderate to high dose sarin exposure that include behavioral effects,

autonomic effects, renal and neuroinflammatory effects, and alterations in gene
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  159

expression.145,230,304,307,860,869,895 In addition, animal studies have identified longer term effects in surviving

animals following high dose sarin exposure, including persistent changes in behavior, central

inflammatory processes, cardiac function, and gene expression profiles.42,308,520,652 Sarin exposure at

lower doses often produces limited or no overt effects that are apparent by simple observation. A large

number of animal studies, however, have described both acute and chronic biological effects associated

with low-dose sarin exposure, often in the absence of observable signs or symptoms. Understanding

effects that may develop or persist over an extended time period after low-dose exposures is of greatest

relevance to the health of Gulf War veterans, as will be described below. In addition, many studies have

described short-term effects of low level sarin exposures. In these studies, animals were observed for

only a limited time after exposure, so it is generally unknown how long identified biological effects might

have lasted had animals been observed for longer periods. In addition to alterations in cholinesterase

activity, low-to-moderate doses of sarin have been shown to produce short-term neurological effects that

include neurobehavioral alterations,652,761,1120,1402,1415,1806 spinal cord lesions and swelling,656,659 and

increased expression of genes associated with neuronal degeneration and apoptosis.1383 Several studies

have also described acute immune alterations with low-level sarin exposure.740,762-764

Evaluation of persistent or delayed effects of low-level sarin exposure in animals. As

described in the Committee’s 2004 report, a growing number of animal studies have, since 2000, assessed

biological effects of lower-level sarin exposure, effects that develop or persist over an extended time

period. Results from these studies are summarized in Table 4. As shown, this research includes a wide

variety of study designs and exposure models. It includes studies in both rodent and primate models,

sarin exposure by inhalation or injection at levels that range from extremely low doses to those that cause

limited symptoms in some animals, and follow-up periods that range from 17 days to more than one year

after exposure. Findings are also diverse, and include effects that are detectable immediately after

exposure and persist through the last observation point, effects that are not apparent until some time after

exposure, changes that normalize over time, and effects that vary with time (for example, a biological

measure that is initially increased, but later decreased).

As with other areas of research considered by the Committee, studies related to persistent effects of lowlevel sarin exposure vary with respect to strength of study design, investigators’ conclusions, and

reliability of publication source. Because of limitations related to individual studies and sources, the

Committee again adopted an inclusive approach in reviewing this literature, considering all relevant

studies and drawing on the breadth of results to inform general conclusions, rather than relying on any

single study or source.

Brain and behavioral effects. The largest number of studies have evaluated long-term effects of lowlevel sarin exposure on the brain and behavior. The earliest published study of this type, from 1976,

reported that monkeys exposed to either a single high dose or repeated low doses of sarin developed

electroencephalogram (EEG) abnormalities that persisted at least one year after exposure.195 A 1999

study identified only minimal long term EEG effects following a single, somewhat higher-level exposure

to sarin in marmosets.1183 A more recent study from the Netherlands,1706 like the initial EEG study,

reported long term EEG effects in monkeys who received a sustained, low-dose sarin exposure by

inhalation. In the 2004 study, Dutch investigators reported that EEG readings were an order of magnitude

more sensitive than pupil measures for detecting low-dose sarin exposure and that exposed monkeys

continued to exhibit significant EEG alterations one year after exposure.

Studies listed in Table 4 indicate that central effects of sarin vary with exposure method, dose, and

duration and also may vary between species. Results from several studies also suggest that the persistent

effects of sarin exposure can differ with the pattern of exposure. That is, repeated low dose exposures can

produce effects that differ from those of single exposures, even at similar or higher doses. For example,

Duke investigators reported that after injecting rats once with sarin at doses that ranged from very low to
160  Effects of Gulf War Experiences and Exposures

Table 4. Studies Evaluating Persistent and/or Delayed Effects

of Low Level Sarin Exposure in Animals

Study Exposure Model Key Findings

Burchfiel195

1976

Monkeys injected with sarin

IV with single, sublethal large

dose or 1 low dose/week for

10 weeks

1 year following exposure, EEG alterations, prominently increased beta activity, persisted

in monkeys exposed both to single, high dose exposure and multiple, low-dose exposures.

Low dose exposure generated biphasic response, with early increase in delta and theta,

which shifted to increase in beta by 1 year post exposure.

Pearce1183

1999

Marmosets given single,

moderate dose injection

No sign. EEG alterations observed over 15 months, ns (p=0.07) increase in beta

amplitude. No sign. cognitive deficits observed.

Jones724

2000

Rats injected IM with single

0.01, 0.1, 0.5, or 1.0 LD50

dose of sarin

90 days post exposure, blood brain barrier permeability sign. decreased, AChE activity

sign. increased, M2 receptors sign. increased in brainstem only after 1.0 LD50 dose. M2

receptors sign. reduced in cortex after 0.5 and 1.0 LD50 dose.

Kassa768

2000

Rats given 1 of 3 levels of

sarin by inhalation for 60 min,

mid level exposure given 1x

or 3x within 1 week

3 months post exposure, DNA replication and synthesis in the liver was sign. decreased

with all single doses, but not with repeat exposure. 6 months post exposure, DNA content

and total protein sign. reduced with all doses. Minimal differences at 12 months post

exposure.

Kassa766

2000

Rats given 1 of 3 levels of

sarin by inhalation for 60 min,

mid level exposure given 1x

or 3x within 1 week

12 months post exposure, sarin repeated dose sign. increased lymphoproliferation, while

single dose at same and lower level sign. reduced it. Repeat dose sign. decreased

macrophage activity, while single dose at same and higher level sign. increased it. No

sign. difference in immune measures 3 months post exposure, limited differences at 6

months.

Kassa767

2001

Rats given 1 of 3 levels of

sarin by inhalation for 60 min,

mid level exposure given 1x

or 3x within 1 week

3 months after exposure, rats that received repeat sarin exposure had sign. locomotor,

gait, and behavioral abnormalities, and sign. greater CNS excitability. Behavioral deficits,

but not enhanced CNS excitability, also with single higher, nonconvulsive dose.

Kassa758

2001

Rats given 1 of 3 levels of

sarin by inhalation for 60

minutes, mid level exposure

given 1x or 3x within 1 week

1 day after exposure, rats with mid and higher level sarin exposure showed sign. deficits in

spatial memory performance on T maze. Differences no longer sign. at one week or 3

months post exposure. No sign. difference between single and repeat dosing.

Kassa759

2001

Rats given 1 of 3 levels of

sarin by inhalation for 60

minutes, mid level exposure

given 1x or 3x within 1 week

Single low and mid level doses produced only brief (< 1 day) reduced spatial memory

performance on Y maze. Repeat dosing or single higher dose produced sign. impairment

for 3 weeks, which normalized at 4-5 weeks.

Kassa757

2001

Rats given 1 of 3 levels of

sarin by inhalation for 60 min,

mid level exposure given 1x

or 3x within 1 week

Gait abnormalities, sign. decreases in automated measures of motor activity, and

increased CNS excitability 3 months after exposure. Sign. increased exploratory activity

and hind limb grip strength 6 months after exposure.

Conn267

2002

Rats exposed to subclinical

levels of sarin by inhalation 1

hour/day for 1,5, or 10 days

with/without heat stress

Low-dose, single or repeated sarin exposure had no acute or delayed effects on body

temperature or locomotor activity with or without heat stress.

Henderson601

2002

Rats exposed to subclinical

levels of sarin by inhalation 1

hour/day for 1,5, or 10 days

with/without heat stress

1 day after exposure, M1 cholinergic receptors were unchanged. After 30 days, sarin alone

sign. reduced M1 receptors in olfactory tubercle; sarin+heat stress sign. reduced M1

receptors in frontal cortex, hippocampus, and olfactory nucleus. Sarin+heat stress also

sign. increased M3 receptors in frontal cortex, olfactory tubercle, anterior nucleus, and

striatum 1 day and 30 days post exposure. Sarin sign. increased brain mRNA for IL-1beta,

TNF-alpha, and IL-6. No apoptosis or brain lesions identified on histopathology.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  161

Table 4. (cont.) Studies Evaluating Persistent and/or Delayed Effects

of Low Level Sarin Exposure in Animals

Study Exposure Model Key Findings

Scremin1377

2003

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

2 weeks post exposure, acoustic startle response was sign. increased and exploratory

behavior decreased, indicating cholinergic hyperactivity. At 16 weeks post exposure,

habituation was sign. decreased. Muscarinic receptor binding was sign. decreased in

multiple brain regions at 2 weeks, sign. increased in cortex at 4 weeks, with no sign.

differences at 16 weeks.

Husain657,658

2003, 2004

10 weeks exercise, with lowdose sarin subQ daily during

weeks 5-6 in mice

4 weeks post exposure, sarin sign. decreased peripheral BChE and AChE, AChE in

striatum, NTE peripherally and in cortex, striatum, and spinal cord, and increased MDA

(indicator of lipid peroxidation) in spinal cord and sciatic nerve.

Kassa765

2004

Rats given low and moderate

doses of sarin by inhalation

for 60 minutes, infected with

tularemia 7 days after

exposure

24 hours after infection, sarin at both levels caused sign. decrease in IgM and IgA

antibodies, sign. increase in lymphoproliferation. Higher dose associated with sign.

more IgM antibodies after 7 days. Both doses sign. decreased lymphoproliferation at

21 days.

Van Helden1706

2004

Monkeys exposed to sarin for

5 hours by inhalation at 5

subclinical doses

During exposure, EEG readings were 10x more sensitive than pupil miosis to low level

sarin. 1 year after exposure, sarin exposure associated with sign. EEG abnormalities on

multiple bands, and sign. more alpha frequency bursts than at baseline.

Scremin1378

2005

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

4 weeks after exposure, sarin exposure associated with sign. increased cerebral blood

flow in multiple areas. Few sign. differences remained at 16 weeks.

Shih

1403

2006

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

Brain acetylcholine levels were sign. increased at 4 weeks post exposure, but not at 16

weeks.

Scremin1379

2006

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

2 and 4 weeks post exposure, sarin associated with sign. decreased heart rate at

different times over 24 hour period. Low frequency HRV at midnight was sign. reduced

at 2 but not 4 or 16 weeks post exposure.

Genovese480

2007

Monkeys injected IM with

single moderate dose of sarin

Sarin exposure was not associated with sign. deficits on cognitive performance (serial

probe recognition tasks) assessed up to 10 weeks post exposure.

Morris1071

2007

Rats injected subQ with 0.05

LD50 sarin on 2 consecutive

days

Low dose sarin produced biphasic autonomic modulation, with sign. increase in HRV

(pulse interval, low and high frequency) 1 week post exposure, followed by a sign.

decrease at 10 weeks. Tyrosine hydroxylase mRNA sign. increased in areas of

brainstem 10 weeks post exposure.

PenaPhilippides1193

2007

Rats exposed to low dose

sarin by inhalation 1 hour/day

for 1 or 5 days

Sarin sign. reduced serum corticosterone and ACTH levels, which persisted through

last observation (8 weeks corticosteroid, 4 weeks ACTH). 5 day repeat exposure sign.

reduced antibody forming cell response, which was autonomically mediated, and

normalized 2-4 weeks post exposure.

Dave314

2007

Guinea pigs injected subQ

with 0.1, 0.2, or 0.4 LD50

1x/day for 10 days

Repeat low dose sarin produced sign. increase in DNA fragmentation in neurons and

leukocytes at 0 and 3 days post exposure, but not at 17 days.

Mach945

2008

Mice injected subQ with 0.4

LD50 sarin on 3 consecutive

days , with/without

intermittent stress

3 weeks post exposure, sarin alone produced sign. reduced motor activity on open field

testing, no interaction with stress. Sarin+stress produced delayed behavior alterations

(increased grooming behavior) at 7 weeks post exposure, and sign. increased size and

reduced catecholamine concentrations in adrenal glands.

Abbreviations: IV = intravenous, IM = intramuscular, subQ = subcutaneous, EEG = electroencephalogram, LD50= dose that is lethal to half of

exposed animals, M1 or M2 or M3 = subtypes of acetylcholine muscarinic receptors, CNS = central nervous system, AChE =

acetylcholinesterase, BChE = butyrylcholinesterase, NTE = neurotoxic esterase, MDA malondialdehyde, ACTH = adrenocorticotropic hormone,

min = minutes, sign. = statistically significant
162  Effects of Gulf War Experiences and Exposures

very high, only rats with the high dose exposure exhibited persistent regional alterations in brain AChE

activity.724 In contrast, several studies have indicated that repeated, low dose sarin exposures over periods

up to two weeks produce persistent regional alterations in central AChE activity.601,657,658

Studies have reported a variety of changes in the brain following repeat, low dose sarin exposure. A 2002

study from Lovelace Respiratory Research Institute reported both persistent and delayed effects on the

brain following repeated inhalation exposures to low dose sarin over periods from one day to two

weeks.601 Some effects were delayed, that is, they were not observed the first day following exposure but

were identified 30 days after exposure. Some effects occurred only with the combination of sarin

exposure and heat stress. Overall, 30 days after repeat low dose sarin exposure, cholinergic M1 receptors

were significantly reduced in several brain regions, including the hippocampus, frontal cortex, and

olfactory areas. With heat stress, M3 receptors were significantly enhanced in striatum, frontal cortex, and

olfactory areas. Increased levels of proinflammatory cytokines were also found in the brain, although no

brain lesions were identified. Research from the Los Angeles VAMC also reported alterations in central

muscarinic receptors after repeated, higher doses of sarin over a longer time period, although specific

receptor subtypes were not distinguished. Overall, muscarinic receptors were significantly decreased in

several brain areas two weeks after exposure, increased in the cortex at four weeks, but no longer differed

significantly from controls at 16 weeks.1377

Multiple studies have reported persistent behavioral effects of low dose sarin exposure, with findings

varying with dosage level, the duration of follow-up, and the type of motor or cognitive function assessed.

Some studies identified no behavioral effects267,480,1183 or only transient effects.758 Several studies have

reported that behavioral alterations were more pronounced with repeat exposures than with single

exposures at the same dosage.759,760,767 One of the earliest reports on sustained behavioral effects

indicated that three repeated, low dose sarin exposures given over one week, but not just one dose,

resulted in significant locomotor, gait, and behavioral abnormalities three months after exposure, and

significantly increased sensitivity to drug-stimulated seizures.767 Additional studies have reported

significant reductions in acoustic startle response, motor activity, grooming behavior, and habituation,

changes that persisted from two to sixteen weeks after repeat doses of sarin.945,1377

In many cases, it is not known how long identified central effects of low dose sarin exposure persist, since

many effects were reported to continue through the final observation point of the study. Other changes

appeared to normalize within the follow-up period of the study, usually over several weeks or months.

These included sarin-related cognitive changes observed in two studies,758,759 alterations in cerebral blood

flow1378 and changes in brain levels of acetylcholine.1403

Autonomic effects of low-dose sarin. Low level sarin exposure has been associated with alterations in

autonomic function in several animal studies. Investigators from Wright State University identified a

biphasic autonomic response following extremely low-dose sarin exposure, given each of two days. One

week after exposure, heart rate variability was significantly elevated in both the low and high frequency

ranges. By 10 weeks, however, heart rate variability was significantly reduced in sarin-exposed

rats.1070,1071 A second study reported that higher-dose sarin, given over a more sustained period, produced

significant alterations in heart rate variability in the low frequency range. These differences were

observed two weeks after exposure, but not at four or 16 weeks after exposure.1379 In addition, immune

suppressive effects of low-dose sarin exposure have been shown to be autonomically mediated, and did

not occur when sarin-exposed animals were pretreated with a ganglionic blocker.740,1193

Neuroendocrine effects of low-dose sarin. An unexpected effect of low-dose sarin has been reported

by two studies from Lovelace Respiratory Research Institute. Investigators found that low-dose sarin

exposure resulted in immune suppression, but that this effect was not the result of elevated levels of

corticosteroid, the adrenal stress hormone. Instead, study findings indicated that low-dose sarin exposure

significantly decreased serum corticosteroid levels.740 A follow-up study indicated that both
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  163

corticosteroid and adrenal corticotropic hormone (ACTH), the pituitary hormone that stimulates

corticosteroid production, were significantly reduced by low-dose sarin, and that this suppression

persisted for as long as animals were observed, four-to-eight weeks.1193 A similar effect was also

associated with other centrally-acting AChE inhibitors.868

Additional neuroendocrine alterations reported in response to low-dose sarin exposure include a persistent

increase in brainstem mRNA for tyrosine hydroxylase, the rate limiting enzyme for synthesis of dopamine

and related neurohormones.1071 Low dose sarin exposure has also been reported to produce significant

adrenal gland enlargement and reduced adrenal catecholamine concentrations, in combination with an

intermittent stress.945

Immune effects of low-dose sarin. Several studies have reported that low-level sarin exposure can

significantly alter the immune response, producing a number of effects that differ over time. Long-term

alterations in lymphoproliferation have been demonstrated in several studies.763,766,767 The first, from

Czech investigators, reported that no sarin-related immune changes were observed three months after

exposure, and very limited differences six months after exposure. Twelve months after exposure,

however, rats who had received repeated, low dose inhalation exposures to sarin had significantly

decreased macrophage activity and significantly increased lymphoproliferation. At the same time, rats

who had received a single dose of sarin, at the same concentration, also had significant changes in both

measures, but in the opposite directions.766 Other studies have identified temporary suppression of

antibody responses following low-dose sarin exposure. Significant reductions in T cell mitogenesis and

antibody forming cells, observed shortly after low dose sarin exposure, were reported to normalize

between two and four weeks after exposure.1193 Czech investigators have also reported a temporary

suppression of antibody response to infection one week after low or moderate dose sarin exposure.765

More recently, a study from Walter Reed Army Institute of Research found that low-level, repeat sarin

exposure produced a significant, but temporary, increase in DNA fragmentation in leukocytes, an effect

observed at three days, but not 17 days after exposure.314

Effects of sublethal and low-level sarin exposure in humans

Interest and research on the effects of chemical nerve agents has historically focused on acute symptoms

and signs, and on lethal effects of acute exposure. It was widely believed, for many years, that there are

no long term effects of sarin following recovery from sublethal exposure, although research on long-term

human health effects of sarin was limited. Experimental studies conducted by government agencies in

chemical warfare programs did not evaluate long term effects, and there were few opportunities for

systematic observational research, since human populations had rarely been exposed to sarin. In the past

25 years, unfortunately, humans have been exposed to chemical weapons, including sarin, in connection

with several situations and incidents. As a result, scientists and clinicians have learned more about

immediate, short term, and long term effects of sublethal exposure to chemical warfare agents on humans.

Prior to more recent exposure events, there was limited information on the potential for lower-level

exposure to chemical agents, including sarin, to produce long term effects. As described in the

Committee’s 2004 report, reports emerged, in the 1950s, of a multisymptom condition affecting a group

of individuals who had worked in the German military’s munitions factories in the 1930s and 1940s,

factories that produced sarin and other chemical agents. A 1963 medical report described a “cerebroorganic delayed effect syndrome” in these workers that was characterized by lowered vitality, defective

autonomic regulation, headache and gastrointestinal symptoms, and cognitive impairment.1467,1491 A case

series report, published in 1969, described symptoms of impaired memory, difficulty concentrating, and

mood alterations, as well as an excess of slow wave activity on electroencephalograms (EEG) in 25

industrial workers in the U.S. who had been exposed to sarin in the 1950s and 1960s.1025
164  Effects of Gulf War Experiences and Exposures

In 1979, investigators from Harvard Medical School and collaborating institutions reported results of a

study of 77 government workers with histories of accidental exposures to sarin, and 38 healthy

controls.368 Researchers explained that they undertook the study because of reports that a number of

civilian government employees working with or around sarin had complained of a variety of symptoms

that included memory loss, trouble concentrating, and excessive dreaming.194 Forty-one of the workers

evaluated in the 1979 study had been exposed to sarin three or more times within the six years prior to

evaluation, but none of the workers in the study had been exposed in the year prior to the study. Sarinexposed workers had normal erythrocyte AChE activity, but differed significantly from controls on both

waking and sleeping EEG, with most marked increases in higher frequency beta activity. Similar

persistent alterations in beta activity had previously been demonstrated in primates one year after sarin

exposure.195

Both the U.S. and British governments have supported chemical weapons research and development

programs that included use of human subjects.780,1652 A 2003 report described results of a follow-up

survey of 2,478 men who, as military volunteers, had participated in the U.S. program between 1955 and

1975.1164 The DOD-sponsored study compared the health of 855 men who had been exposed to

cholinergic agents (sarin, VX, and eserine), 871 men exposed to other chemical agents (e.g. blister agents,

LSD), and 752 men not exposed to chemical agents. Overall, no differences were reported in rates of

diagnosed diseases and only minimal differences on general health measures. Individuals exposed to

cholinergic agents in the program had a slightly lower overall death rate than men not exposed to

chemical agents. This report is reassuring, providing a general indication that military personnel exposed

to chemical agents were not, overall, affected by excessive long-term health problems many years later.

Important limitations include the lack of information on health outcomes in relation to specific nerve

agents, dosages, or duration of exposure, and the lack of information on the health of individuals whose

program participation was limited due to short term difficulties with chemical exposures.

The British Medical Research Council has commissioned a series of projects to evaluate health outcomes

among the thousands of military personnel who participated in research programs at the British chemical

research facility at Porton Down. An initial report on an evaluation of 289 members of a Porton Down

veterans’ support group was published in 2006. Multiple symptoms, including fatigue, sleep, and mood

difficulties, were reported to have occurred in the first five years after program participation, and

continued to be problematic in the years that followed.40 This preliminary project did not have an

unexposed comparison group of veterans, but did report that SF36 measures of function and healthrelated quality of life were significantly lower in the Porton Down veterans than in comparably aged men

in the general population. These findings do not provide information on whether Porton Down veterans

have excess problems due to their program participation, since veterans in the support group are not likely

representative of all program participants. But the report does provide a preliminary indication that a

selected subgroup of program participants are in worse health than the general population.

Chemical weapons, both nerve and blister agents, were used in the Iran-Iraq War during the 1980s.178,693

Blister agents are said to have been used the most extensively by Iraq. Reports indicate that as many as

100,000 Iranians may have been exposed to sulfur mustard and that tens of thousands still suffer long

term health effects that include respiratory disorders and eye and skin abnormalities.90,484 In 1988, the

Kurdish town of Halabja, near the Iranian border in Northern Iraq, was bombarded with what is believed

to be a mix of chemical agents—mustard gas and nerve agents that included sarin, tabun, and VX.509,1566

The attack lasted several days and had tragic and lasting consequences, reportedly killing 5,000 people

and producing an additional untold number of serious casualties.496 No scientific or systematic reports

have provided information on the extent and types of injury and disease caused by this attack, nor on rates

of medical conditions or persistent symptomatic illness in the years since the attack. Reports from

clinicians and the media have described increased rates of cancers, respiratory conditions, psychiatric

disorders, and birth defects among survivors.496,509,597 Because of the mixed effects of multiple, high
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  165

dosage exposures in these attacks, it is not known whether any long-term effects can be attributed to

effects of OP nerve agents.

Survivors of 1990s terrorist incidents in Japan. The most extensively studied sarin-exposed

populations are Japanese citizens who were exposed to sarin in two terrorist incidents in the 1990s. The

first attack occurred in 1994 when sarin was released in the middle of the night in a residential area of the

city of Matsumoto, Japan. Area residents, rescue workers, and clinical staff exposed to sarin when

victims were brought into hospitals exhibited acute cholinergic symptoms of exposure. In all, 600 people

were poisoned, 58 were hospitalized, and seven died.1068,1092,1133 The following year, a religious cult

released sarin on three different lines in the Tokyo subway system during Monday morning rush hour.

About 5,500 people are reported to have been poisoned, and 12 died.1147,1818,1825

Initial clinical reports focused on exposed individuals who sought evaluation and treatment, most of

whom had acute signs and symptoms of cholinergic toxicity—pupil miosis, headache, nausea and

vomiting, rhinorea, and fatigue.1818 In the years since, a large number of studies have evaluated multiple

health parameters in these populations, with most focused on neurological and psychiatric sequelae of the

exposure events.1825 For many of those exposed, acute symptoms resolved in a matter of weeks. Some

individuals, however, exhibited persistent symptoms when evaluated years after exposure. Three years

after the Matsumoto incident, a substantial number of victims continued to report symptoms that included

eye weakness (24%), fatigue (15%), and headache, at rates significantly higher than controls.1091

Persistent symptoms reported by Tokyo survivors five years after exposure included eye fatigue (39%),

visual abnormalities (21%), general fatigue (16%), muscle stiffness (15%), and headache (10%), as well

as psychological symptoms including flashbacks (13%) and depressed mood (13%).778

Six to eight months after the Tokyo subway attack, exposed individuals who no longer exhibited clinical

signs of poisoning, were shown to have a variety of subtle central nervous system alterations, including

poorer performance on neurobehavioral tests, prolonged auditory and visual evoked potentials, and

postural sway abnormalities.1826-1829 Heart rate variability, assessed six to eight months after exposure,

was significantly correlated with the degree of AChE reduction measured at the time of exposure.1086

Studies conducted in the years that followed the Tokyo attack continued to identify psychomotor and

memory alterations in individuals exposed to sarin, three years 1128 and seven years1054 after exposure.

Some individuals also continued to have symptoms of posttraumatic stress disorder (PTSD). Studies

indicated that some neurobehavioral measures were significantly associated with PTSD symptoms in

those individuals. Others were significantly associated with sarin exposure, after controlling for effects of

PTSD.1128,1828 Investigators concluded that some survivors exhibited persistent or delayed central nervous

system effects resulting from sarin exposure, in addition to persistent psychological effects resulting from

trauma.1828

Neuroimaging studies have identified persistent brain structure abnormalities in relation to sarin exposure.

Five to six years after the Tokyo attacks, a study of 38 individuals exposed to sarin found them to have

significantly smaller regional grey matter volume in the right insular and temporal cortex, smaller white

matter volume in the temporal stem near the insular cortex, and smaller left hippocampus volume,

compared to matched controls.1816 White matter reductions were significantly correlated both with the

severity of somatic symptoms at the time of the study and with the degree of AChE reduction years

earlier, on the day of sarin exposure. No associations were identified between brain volume and measures

of psychological stress. Study results therefore supported direct links between sarin exposure, persistent

symptoms, and brain structure alterations.1816 A small study had previously reported that nine individuals

with PTSD following sarin exposure in the Tokyo subway showed a significant reduction in grey matter

in the left anterior cingulate cortex.1817

Overall, follow up evaluations of individuals exposed to sarin in Japanese terrorist events indicate that

sarin exposure, at levels sufficient to cause acute symptoms, is associated with persistent symptoms and
166  Effects of Gulf War Experiences and Exposures

central nervous system effects, in a subset of those exposed. These findings contrast with earlier

assumptions that sublethal exposure to sarin does not lead to long-term health sequelae following

recovery from acute effects of exposure. This research does not indicate whether low-level sarin

exposure that does not produce acute symptoms can lead to persistent central nervous system effects,

however. Studies have not evaluated the health of individuals who were located near areas where sarin

was released in the Japanese events and potentially exposed to lower levels of sarin, but did not exhibit

acute symptoms at the time.1146

Summary. Chronic health effects of low-level sarin exposure. Acute toxic effects of high dose

exposure to the organophosphate nerve agent sarin have been characterized for many years in both

humans and animals. Recent studies have provided important insights into long term effects of lowerdose sarin exposure and indicate that, contrary to earlier assumptions, exposure to sarin at relatively low

doses can result in long-term biological effects. Animal studies have identified multiple central nervous

system effects of low-dose exposure that include persistent EEG abnormalities, cognitive and behavioral

changes, and alterations in regional expression of cholinergic receptors in the brain. Persistent or delayed

autonomic effects have also been described in animal studies, as well as neuroendocrine and immune

effects of low-level sarin exposure. Identified effects of low-dose sarin exposure in animal models have

varied, in some cases, over the duration of follow up, as well as with the dose, route, and pattern of

exposure. Humans exposed to sarin at levels sufficient to cause short-term symptoms have also been

shown to have persistent EEG abnormalities and subtle neurobehavioral decrements years after exposure.

Studies have also identified brain volume differences in several areas, audiovestibular abnormalities, and

elevated rates of symptoms such as vision problems, headache, fatigue, and mood disturbances that

persist for months or years in some individuals after exposure to symptomatic doses of sarin.

Effects of Combinations of Gulf War Neurotoxicant Exposures

It seems prudent to recommend avoidance when possible of untoward levels of simultaneous

exposure to incompletely studied combinations such as PB, permethrin, and DEET while at

the same time realizing that currently available evidence is insufficient to warrant abandoning

current doctrinal guidance concerning the military use of these compounds.

--U.S. Army Medical Research Institute of Chemical Defense, 2003951

As described throughout this report, military personnel serving in the Gulf War experienced a uniquely

complex mix of exposures in theater. In its 2004 report, the Committee pointed out the potential for the

diverse exposures encountered during the Gulf War, particularly those associated with neurotoxicity, to

have interactive effects that differed from those expected from individual exposures. The report included

a table that described the results of 28 animal studies that assessed effects of combinations of Gulf Warrelated exposures in a variety of models, most of which identified significant effects. More recent studies

have continued to report on effects of combinations of Gulf War exposures, providing more detailed

information on specific combinations and persistent effects. Results indicate that some, but not all

combinations of Gulf War exposures can act synergistically, and that specific effects vary with the

specific chemicals assessed and with the dosage, route, and pattern of exposures.

An extensive number of scientific studies and government-sponsored investigations has provided diverse

types of evidence related to health effects of individual Gulf War exposures. By comparison, information

on health effects of combinations of exposures encountered by military personnel in theater is quite

limited. Synergistic effects of mixtures of anticholinesterase pesticides have been described in the

medical literature for over 50 years.455 But most research on combined effects of the specific chemicals
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  167

associated with Gulf War service has been conducted in recent years, as part of the federal Gulf War

research effort. Nearly all information on combined effects of Gulf War exposures comes from animal

models. Ethical considerations generally prohibit exposing humans to combinations of toxicants for

purposes of understanding their synergistic effects, and observational studies of exposures in human

populations have generally focused on individual chemicals. Very little information on effects of

combinations of exposures has been provided by Gulf War epidemiologic studies, although such analyses

can and should be done. The few Gulf War studies that statistically evaluated interactions between two

selected exposures did not take into account effects of other prominent exposures, and so have provided

little useful information on synergistic effects of multiple exposures.

Available information from Gulf War studies and government reports, however, indicates that combined

effects of exposures in theater are potentially an important concern. Gulf War studies have consistently

indicated that exposures in theater were highly correlated. That is, veterans’ exposures during

deployment were “grouped” in identifiable ways, as opposed to being randomly experienced.241,458,1466

Important examples were identified in the RAND pesticide investigation, which found that Gulf War

personnel who used a large amount of one type of pesticide were also significantly more likely to use

other types of pesticides, and that individuals who used the most pesticides also used the most PB.458

Interactive effects of potentially hazardous chemicals can occur in different ways. Compounds can affect

the degree to which other chemicals are taken into the body or the efficiency with which they are

neutralized and eliminated from the body. Both processes can directly affect the dose of chemical

delivered to target organs, and can also affect the duration of the delivered exposure. Once in the body,

compounds can also interact with one another biologically, altering effects of one another on specific

biochemical processes in the brain or the periphery.

Dermal absorption of combined exposures.

Significantly, systemic exposure to certain chemicals such as pyridostigmine and DFP can

modulate the percutaneous absorption of an unrelated chemical. This scenario is not usually

assumed to be relevant to dermal risk assessment, and further supports the contention that

risk assessment of chemical mixtures cannot be based solely on individual chemical studies.

--J. Riviere, 20031294

Several studies have assessed the degree to which different mixtures of Gulf War exposures alter

absorption of insecticides and repellants, and their dermal effects. Those studies are summarized in Table

5. Findings from these studies demonstrated that skin absorption of repellants, and their penetration

through dermal layers, varies with the type of carrier used in the chemical preparation. Overall, results

indicated that permethrin absorption, alone, was generally minimal and that combined skin exposure to

both DEET and permethrin did not enhance absorption of either compound. Neither was absorption of

DEET or permethrin enhanced by topical exposure to PB or the organophosphate DFP, an exposure used

to simulate nerve agent exposure. Topical exposure to JP-8 fuel did, however, significantly increase

absorption of permethrin.

The major finding from these studies was somewhat unexpected. In contrast to topical applications, PB

in the circulation significantly increased both dermal absorption and skin penetration of permethrin. In

addition, the combination of circulating PB and DFP further enhanced absorption of both permethrin and

DEET, increasing permethrin absorption by nearly six-fold. Pyridostigmine also significantly attenuated

the dermal inflammatory response that normally develops in response to topically applied DEET and PB.

This group of studies therefore indicates that systemic PB increases the absorption and bioavailability of

permethrin. In combination with DFP, PB further enhances absorption of both permethrin and DEET. In

addition, circulating PB inhibits the protective inflammatory response normally stimulated by topical

exposure to either permethrin or DEET.
168  Effects of Gulf War Experiences and Exposures

Table 5. Effects of Combined Gulf War-related Exposures on Dermal Absorption

and Response to Pesticides and Insect Repellants

Study Exposure Model Key Findings

Baynes110

1997

DEET, permethrin, carbaryl applied to

rodent skin and perfused porcine skin

Absorption and penetration of each compound varied with carrier. DEET

did not enhance dermal absorption of permethrin or carbaryl.

Baynes111

2002

Permethrin applied to perfused

porcine skin and an in vitro model,

with or without PB, DFP, and DEET.

Intrarterial perfusion of PB and/or DFP sign. enhanced dermal absorption

and deposition of permethrin; DFP+PB yielded a 6-fold increase. Topical

DEET and topical DFP reduced permethrin absorption.

Riviere1295

2002

Permethrin, DEET, and JP-8 jet fuel

applied to perfused porcine skin

JP-8 enhanced permethrin absorption and penetration. DEET did not

affect absorption.

Riviere1294

2003

DEET applied to perfused porcine skin

and an in vitro model, with or without

PB, DEET, and permethrin

Intrarterial perfusion of PB and DFP sign. enhanced dermal absorption and

deposition of DEET. Topical DFP or permethrin had no effect on DEET

absorption.

MonteiroRiviere1064

2003

Permethrin and DEET applied to

perfused porcine skin and an in vitro

model, with or without PB and DFP.

Permethrin and DEET produced time-related increases in IL-8,

prostaglandin E2, and TNF alpha. Intrarterial perfusion of PB sign.

suppressed release of IL-8 and prostaglandin. TNF alpha effects differed

with different combinations and vehicles.

Abbreviations: DEET = diethyl-m-toluamide, PB = pyridostigmine bromide, DFP =diisopropyl fluorphosphate, an organophosphate used

as a nerve agent stimulant, sign. = statistically significant

Metabolic interactions of Gulf War-related toxicants. After potentially hazardous chemicals

enter the circulation, their adverse effects can be reduced or eliminated through biological

mechanisms that protect the body from chemical toxins. This involves a cascade of biological

processes that bind and metabolize the chemical, convert it to a form that is less toxic, and excrete it

from the body. Metabolic processes can also convert relatively harmless chemicals that enter the

body into more toxic forms. Toxicant metabolism is therefore an important determinant of the

degree to which chemical exposures produce adverse effects.

Investigators who first identified synergistic effects of combined exposure to PB and pesticides

hypothesized that the increased toxicity observed was due, in part, to competitive alterations in the

capacity for liver and plasma hydrolyzing enzymes to effectively neutralize the chemicals.16,17 Only

limited information was available at that time, however, concerning the specific chemical processes

involved in human detoxification of pesticides and related compounds.1440 Since then, a growing

body of research has provided important insights into how concurrent exposure to multiple chemicals

can alter metabolism of toxic substances.

Human enzymes involved in metabolizing toxic chemicals differ from those of rodents and other

species commonly used in toxicological research.1440,1525 Research sponsored by DOD in recent

years has begun to provide detailed information concerning the complex biochemical processes

involved in the metabolism of Gulf War-related chemicals in models that utilize human liver cell

fractions. Much of this work has been conducted by investigators at North Carolina State University.

Initial studies have characterized details of metabolism of PB, DEET, permethrin, chlorpyrifos, and

other pesticides by multiple cytochrome p450 enzyme isoforms, esterases, and other hydrolyzing

enzymes. Results consistently demonstrate that the effectiveness of liver hydrolysis of chemical

toxicants depends on the specific amounts and types of the different enzymes involved in

metabolizing each compound, which can vary significantly between individuals.305,611,1525
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  169

These studies have also identified diverse types of interactions that result in one chemical inhibiting

the metabolism of another. For example, the first step of permethrin metabolism involves ester

hydrolysis, a process that is inhibited by chlorpyrifos. Incubation of liver microsome or cytosol

fractions with chlorpyrifos prior to addition of permethrin results in dramatic inhibition of

permethrin metabolism.1312 A second type of interaction is illustrated by the observation that both

chlorpyrifos and carbaryl are hydrolyzed by the same cytochrome p450 isoform. Coincubation of

these two compounds in human liver microsomes yields significant inhibition of carbaryl

metabolism, even at low doses.1312

Overall, these studies have most consistently demonstrated that chlorpyrifos can markedly inhibit, in

vitro, metabolism of several other compounds associated with Gulf War service, including

permethrin, DEET and carbaryl. Several other compounds can also modulate metabolism of one

another.245 For example, PB, permethrin, and chlorpyrifos can either stimulate or inhibit DEET

metabolism, in different combinations.611,1701 Investigators from Duke University recently reported

that, using in vitro models, PB and permethrin both inhibited metabolism of one another in plasma.

DEET did not affect metabolism of either PB or permethrin, but both PB and permethrin

significantly inhibited DEET metabolism.22

Overall, research in this area provides evidence that metabolic interactions between combinations of

anticholinesterase compounds and insect repellants can significantly affect the degree to which these

compounds are effectively neutralized by the body. The extent to which such interactions

contributed to adverse effects of Gulf War exposures and the development of Gulf War illness can

not be deduced from studies of this type. But this information provides extremely useful insights

into specific biochemical processes potentially involved in interactions between combinations of

Gulf War exposures. Information from this research can also improve assessments that extrapolate

findings on biological effects of Gulf War exposures from animal studies to humans.

Scientific understanding of the specific biological effects of combinations of chemical exposures on

human health is relatively limited. But as described in the Committee’s 2004 report, a relatively

large number of studies have been conducted in recent years, as part of the federal Gulf War research

effort, to evaluate biological effects of combinations of Gulf War-related exposures in animal

models. These studies have demonstrated diverse effects resulting from combinations of

neurotoxicant exposures, which differ from those of individual chemicals.

Effects of mixtures of PB and Gulf War-related pesticides and repellants. The largest number

of federally-sponsored studies evaluating combined effects of Gulf War-related neurotoxicants have

assessed effects of mixtures of PB, pesticides, and insect repellants on a variety of central nervous

system and behavioral parameters. Findings from these studies are summarized in Table 6. As

shown, the earliest studies of this type were conducted in the middle and late 1990s, and used

exposure protocols that differed in important ways from Gulf War-related exposures. These studies

were important, however, for providing a first look at the potential for synergistic effects of

combinations of Gulf War-related exposures on the central nervous system.

Since 2001, multiple studies have used animal exposure models that provided a closer approximation

to the types and levels of exposures experienced by Gulf War military personnel. Many of those

studies have been conducted by Duke University investigators, and are noteworthy for two important

reasons. First, the exposure models used were specifically developed to parallel exposures during

the Gulf War. For example, permethrin and DEET were administered topically to the skin and PB

was given orally at doses, calibrated by body weight, comparable to those of veterans. Second,

many of the Duke studies evaluated effects that developed after an extended exposure period. Rats

were typically given PB and pesticides in a repeated dosing schedule for 15-30 days,
170  Effects of Gulf War Experiences and Exposures

Table 6. Animal Studies Evaluating Combined Effects of PB, Pesticides, and Insect

Repellants Used in the Gulf War on the Brain and Behavior

Study Exposure Model Key Findings

AbouDonia16

1996

High doses of oral PB, subQ

DEET, subQ chlorpyrifos to

hens for 2 months

All combinations of 2 compounds produced multiple signs of toxicity (cholinergic

symptoms, locomotor dysfunction, spinal cord swelling) that sign. exceeded single

compounds, especially with PB+chlorpyrifos combination. Three chemicals

combined yielded sign. greater toxicity than 2 chemicals combined.

AbouDonia17

1996

High doses of oral PB, subQ

DEET, subQ permethrin to

hens for 2 months

Combinations of 2 compounds produced multiple signs of toxicity (gait

abnormalities, weakness, tremors, decreased locomotor activity) that sign.

exceeded single compounds. Combination of all 3 chemicals yielded sign. greater

toxicity, spinal cord abnormalities than 2 chemicals combined.

Bucholz185

1997

Moderate dose of oral PB,

very low dose of subQ

permethrin to rats for 10 days

PB sign. decreased the amount of permethrin in the brain.

Chaney228

1999

High doses of PB and DEET

given once IP to mice

Combination produced seizures and death by mechanisms that differed from single

compounds. Effects were not altered by preadministration of anticonvulsant drugs.

Chaney229

2000

High dose DEET and varying

doses of PB given once IP to

rats

1 hour post exposure, DEET alone had no effect on AChE activity, PB alone did not

affect brain AChE activity. High dose PB+DEET produced 40% reduction in whole

brain AChE activity.

Hoy649

2000

High dose PB, DEET by

gavage, permethrin IP given

once to rats

2 hours post exposure, single compounds had minimal effects. Permethrin

combined with PB or DEET sign reduced locomotor speed in males but not

females. Serum levels of permethrin increased with coadministration of PB.

Hoy650

2000

High dose PB, DEET by

gavage, permethrin IP given

daily for 7 days to rats

24 hours after last dosing, no effects with single compounds. PB+DEET produced

sign. reduced locomotor speed; permethrin + DEET sign. increased speed in male

rats only.

Van

Haaren1704

2000

GW-relevant dose of PB by

gavage, high dose of

permethrin IP given for 7

days to rats

Serum permethrin levels sign. greater in rats given PB, sign. greater in female than

male rats. PB alone caused sign. learning deficits that were not affected by

permethrin.

AbouDonia13

2001

GW-relevant doses (also

0.1x, 10x GW doses) of

DEET and permethrin

dermally applied for 60 days

to rats

DEET alone reduced blood brain barrier permeability in brainstem, DEET+

permethrin decreased permeability in cortex. 30-60 days after exposures initiated,

all single compounds produced sign. reductions in sensorimotor performance;

some deficits increased with time and dosage, and were sign. greater with

combined exposures at highest doses.

AbouDonia14

2001

GW-relevant doses of PB by

gavage for 15 days, dermally

applied DEET, permethrin

daily for 45 days to rats

Locomotor performance on different tests was sign. reduced for each compound

alone, with deficits increasing over time. Greatest deficits with PB; no interactive

motor effects between compounds. PB alone produced 40% decline in midbrain

AChE activity. DEET produced sign. increase in brainstem AChE activity, and

permethrin produced sign. increase in cortical AChE activity. PB + DEET and/or

permethrin produced sign. decrease in brainstem AChE.

Abu-Qare20

2001

GW-relevant doses of

permethrin and high dose of

DEET dermally applied once

to rats

Brain mitochondria assessed at multiple time points 0.5 – 72 hours after exposures.

Starting 24 hours after exposure, rats exposed to both DEET and permethrin had

sign. increased release of brain mitochondrial cytochrome c. No effect with single

exposures.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  171

Table 6. (cont.) Animal Studies Evaluating Combined Effects of PB, Pesticides, and Insect

Repellants Used in the Gulf War on the Brain and Behavior

Study Exposure Model Key Findings

AbdelRahman5

2001

GW-relevant doses of DEET

and permethrin dermally

applied for 60 days to rats

DEET and permethrin, individually and combined, produced hypertrophy of

astrocytes and sign. increased GFAP expression in hippocampus and cerebellum.

All treatments resulted in sign. neuronal cell death in motor cortex, hippocampus,

and dentate gyrus. Neuronal effects were attenuated with combination of DEET

and permethrin.

Van

Haaren1705

2001

Variable doses of PB and

DEET by gavage, high doses

of permethrin IP in rats

With PB treatment, rats had sign. decreased behavioral responses in doseresponse manner. Only highest exposures to DEET and permethrin sign. reduced

behavioral responses. Synergistic responses observed only with low dose PB

combined with low dose DEET or permethrin. Some effects differed in male vs.

female rats.

Vogel1727

2002

Assessment of DFP binding,

in combination with varying

low dose PB and permethrin,

given in feed to mice

Outcomes observed 48 hours after dosing. Permethrin produced sign. (25-30%)

increase in DFP binding in the brain. PB reduced DFP binding in plasma, red blood

cells, muscle, and brain.

AbdelRahman6

2002

GW-relevant doses of PB by

gavage for 15 days, dermally

applied DEET, permethrin

given daily to rats for 28 days

with/without 5 min restraint

stress to rats

All chemicals together, plus stress, produced disruption of blood brain barrier in

cingulate cortex, dentate gyrus, thalamus, and hypothalamus but not in other brain

regions. Neuronal death and increased GFAP were observed in those four brain

regions. Exposures plus stress also sign. reduced AChE activity and m2 receptors

in the forebrain. Minimal effects of combined chemicals alone or stress alone.

AbdelRahman3

2004

GW-relevant doses of PB by

gavage, dermally applied

DEET and permethrin given

daily to rats for 28 days

with/without 5 min restraint

stress

Following up above study, evaluated changes in brain regions in which no

disruption of blood brain barrier occurred. Combination of chemicals and stress

yielded sign. decreased AChE activity in midbrain, brainstem, and cerebellum, and

decreased m2 cholinergic receptor binding in midbrain and cerebellum. Stress plus

chemicals also produced sign. neuronal death and increased GFAP in cerebral

cortex and hippocampus. These changes not seen with stress or combined

chemicals alone.

AbdelRahman

4

2004

GW-relevant doses of

dermally applied malthion,

DEET and permethrin given

daily to rats for 30 days

24 hours after last treatment, all behavioral tests (beam walk time and score,

inclined plane, forepaw grip) showed sign. impairment with all single and combined

exposures. DEET combined with either malthion or permethrin produced sign.

increase in plasma BChE activity. Permethrin plus either malthion or DEET

produced sign. reduced midbrain AChE, while DEET and permethrin alone sign.

increased cortical AChE. Treatments also associated with reduced neuron density

in several brain regions.

AbouDonia10

2004

GW-relevant doses of PB by

gavage for 15 days, dermally

applied DEET, permethrin

(also 0.1x,10x GW doses)

given daily for 60 days to rats

24 hours after last treatment, PB alone, DEET+ permethrin produced sign.

locomotor and behavioral deficits (beam walk score and time, incline plane,

forepaw grip). PB alone slightly reduced plasma BChE activity, but PB + DEET or

permethrin sign. increased plasma BChE activity. DEET + permethrin sign.

increased brainstem AChE activity. PB+DEET+permethrin sign. reduced AChE

activity in midbrain. Results similar at different doses.

Abbreviations: DEET = diethyl-m-toluamide, PB = pyridostigmine bromide, DFP =diisopropyl fluorphosphate, an organophosphate used

as a nerve agent simulant, subQ = subcutaneous, IP = intraperitoneal administration, GW = Gulf War, GFAP = glial fibrillary acidic

protein, AChE = acetylcholinesterase, BChE = butyrylcholinesterase, sign. = statistically significant
172  Effects of Gulf War Experiences and Exposures

and up to 60 days in different studies, an exposure profile that parallels that experienced by many

Gulf War veterans. As a result, these studies have been extremely valuable not only for describing

synergistic effects of multiple exposures, but also for characterizing central nervous system effects of

single exposures, delivered orally and to the skin using a repeated dosing schedule over an extended

period of time. As summarized in Table 6, these studies have produced an extensive number of

detailed findings.

Effects of high dose exposures, evaluated by earlier studies, consistently indicated that different

combinations of PB, DEET, permethrin, and chlorpyrifos yielded significantly greater neurotoxicity

than single exposures. Synergistic neurotoxic effects were reflected by overt clinical signs of ill

health, tissue damage in brain and spinal cord, behavioral changes, and reduced levels of AChE

activity in the brain. These studies also suggested that moderate-to-high exposure to PB can effect

levels of permethrin, increasing it in serum649,1704 and decreasing it in the brain.185 Two studies also

suggested that immediate effects of high-dose exposures differ from effects that develop shortly

thereafter. Male rats exposed to both permethrin and DEET (but neither compound alone) had

significantly reduced locomotor speed after two hours,649 but significantly increased speed after 24

hours.650

Later studies that used more Gulf War-relevant exposure protocols and doses identified diverse

central nervous system effects following both individual and combined exposures. Some of the most

noteworthy findings from these studies were effects observed from individual exposures to PB and

insect repellants, effects not observed in previous studies that used single high dose and/or short term

exposures. Identified changes resulting from a repeated dosing schedule were most pronounced, and

most consistently demonstrated with PB. All four studies that evaluated behavioral measures

following Gulf War-relevant doses of PB given orally to animals in a repeated and extended dosing

pattern identified significant alterations in learning and/or locomotor activity.10,14,1704,1705 Additional

central nervous system effects of exposures to PB, permethrin, and DEET alone were noted in

relation to low-dose, repeated administration, effects not observed in earlier studies that evaluated

effects of higher dose, single dose, and short-term exposures. As summarized in Table 6, these

effects included alterations in blood brain barrier permeability, regional alterations in brain AChE

activity, and behavioral effects.

In addition, studies utilizing Gulf War-relevant protocols have identified diverse interactions

between different mixtures of cholinergic neurotoxicants and insect repellants used in the Gulf War.

It is important to note that different studies have evaluated different exposure combinations and

durations, and that the majority of synergistic effects reported have been identified by only one or

two studies, usually from the same team of investigators. These studies are generally consistent in

showing that combined exposures can produce synergistic effects. However, many of the specific

effects identified can only be considered preliminary, pending additional investigation. It is also

important to note that relatively few three-way interactions were identified in these studies. That is,

few synergistic effects resulting from combinations of three compounds were identified that differed

from those observed with only two of the compounds.

As detailed in Table 6, a variety of synergistic effects have been reported in relation to combined

exposure to PB and DEET in rat models, which differ from those observed with PB or DEET

individually. These are generally similar to effects reported with combined exposure to PB and

permethrin, and include significantly decreased AChE activity in brainstem,14 increased plasma

levels of BChE,10 and behavioral deficits at low-dose exposures that were not observed with higher

doses.1705 Synergistic effects resulting from combined exposure to DEET and permethrin in rat

models include reduced permeability of the blood brain barrier in the cortex,13 reduced AChE

activity in the midbrain,4increased AChE activity in brainstem,10 and increased production of brain

mitochondrial cytochrome c.20 The combination of DEET and permethrin was also reported to
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  173

attenuate the degree of neuronal cell death observed in the hippocampus and cerebellum following

exposure to either DEET or permethrin alone.5

Two studies have reported significant interactive effects between exposure to three chemicals

together—PB, DEET, and permethrin—and a mild stressor. This combination produced significant

increases in blood brain barrier permeability in four regions—the cingulate cortex, the dentate gyrus,

the thalamus, and the hypothalamus.3,6 Investigators also reported glial fibrillary acidic protein

(GFAP) staining in those regions, an indicator of astrocytic response to underlying neural injury.

This response was consistent with reported indicators of neuronal cell death in those regions, as well

as in the cerebral cortex and hippocampus.3 None of these changes was observed with exposure to

the three chemicals without the stressor, or with the stressor alone.

Findings indicative of neuronal cell death in these studies have been challenged by a suggestion that

the dark neurons described as indicating cell death in exposed animals may be an experimental

artifact that can be produced by a number of experimental conditions.726 The Committee was not in

a position to determine the validity of this concern, but notes that the neurons in question were

observed only in some subgroups of exposed animals and not in unexposed animals, and were

accompanied by other indicators of neurotoxicity, such as astrocyte hypertrophy and increased

GFAP levels.3,5,6

In addition to the published animal studies summarized in Table 6, a DOD report on a project

conducted by the U.S. Air Force Research Laboratory indicates that combined exposure to low doses

of PB, DEET, JP-4 jet fuel, and stress produced significant neurobehavioral deficits and increased

levels of serotonin in multiple brain areas, increases that were sustained at least 88 days after

exposure.948

A limited number of animal studies have also evaluated combined effects of pesticides and PB on

outcomes not directly related to neurological function and behavior. Increased urinary excretion of

markers of oxidative stress and DNA damage have been reported in rats after combined low dose

exposure to PB, DEET, and permethrin.18,19 Apoptosis in testicular germ cells and spermatocytes

have also been reported in rats following low dose, combined exposure to PB, DEET, and

permethrin, an effect that were significantly enhanced by a moderate stressor.15 A series of animal

studies sponsored by the British Ministry of Defence generally found no interactive effects between

PB and receipt of multiple vaccines given to British troops in the Gulf War, as detailed in the earlier

discussion of vaccines. Combined exposure to DEET, PB, and JP-8 jet fuel in a mouse model

produced only limited effects on the immune response.1187 Higher level exposures to combinations

of PB, permethrin, and DEET have been shown to significantly increase the lethality of each

compound.986,1076 Caffeine and adrenergic drugs have also been shown to potentiate the lethality of

PB.227

Preliminary insights concerning the potential for biological interactions between Gulf War-related

pesticides have also been provided by cell culture studies. Combinations of lindane, malthion, and,

permethrin have been reported to act synergistically to increase markers of oxidative stress, stimulate

increased levels of antioxidant enzymes, and produce necrotic and apoptotic cell death in

thymocytes.1151,1152 And, using a novel in vitro screen for neurotoxicity, significant interactive

effects have also been demonstrated when chlorpyriphos was combined with pyrethrum or with a

solvent commonly used in pesticide formulations.77

Just one human study has specifically evaluated effects of combined exposure to DEET, permethrin, and

PB. Investigators from the U.S. Uniformed Services University of the Health Sciences conducted a

placebo-controlled crossover trial to assess effects of short term, low level exposure to PB, DEET,

permethrin, and stress in 64 healthy, mostly military, volunteers.1322,1323 During one and a half days in a
174  Effects of Gulf War Experiences and Exposures

clinical research unit, subjects wearing untreated or permethrin-treated uniforms took a total of four 30

mg. PB tablets, or placebo, at eight hour intervals. They also applied a measured amount of 32 percent

DEET cream, or placebo, three times to their neck, face, and legs, with gloved hands, at 12 hour intervals.

Following the last use of DEET and PB, subjects were given a one hour rest session or a one hour stress

session that involved marching on a treadmill with a weighted backpack. During the treadmill session,

subjects watched a video depicting battle scenes from popular movies, and also performed mental

arithmetic stress tests. The trial identified few differences between treatment and placebo groups on

measures of neurobehavioral function, physical performance, or blood hormone levels.

The study was useful in showing that brief use of these products, at levels similar to or below those

directed by current military policy, does not produce acute, observable adverse effects in military

personnel. It provides only limited information directly relevant to the Gulf War scenario, however, in

light of the types of DEET, permethrin, and stress applications evaluated in comparison to what is known

about types and patterns of pesticide and repellant use during the Gulf War.

Interactive effects of PB with sarin. As previously described, the 1990-1991 Gulf War was the

first time the military had used PB on a wide scale as a preventive measure in the event of nerve gas

exposure. Since the war, questions have been raised about the potential for PB to have interacted

with low-level sarin exposure to produce long-term adverse effects. Multiple studies have

specifically assessed combined effects of exposure to PB and sarin, as summarized in Table 7. As

shown, these studies have utilized a variety of designs and dosing methods to evaluate the potential

for mixtures of PB and sarin to produce short and long-term effects.

Most of the studies listed in Table 7 identified significant effects resulting from exposure to sarin or PB,

individually. These included effects on the brain and behavior, on autonomic function, and on peripheral

metabolizing enzymes and muscle function. In addition, a number of interactive effects were reported

that exceeded effects of PB and sarin individually. These include acute and long-term EEG

alterations,1706 increased levels of cholinergic M2 receptors in the cortex and brain stem,11 increased

startle threshold and locomotor activity,1377 time-limited increases in regional cerebral blood flow1378 and

autonomic alterations in heart rate variability,1379 and alterations in brain levels of acetylcholine.1403 No

studies identified interactive effects between PB and sarin on AChE levels in the brain.

It is important to note that many of the significant PB/sarin interactive effects identified in these studies

were initially observed days or weeks after dosing ended. Studies also identified a number of effects that

changed over time. Some alterations were most pronounced two or four weeks after exposure, with

values similar to unexposed controls at later time points. Findings therefore provide some answers to

questions concerning potential interactions between sarin and PB, but raise others. Most importantly, it is

unknown whether time-related effects identified by some studies persisted or changed further at time

points beyond those included in the study. Longer-term effects appear to be plausible, in light of longterm effects described following exposure to sarin alone, as well as results of some of the sarin/PB studies

listed in Table 7.

For example, the 2003 study from researchers at the Army Medical Research Institute of Chemical

Defense and the Los Angeles VA identified delayed behavioral changes that potentially reflect a

hypercholinergic state, after exposure to sarin and PB. These changes were first observed 16 weeks

after exposure, the latest time point evaluated, so it is not known if they were sustained for a longer

time.1377 A separate study, using a similar dosing protocol, evaluated choline and acetylcholine

levels following exposure to PB and sarin. Exposure to AChE inhibitors, in general, leads to an

acute increase in acetylcholine. In the Army study, rats exposed to sarin had significantly elevated

cerebral acetylcholine levels four weeks after exposure.1403 In comparison, rats exposed to both sarin

and PB had significantly reduced levels of acetylcholine between 2 and 4 weeks after exposure.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  175

Table 7. Animal Studies Evaluating Combined Effects of Sarin and Pyridostigmine Bromide

Study Exposure Model Key Findings

Central and behavioral effects

Abou-Donia11

2002

GW-relevant oral dose of PB

for 15 days, and single low-tohigh sarin dose IM on day15

in rats

At 7 and 15 days post exposure, sarin and PB individually produced sign.

sensorimotor deficits. Sarin+PB together produced sign. sensorimotor deficits that

worsened with time, sign. increase in m2 cholinergic receptor binding.

Scremin1377

2003

PB given in drinking water,

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

Effects varied over time. Interactive effects of PB+sarin first observed at 16 weeks

post exposure (sign. increased nociceptive threshold, increased startle threshold,

increased locomotor activity, increased habituation). Sarin alone produced

increased startle response and down regulated muscarinic receptors in several

brain regions 2 weeks post exposure. No effects on brain AChE levels.

Van Helden1706

2004

PB given subQ to marmosets,

prior to varying doses of sarin

(5 hours in air)

PB+sarin treated animals exhibited EEG abnormalities at lower sarin doses than

animals exposed to sarin alone. One year after exposure, PB+sarin exposure

associated with sign. more EEG alpha frequency bursts than sarin alone.

Scremin1378

2005

PB given in drinking water,

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

Effects varied over time. At 2 weeks post exposure, PB+sarin produced sign.

increased cerebral blood flow in several areas. Similar patterns with sarin only at 4

weeks. Few differences remained at 16 weeks.

Scremin1379

2006

PB given in drinking water,

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

2 weeks post exposure, heart rate sign. reduced in single and combined exposed

animals. Sarin+PB produced sign. decrease in low frequency HRV at midnight and

early morning, and sign increase in total power. Minimal HRV differences at 4 and

16 weeks. No differences in locomotor measures between groups.

Shih1403

2006

PB given in drinking water,

0.5 LD50 sarin dose subQ,

3x/week for 3 weeks in rats

Sign. regional differences in brain levels of choline and acetylcholine at 2, 4, and 16

weeks post treatment. Overall, acetylcholine levels were sign. lower with sarin+PB

than with sarin alone at 2 and 4 weeks, but not at 16 weeks.

Peripheral effects

Abu-Qare19

2001

Single moderately high oral

dose of PB and moderately

high sarin dose IM in rats

48 hours after exposure, rats who received PB+sarin excreted sign. elevated levels

of 2 markers of oxidative stress in urine. No oxidative stress markers with either

PB or sarin alone.

Husain657,658

2003, 2004

10 weeks exercise, with GWrelevant doses of oral PB and

low-dose sarin subQ at weeks

5-6 in mice

Four weeks after exposure, exercise+sarin and exercise+PB yielded sign.

decreased respiratory exchange, plasma BChE, peripheral and central AChE

activity, and increased plasma CK activity. Little indication of 2-way interaction of

PB+sarin or 3-way interaction of exercise+PB+sarin.

Dabisch303

2006

GW-relevant doses of PB

injected in rats IM 2x/day for 8

days, followed by sarin

inhalation

Pupil miotic response to PB decreased over the treatment period, indicating

increased tolerance to PB. PB pretreatment did not affect initial pupil response to

sarin, but shortened pupil recovery time.

Abbreviations: GW = Gulf War, PB = pyridostigmine bromide, IM = intramuscular, AChE = acetylcholinesterase, BChE = butyrylcholinesterase,

EEG = electroencephalogram, HRV = heart rate variability, LD50 = dose that is lethal to half of exposed animals, sign. = statistically significant
176  Effects of Gulf War Experiences and Exposures

At 16 weeks, brain acetylcholine levels had “rebounded” in rats exposed to both compounds, and

were nonsignificantly higher than levels in rats exposed to sarin alone. These findings are unique,

and suggest an unexpected course for time-related changes in brain acetylcholine levels following

combined exposure to PB and sarin. It is unknown, however, if brain acetylcholine levels continued

to increase in rats exposed to both sarin and PB after 16 weeks.

It is also not known the extent to which alterations in brain chemistry sustained over a limited period

of time, such as the 2-16 week time frame in most of the PB/sarin studies, can lead to other,

downstream biological effects that have not been assessed in studies focused on immediate

outcomes. In the real-world situation of the Gulf War, neurochemical alterations sustained over a

period of days or weeks might potentially have been the first in a cascade of additional effects

triggered by the initial exposures. Alternatively, changes that occur within a limited time frame

might alter the impact of other exposures encountered during that time frame, exposures that might

not normally have produced adverse effects. Therefore, although a number of synergistic effects

have been described following repeat, low-level exposure to sarin and PB, the long-term implications

of those effects remain to be more fully elucidated.

Summary. Health effects of combinations of Gulf War exposures. Gulf War veterans were

exposed to unique mixtures of neurotoxicants during deployment, and possible health effects resulting

from those mixtures are an important concern. Studies indicate that veterans exposed to one type of

neurotoxicant, for example, PB or a certain class of pesticide, were usually exposed to others. Little

information on health effects of combined exposures is available from studies of Gulf War veterans or

other human populations. Animal studies have demonstrated that combinations of Gulf War-related

exposures can interact at different stages of exposure, and that some combinations produce effects that

differ from those of individual exposures. Studies have indicated, for example, that pyridostigmine in the

circulation significantly increases absorption of permethrin through the skin, but topically applied DEET

does not. Recent research has also described mechanisms through which toxicants inhibit metabolism of

other toxicants in liver cells and consistently indicate that the organophosphate pesticide chlorpyrifos

significantly inhibits the breakdown of other compounds, including permethrin and DEET.

The largest number of studies has evaluated combined effects of PB, DEET, and permethrin on the brain

and behavior. Early studies reported that high doses of mixtures of these chemicals produced

significantly greater neurotoxicity than each compound individually. More recently, studies have

assessed effects of combinations of these exposures using dosing levels and patterns comparable to those

experienced by veterans in the Gulf War. These studies have identified multiple effects of single

chemicals using low-dose, repeated exposures, effects not identified in earlier studies using higher dose

exposures. Significant effects from mixtures of two or more exposures have also been identified, effects

that did not occur with individual exposures. These include significant neurobehavioral changes, and

regional alterations in the blood brain barrier and brain AChE activity, which varied with different

chemical combinations. A limited number of neurochemical, autonomic, and behavioral effects have also

been identified in relation to combined exposures to PB and sarin.

Overall, these studies consistently indicate that combinations of Gulf War-related neurotoxicants can

produce effects that differ from those of individual exposures. Important questions remain, however,

concerning the contribution of these effects to Gulf War illness. Existing studies provide little

information on the degree to which interactive effects persist for an extended period of time after

exposure. There is also little information on central effects of OP pesticides or the organochlorine

lindane, in combination with other Gulf War neurotoxicants. In addition, Gulf War epidemiologic studies

have not systematically evaluated combinations of self-reported and/or modeled exposures in theater in

relation to Gulf War illness and other health outcomes.
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  177

Research on the Health of Gulf War Veterans in Relation to Cholinergic and Related

Neurotoxicants

DG was a Staff Sergeant with the 1165th Military Police Company. He recalled being

awakened at 3:30 a.m. The Battalion NBC NCO was announcing that they were under

chemical attack. An M-256 kit registered a positive reading for a chemical agent. They went

to MOPP level 4 for four hours. Afterward, all of them had runny noses. When asked if people

were made sick from the attack, DG responded that most people were already sick from the

pyridostigmine bromide pills. He said that they had been taking them for two or three days

before the attack and that ‘a lot of people got sick and three or four had to be medevaced out.’

DG currently suffers from headaches, fatigue, joint and muscle pain, an inability to

concentrate, recurring rashes, irritability, night sweats, insomnia, diarrhea, gastrointestinal

problems, dizziness, blackouts, excessive photosensitivity, sore gums, swollen lymph nodes,

and a spot on his brain.

--1994 Senate Committee report on Gulf War veteran1688

A substantial proportion of U.S. military personnel who served in the Gulf War, including most ground

troops, were exposed to one or more of the neurotoxicants described in this section, in different doses and

combinations. Toxicological research in animal models indicates that compounds of this type can have

persistent effects on the brain, and on behavioral, autonomic, and neuroendocrine parameters, effects that

are generally compatible with types of biological alterations observed in Gulf War veterans. Studies in

human populations have identified elevated rates of persistent symptomatic illness and subtle neurological

alterations in relation to subsymptomatic exposure to pesticides and in relation to symptomatic, but

sublethal, exposure to sarin. These research findings are extremely useful but, as previously described, do

not precisely reflect characteristics of Gulf War exposures and Gulf War illness. Studies in the general

population and in animals provide an indication that exposures of this type could have contributed to Gulf

War illness. But given the complexity of the Gulf War exposure scenario and the unusual nature of Gulf

War illness, it is important to evaluate studies of Gulf War veterans to determine what available evidence

most clearly indicates did cause Gulf War illness.

Research findings on the effects of neurotoxicant exposures on the health of Gulf War veterans differ

from those of all other exposures evaluated by Gulf War research studies. Epidemiologic studies have

consistently identified two Gulf War-related exposures—PB and pesticides—to be significantly

associated with Gulf War illness, after adjusting for effects of other exposures in theater. Clinical studies

have also identified objective measures that distinguish Gulf War veterans exposed to PB, pesticides, and

nerve agents, from veterans who were not exposed. Neurotoxicant-related effects have been identified on

neuroimaging scans, neurobehavioral assessments, and neuroendocrine measures. Pyridostigmine and

pesticides are also the only Gulf War-related exposures that previous government reviews and reports

have suggested may be associated with Gulf War illness.504,1632 Overall, the many different types and

sources of evidence evaluated by the Committee—information on exposure patterns, toxicological and

human population research, and studies of Gulf War veterans—most strongly and consistently implicate

PB and pesticides as causal factors in Gulf War illness.

Results from Gulf War epidemiologic studies that evaluated independent associations of PB, pesticides,

and variables related to chemical agents with symptomatic illness in Gulf War veterans are summarized in

Table 8. Studies listed are those that controlled for confounding effects of multiple exposures in theater

since, as described, failure to account for these effects can introduce serious error into study findings.

The overall consistency of findings related to PB and pesticides is particularly noteworthy given the

diversity of methods used to assess both exposures and symptomatic illness in different Gulf War veteran

populations. Results related to the association of symptomatic illness with chemical agents, as shown,

are mixed. Detailed findings from all assessments of associations of symptomatic illness in Gulf War
178  Effects of Gulf War Experiences and Exposures

veterans with PB, pesticides, and variables related to chemical agents are provided in Appendix A.

Results from these studies are summarized below.

The health of Gulf War veterans in relation to pyridostigmine bromide (PB). Studies of Gulf

War veterans have assessed veterans’ use of PB during deployment in different ways. Most simply posed

a yes/no question, asking veterans whether they took the small white pills, variously described as “anti

nerve gas pills” or “NAPPs” in the U.S. and “NAPs” in the U.K. Some asked veterans to report how

many pills they took, or how many days they took the pills. Several studies also asked veterans if they

had experienced side effects from PB pills when they took them during the war.

SH, assigned to the 145th Transportation Company, also reported getting very sick from the

nerve agent pre-treatment pills. He reported severe nausea and diarrhea that did not abate

until he stopped taking the pills after two days. He recalled thinking that ‘if I’m going to feel

like this I might as well be dead.’

-- 1994 Senate Committee report on Army Gulf War veteran1688

Acute side effects from PB during the Gulf War. Surveys of military personnel during the Gulf War

indicated they experienced higher-than-expected rates of side effects from taking PB. Medical officers

for the XVIII Corps reported that about half of the soldiers in their units had side effects.781

Gastrointestinal effects were most common, but headaches were more problematic than had been

expected. A small survey of Army personnel, mostly aviators, conducted just before their return from

theater indicated that 37 percent of those who took PB had “problems” with it.207 Few details are

provided from these surveys, but both suggest higher rates of side effects from taking PB during the Gulf

War than is typically reported for healthy individuals evaluated in research studies.271,272,1323 An even

higher proportion of Israeli soldiers (75%) who took PB during the Gulf War were reported to have side

effects.1396 The types of symptoms reported by these soldiers were also reported to differ from those most

commonly seen in clinical settings, with Gulf War military personnel reporting higher rates of central

nervous system complaints (headaches, cognitive difficulties) than typically affect healthy subjects in

clinical studies.460

Gulf War veterans in the U.S. and the U.K. who reported they had acute side effects from PB during the

war have also been shown to have significantly higher rates of symptomatic illness, six to 10 years after

the war.241,564 These findings are of particular interest, because both studies found an association of PB

side effects with Gulf War illness, after controlling for effects of other exposures during the war. A third

study, of Ohio reservists who served in the Gulf War, reported a significant correlation between adverse

reactions to “medications” during the war and poorer overall health status since the war.1373

Association of PB with multisymptom illness in Gulf War veterans. Like most other exposures

evaluated in Gulf War epidemiologic studies, PB use was reported to be significantly associated with Gulf

War-related multisymptom illness in nearly all studies, when results were not adjusted for effects of other

exposures during the war, as detailed in Appendix A-9. But unlike most other exposures, the use of PB

in theater was also consistently associated with Gulf War illness in studies that conducted more credible

analyses, adjusting for possible confounding effects of other exposures. As shown in Table 8, PB use

and/or PB side effects were significantly associated with Gulf War-related symptomatic illness in all six

of the six studies that evaluated this association, while controlling for effects of other exposures.

Dose-response effects, that is, a graded association between the amount of PB taken and greater risk of

illness or more severe illness, have also been identified by multiple studies. Two U.S. studies have

reported that taking less than 22 PB pills during the war was associated with a modestly increased risk for

Gulf War illness, but that 22 or more PB pills was associated with a significantly increased risk for Gulf

War illness, after controlling for effects of other exposures.1466,1804 This is the equivalent of taking PB, at
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  179

Table 8. Associations of Pyridostigmine Bromide, Pesticides, and Chemical Agents

with Multisymptom Illness in Gulf War Veterans

Association of Neurotoxicant

Exposure with Symptomatic Illness

(adjusted for effects of other exposures)

Study

Gulf War

Veterans Studied

Symptomatic Illness

Evaluated PB

Pesticides,

Repellants

Chemical

Agents Additional Information

Haley564

1997

249 GWV Navy

Seabees Haley syndromes + 1 + +

PB side effects “dose response”

effect.; DEET dose response effect

Ishoy695

Suadicani1507

1999

686 Danish GWV Gastrointestinal and/or

neuropsych symptoms + ns

Nisenbaum1124

2000

1,002 Air Force

GWV

Chronic multisymptom

illness 464 + + +

Cherry241

2001 7,971 U.K. GWV Overall symptomseverity + 2 +

PB dose response effect

Pesticide dose response effect

Spencer1466

2001

1,119 GWV from

Washington,

Oregon

Gulf War unexplained

illness (study defined) + ns

PB dose response effect; DEET was

only pesticide evaluated in model

Gray527

2002

3,831 GWV Navy

Seabees

Gulf War illness

(study defined) + + +

Wolfe1804

2002

945 U.S. Army

GWV

Chronic multisymptom

illness464 + ns

PB dose response effect

no association with “pesticide odor”

Abbreviations: PB = pyridostigmine bromide, GWV = Gulf War veterans

Notes: blank cell = association not assessed in multivariable model, + = statistically significant association, ns = association not statistically

significant, 1 = association with PB side effects only, 2 = association with PB use and PB side effects

recommended doses, for more than seven days. Other studies have reported that veterans who took PB

during the war are at greater risk for more severe multisymptom illness,1124 and that veterans who took

PB for longer periods of time have more severe symptomatic illness than those who took PB for shorter

periods.241 Dose response effects for PB in relation to chronic ill health and multisymptom illness have

also been reported by three studies that did not control for confounding effects of other

exposures.788,789,938,1371-1373 Overall, the highly consistent association of PB with multisymptom illness in

epidemiologic studies analyzed to minimize effects of confounding, as well as identified dose response

effects of PB, provide compelling evidence that supports PB as a causal factor for Gulf War

multisymptom illness.

Association of PB with other health outcomes in Gulf War veterans. In addition to PB’s association

with Gulf War multisymptom illness, a number of studies have identified significant associations between

PB use and measured clinical outcomes in Gulf War veterans. Veterans who used PB during the war

have been reported to have significant decrements on neurobehavioral measures, compared to veterans

who did not use PB.1512 Studies have also identified significant neuroendocrine alterations in relation to

veteran-reported PB use. Specifically, veterans who took PB during the war exhibited significantly

greater cortisol suppression with dexamethasone (DEX) challenge, and significantly reduced 24-hour

levels of adrenocorticotropic hormone (ACTH), compared to veterans who did not take PB. Neither

measure was associated with PTSD or with combat stress during the war.502,503 Additional studies have

indicated that PB use was not associated with handgrip strength,738 but may be associated with more

subtle alterations in peripheral nerve function.241,1186
180  Effects of Gulf War Experiences and Exposures

The Committee has reviewed results from two additional federally funded projects that have not yet been

published, but also suggest an association between PB and clinical measures. One study, conducted by

Midwest Research Institute, found that use of PB is associated with a dramatic, 40-fold increased risk for

Gulf War illness among veterans with butyrylcholinesterase (BChE) genotypes associated with very low

BChE activity.1353 Preliminary findings from a second study, conducted by researchers at Boston

University, indicate that use of high levels of PB during the war, in combination with higher-level

pesticide exposure, is associated with significantly greater risk both for symptomatic illness and for

measured neurobehavioral decrements.836

The health of Gulf War veterans in relation to pesticides. As previously described, a large

number of pesticides and insect repellants were used by military personnel during the Gulf War, including

personal pesticides used by the general military population, and area-use pesticides sprayed by pesticide

applicators. Unfortunately, most Gulf War epidemiologic studies evaluated veteran-reported pesticide

use only in very general terms, for example, by simply asking veterans if they had been exposed to

“pesticides” during the war. A very limited number of studies asked how much pesticide was used, the

number of days pesticides were used, or the specific types of pesticides to which veterans were exposed.

One study indicated that the use of DEET and permethrin were highly correlated, and that the majority of

personnel used either both repellants or neither.1466

Association of pesticides with multisymptom illness in Gulf War veterans. As detailed in Appendix

A-7, nearly all Gulf War epidemiologic studies identified significant associations between pesticide

exposure and symptomatic illness, in analyses that did not control for effects of confounding by other

exposures in theater. Several associations identified by these analyses were quite pronounced, however,

including a finding that British veterans who reported personal pesticide use had a 12 times greater risk of

multiple chemical sensitivity than veterans who reported no use of personal pesticides.1264

Studies also consistently found that pesticide exposure was significantly associated with Gulf War

symptomatic illness, after controlling for effects of other exposures in theater. As shown in Table 8,

pesticide exposure was identified as a significant risk factor for Gulf War illness in five of the six studies

that adjusted for effects of other exposures. The single study in which this association was not significant

had evaluated only effects of DEET in multivariable modeling, although initial analyses indicated that use

of insecticide spray was more strongly associated with Gulf War illness than DEET.1466 Overall, the

general consistency of results demonstrating an association of pesticides with Gulf War illness is

especially noteworthy, give the variability in how pesticide use was assessed by different studies.

Only two epidemiologic studies evaluated dose-response effects in relation to pesticide use during the

Gulf War. Both identified significant correlations between greater pesticide use and greater illness risk or

severity. The University of Texas Southwestern study of Navy Seabees found that using larger amounts

of government-issued DEET repellant, but not OFF or Skin-so-Soft, was significantly correlated with

greater illness risk, adjusting for effects of other exposures. In addition, the large University of

Manchester study of British Gulf War veterans reported a significant correlation between severity of

symptomatic illness and the number of days that veterans reported using insect repellants or handling

pesticides.241

Association of pesticides with other health outcomes in Gulf War veterans. Several studies have

reported that pesticide use during the Gulf War is associated with measured clinical outcomes. This

includes one published finding that veterans who reported using pesticides during the war had

significantly poorer performance on neurobehavioral tasks, compared to veterans who did not.1782 Use of

pesticides in theater was also reported, in one study, to be significantly associated with lower 24-hour

ACTH levels.503 Preliminary results from an additional federal research project, which are not yet

published, suggest that both symptomatic illness and reduced neurobehavioral performance are
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  181

significantly more pronounced among individuals with the highest levels of both pesticide exposure and

PB use during the war.836

The health of Gulf War veterans in relation to chemical agents. A large number of studies

have evaluated associations between variables related to possible nerve agent exposure and the health of

Gulf War veterans. Results of these studies are much less consistent and interpretable than findings

related to PB and pesticides. Difficulties in determining who was exposed to low level nerve agents

during deployment introduce major ambiguities into this research. Although information related to all

self reported exposures during the war is subject to inaccuracies, self-reported exposure to low-levels of

nerve agents is particularly problematic. Veterans might not have known if they had been exposed to

subsymptomatic levels of sarin in any case, but repeated chemical alarms and alerts, disregarding and

turning off alarms, and information and misinformation conveyed through the ranks further undermined

their ability to know whether or not they had been exposed. Studies indicate that chemical agent

exposures are among the least reliably-reported exposures in Gulf War research.1165 Modeled exposures

related to the Khamisiyah demolitions are also subject to question, as previously detailed, and additional

questions remain concerning chemical agent exposures in other locations.

Did Gulf War veterans have symptoms of chemical agent exposure in theater? It has generally

been believed that few if any Gulf War veterans exhibited symptoms of exposure to chemical weapons

during the war,1232 but there is little systematically-collected data that addresses this question. The 2000

RAND report on possible health effects of chemical agents in the Gulf War pointed out that nonspecific

symptoms of low-level exposure to nerve agents might have gone unnoticed or been attributed to other

causes.74 Department of Defense Case Narrative reports often indicate that few, if any, individuals

interviewed in relation to suspected chemical events had symptoms of exposure at the time of the

incident.1617,1628,1630 Other suspected chemical incidents came to light specifically because of reports that

individuals had experienced symptoms suggesting exposure.1558,1589,1614,1627,1688 A recent survey of 335

U.S. Gulf War veterans indicated that 25 percent of veterans who said they had been exposed to chemical

agents during the war based their belief on symptoms they had experienced at the time of the suspected

incident.168

The only study of Gulf War veterans who were in the immediate vicinity of the Khamisiyah demolitions

found that some did have symptoms of nerve agent exposure at the time. Investigators from VA’s

Portland Environmental Hazards Research Center surveyed nearly 3,000 Gulf War veterans who had been

in different areas during the first two weeks after the cease fire, when the major Khamisiyah demolitions

had taken place. Veterans were asked about symptoms they experienced during that period, as well as

symptoms they had at the time of the survey, nine years after the war.990 Overall, symptoms reported by

veterans who were within a 50 km. radius of Khamisiyah during early March of 1991 were similar to

those of veterans in other areas of theater. However, veterans who had directly participated in the

Khamisiyah demolitions, or had witnessed the demolitions, reported significantly higher rates of a

number of symptoms during that period, primarily symptoms suggestive of nerve agent exposure—

headaches, nausea, vision problems, cramping, runny nose, and muscle twitching.990 Results suggest that

some veterans in close proximity to the Khamisiyah demolitions may have had cholinergic symptoms at

the time of exposure.

Association of chemical agents with multisymptom illness in Gulf War veterans. In epidemiologic

evaluations of health effects potentially resulting from chemical agents during the Gulf War, exposure has

been assessed using a variety of self report measures, or using modeled estimates related to the

Khamisiyah demolitions. Results of these studies are detailed in Appendix A-2. As has been described in

relation to other Gulf war exposures, nearly every variable potentially indicative of chemical agent

exposure—such as receiving notification from DOD about the Khamisiyah releases, wearing a gas mask,

hearing chemical alarms, belief that chemical and biological weapons were used—has been shown to be

significantly associated with symptomatic illness in analyses that made no adjustments for effects of other
182  Effects of Gulf War Experiences and Exposures

exposures. Although subject to confounding, results from several of these studies are worth noting. The

large U.S. National Study of Gulf War veterans indicated that veteran-reported exposure to “nerve gas”

was associated with a 15-fold increased risk of the unique “Gulf War illness” symptom complex

identified by that study.752 In addition, the Portland study reported that individuals within 50 km. of the

Khamisiyah demolitions, overall, had symptom profiles similar to those of veterans in other areas of

theater.989 In contrast, veterans who had assisted with or observed the demolitions had significantly

higher symptom rates, nine years after the war, than other veterans who had been within 50 km. of the

demolitions.

Results from epidemiologic studies that controlled for effects of other exposures in theater are less

consistent and less clear. As shown in Table 8, of the five studies that evaluated associations between

symptomatic illness and chemical agent variables, three identified significant associations, after adjusting

for effects of other exposures. Each of these studies relied on different self-reported indicators of

chemical agent exposure; none used exposure estimates from the Khamisiyah models. Individual results

from the studies listed in the table also raise questions concerning the degree to which they do or do not

support an association between Gulf War illness and chemical exposures. For example, of the two studies

that found no association between chemical agents and symptomatic illness, one evaluated Danish

veterans, who served only in peacekeeping missions and might not have been exposed to chemical agents

at any time.695,1507 Studies that identified positive associations also raise questions. The positive finding

from the large Air Force study, for example, reflects an association between chronic multisymptom illness

and veterans’ perceptions that “chemical or biological weapons were being used,” but not specifically

with whether a veteran had reason to believe that he or she had personally been exposed to chemical

weapons.1124

Overall, an association between Gulf War illness and exposure to chemical warfare agents in theater is

not clearly supported nor clearly refuted by results of Gulf War epidemiologic studies. This is due to the

inconsistency of study findings, overall, and to ambiguities in variables used to evaluate chemical agent

exposures.

Association of chemical agents with other health outcomes in Gulf War veterans. In addition to

the many studies of Gulf War-related multisymptom illness, studies have assessed other health outcomes

in relation to chemical agent exposures during the Gulf War. In contrast to studies evaluating Gulf War

illness, most other health outcomes have been assessed in relation to modeled chemical agent exposures

associated with the Khamisiyah demolitions.

Department of Veterans Affairs investigators in Washington, D.C. used the 2000 Khamisiyah models to

assess mortality rates in Gulf War veterans relative to nerve agent exposure. In 2005, they reported that

modeled exposure to nerve agents was associated with a significantly increased rate of death due to brain

cancer.190 The rate of brain cancer mortality among veterans downwind from the Khamisiyah demolitions

was about twice as high, overall, as the rate in veterans who had been located elsewhere. This reflected

25 brain cancer deaths prior to the year 2001 among the 100,487 Gulf War veterans identified as

potentially exposed to nerve agents. A dose response effect was also identified, indicating that exposure

for two or more days was associated with a greater than three-fold increased risk of death due to brain

cancer. No other mortality effects, related to either disease or motor vehicle accidents, have been

reported in relation to nerve agent exposure at Khamisiyah.190,470

Studies have also reported measurable difference in neurobehavioral performance and brain structure in

relation to low-level nerve agent exposures following the Khamisiyah demolitions. Investigators from

VA’s Boston Environmental Hazards Center assessed neurocognitive performance in veterans in the Fort

Devens cohort between 1994 and 1996, and initially found that veterans who reported being exposed to

chemical or biological warfare agents had significant decrements on a number of specific cognitive

tasks.910 Years later, testing results were reevaluated to assess measured outcomes in relation to DOD-
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  183

modeled exposures to sarin and cyclosarin following demolitions at Khamisiyah. Since testing had

occurred before the Khamisiyah exposures had been made public, the available data allowed assessment

of cognitive performance that was effectively blinded to exposure status. In tests conducted four to five

years after exposure, modeled levels of nerve agent exposure were significantly associated with reduced

performance on neurobehavioral tasks related to visuospatial and psychomotor abilities, in a dose

response manner.1237

Twenty-six individuals in the Fort Devens cohort also received magnetic resonance imaging (MRI) scans

of the brain between 1999 and 2001. Volumetric measures were evaluated in relation to DOD modeled

exposure levels to sarin and cyclosarin in connection with Khamisiyah. No differences were identified by

simple comparisons between “exposed” and “unexposed” individuals, that is, comparisons between all

veterans identified as being potentially exposed at any level, and those who were not in areas affected by

Khamisiyah. In contrast, dose-response analyses identified significant associations between levels of

nerve agent exposure and structural differences in several brain areas. Specifically, veterans with the

highest level of nerve agent exposures had significantly reduced white matter volume, and enlarged right

and left ventricular volumes, controlling for both age and PTSD symptomatology.599 These effects

suggest subtle, persistent alterations in brain structure associated with low level exposure to nerve agents

during the Gulf War. Identified differences related to the degree of exposure estimated by the

Khamisiyah models, but were obscured in comparisons between all unexposed individuals and all those

identified as exposed at any level.

Additional studies have reported on rates of medical diagnoses, healthcare utilization, and hospitalization

in relation to the Khamisiyah demolitions. A 2002 survey indicated that Gulf War veterans located within

50 km. of the Khamisiyah demolitions reported similar rates of medical diagnoses and hospitalizations as

veterans in other locations of theater.989 In a later survey, U.S. Gulf War veterans who had been notified

that they may have been exposed to nerve agents in relation to Khamisiyah reported generally similar

rates of symptoms, medical conditions, and healthcare visits as veterans located elsewhere. Exposed

veterans reported significantly higher rates of recurrent headaches, but significantly lower rates of

diagnosed cancer and neuralgia.1165 Findings suggest that veterans identified by the Khamisiyah plume

models, overall, are generally similar to other Gulf War veterans in relation to most self-reported

diagnoses and symptoms. They also indicate that veterans’ belief that they may have been exposed to

nerve agents was not associated with a tendency to “over report” health problems or increased healthcare

utilization.1165

Studies conducted by the U.S. Naval Health Research Center evaluated hospitalizations in military

hospitals in relation to nerve agent exposures, estimated using both the 1997 and 2000 Khamisiyah

models. Overall, military hospitalizations from 1991 through 1995 were generally similar in “exposed”

and “not exposed” active duty personnel veterans identified by the 1997 plume models.529 Later analyses

compared military hospitalizations between 1991 and 2000 in relation to exposures estimated using the

2000 plume models.1433 All-cause hospitalization rates were similar in exposed and unexposed veterans.

Of the 15 disease-specific categories evaluated, hospitalization for diseases of the circulatory system was

slightly (RR=1.07) but significantly elevated in exposed personnel. Within that category, a significantly

greater proportion of Khamisiyah-exposed veterans had been hospitalized for cardiac dysrythmias

(RR=1.22), but no other specific conditions.1433 No information was provided on hospitalizations relative

to different nerve agent exposure levels estimated by the 2000 Khamisiyah models.

In general, studies that have used modeled estimates of nerve agent exposures in the Gulf War have

provided more interpretable information than epidemiologic studies that relied on veterans’ reports of

chemical alerts or their beliefs concerning chemical exposures. When all veterans identified as “exposed”

in relation to Khamisiyah are considered as a single group, only two significant differences have been

identified using “hard” endpoints—a significant increase in brain cancer mortality, and an excess of

hospitalization for cardiac dysrythmia. Overall, self-reported symptoms, self-reported medical diagnoses,
184  Effects of Gulf War Experiences and Exposures

and healthcare utilization are similar among veterans identified as “exposed” and “not exposed” using the

Khamisiyah models.

Differences related to possible nerve agent exposure were more consistently identified when levels of

exposure estimated by the Khamisiyah models were considered, rather than combining all potentially

“exposed” veterans into a single group. Identified health outcomes associated with greater and/or more

sustained nerve agent exposure include higher rates of brain cancer mortality, differences in brain

structure volume, and decrements in performance on neurobehavioral tasks. It is important to emphasize

that these studies did not specifically identify excess rates of Gulf War multisymptom illness in relation to

the Khamisiyah exposures, and none provided results that were adjusted for effects of other exposures

during deployment. Epidemiologic studies that identified increased rates of symptomatic illness in

relation to Khamisiyah also did not consider effects of other exposures.142,990,1476 Therefore, despite

important findings related to neurological effects of modeled nerve agent exposures, there is still no clear

information that indicates whether Gulf War multisymptom illness is associated with nerve agent

exposures related to the Khamisiyah weapons demolitions.

Although the accuracy of the Khamisiyah models has been questioned, it is unlikely that the exposure

effects observed in studies of Gulf War veterans were anomalies introduced by shortcomings in the

models. All identified effects related to modeled levels of nerve agent exposures resulting from

Khamisiyah were related to brain pathology, and all occurred in a dose-response pattern. Inaccuracies in

the Khamisiyah models are unlikely to differ with respect to the health outcomes assessed. Such

“nondifferential” exposure misclassifications due to model inaccuracies would therefore be expected to

diminish the apparent associations between nerve agents and the neurological outcomes reported. This

raises the possibility that the actual effects of exposures in the Khamisiyah area could be more

pronounced than those suggested by reported study results.

Results of these studies underscore the importance of evaluating effects of dosage and duration in

assessing effects of Gulf War exposures, where possible, and evaluating health outcomes in identifiable

subgroups of Gulf War veterans. Comparisons between all veterans identified as potentially “exposed” to

nerve agents in relation to Khamisiyah obscured effects identifiable when different exposure levels were

considered. Similarly, studies indicate that higher-dose or more sustained exposures to PB and pesticides

were more strongly associated with Gulf War illness than lower-dose or brief exposures. In a broader

sense, these studies provide an important example of the potential for overly generalized comparisons, for

example, between all deployed Gulf War veterans and nondeployed veterans, to obscure findings related

to specific veteran subgroups.

Summary. Research on health effects of cholinergic and related neurotoxicant

exposures in Gulf War veterans. A large proportion of Gulf War veterans were exposed to different

combinations of cholinergic and related neurotoxicants during deployment, compounds that include PB

pills, pesticides, and low levels of nerve agents. Research in human populations and in animal models

has shown that low level exposure to cholinesterase inhibitors can be associated with persistent

symptomatic illness and with brain and autonomic alterations that parallel the types of problems affecting

Gulf War veterans. Of the many diverse types of exposures evaluated by epidemiologic studies of Gulf

War veterans, only two—PB and pesticides—are consistently identified as significant risk factors for Gulf

War illness. Gulf War studies have also reported significant dose-response effects for both PB and

pesticides in relation to Gulf War illness. In addition, clinical studies of Gulf War veterans have

identified persistent alterations in neurobehavioral and hypothalamic-pituitary-adrenal measures related to

PB and pesticide exposure during the Gulf War.

Findings related to the effects of low-level nerve agent exposures in the Gulf War have been less clear

and consistent. Epidemiologic studies that have evaluated nerve agent exposure in relation to Gulf War

illness have yielded mixed results. Modeled nerve agent exposures resulting from the Khamisiyah
Cholinergic and Related Neurotoxicants: Pyridostigmine, Pesticides, and Nerve Agents  185

weapons demolitions have, however, been associated with increased rates of brain cancer mortality, and

with significant differences in brain structure and cognitive function in Gulf War veterans, all in doseresponse patterns.

Taken together, consistent evidence from studies of Gulf War veterans, along with supporting evidence

from research in other human populations and in animals, provide strong support for both PB and

pesticides as causal factors in Gulf War illness. Questions about the extent of exposure to chemical

agents in the Gulf War, and mixed findings from epidemiologic studies do not allow clear conclusions

concerning nerve agents as risk factors for Gulf War illness. However, indications that low level nerve

agent exposures have had adverse neurological effects in Gulf War veterans and additional evidence from

research in humans and animals exposed to sarin, indicate that low-level nerve agent exposure cannot be

ruled out as a contributing factor in Gulf War illness, for the subset of veterans who were exposed.
186  Effects of Gulf War Experiences and Exposures

Recommendations

During the 1990-1991 Gulf War, military personnel were widely exposed to a variety of neurotoxic

compounds that included pyridostigmine bromide pills, different types and dosages of pesticides and

insect repellants, and low-level exposure to nerve agents. The chemical action of many of these

compounds is similar, involving dysregulation of the neurotransmitter acetylcholine. Animal studies have

also found that these neurotoxicants, in combination with one another, can have effects that differ from

those of individual exposures.

Epidemiologic studies that have assessed independent effects of multiple exposures during the Gulf War

have consistently identified only two as significant risk factors for Gulf War illness—pyridostigmine

bromide and pesticides. Evidence relating low-level nerve agent exposure to Gulf War illness has been

inconsistent, but studies have identified adverse neurological effects in Gulf War veterans potentially

exposed to low levels of nerve agents as a result of the Khamisiyah weapons demolitions.

The Committee gives high priority to studies that further characterize specific effects of Gulf War-related

neurotoxicant exposures, and recommends the following research:

 Studies that evaluate and characterize delayed and persistent molecular, cellular, systemic, and

behavioral effects of individual and combined exposures to pyridostigmine bromide, pesticides,

insect repellants, and low-level sarin

 Studies that identify markers indicative of past exposure to Gulf War-related neurotoxic

compounds that can be applied to Gulf War veterans. This might include studies that utilize

technologies capable of detecting toxins or secondary metabolites retained for many years

following exposure, studies that identify persistent or “downstream” changes in biochemical

processes in relation to past neurotoxic exposures, and studies that identify delayed or persistent

changes in the central nervous system and autonomic function associated with exposure to Gulf

War-related neurotoxicants.
Infectious Diseases in Gulf War Veterans  187

Infectious Diseases in Gulf War Veterans

The Gulf War theater was home to insects and other pests that carried diseases that posed a potential

health threat to American troops. In earlier times, high rates of infectious diseases such as sandfly fever

and malaria had affected large numbers of military personnel stationed in the Middle East. A variety of

organisms, some endemic to the region, can produce persistent conditions with symptoms that can, in

some cases, resemble the symptoms of Gulf War illness—fatigue, cognitive difficulties, persistent

diarrhea, muscle and joint pain, and unusual skin rashes. In addition to naturally acquired infections,

there has also been concern that Gulf War veterans might have been exposed to biological warfare agents

in theater. Information available before and since the Gulf War indicated that Iraq had developed

biological weapons, and had readied them for use prior to the war.

Throughout Operations Desert Shield and Desert Storm, protective measures were fielded to minimize

problems resulting from infectious diseases in theater. Vaccines were given to prevent some diseases and

ample amounts of repellants and pesticides were supplied to ward off biting insects. Surveillance efforts

and an advanced diagnostic laboratory were established to identify and contain infectious disease

problems that emerged during deployment. As a result of these measures, some infections that had posed

serious problems in earlier military deployments had little impact on Gulf War personnel. Other familiar

infectious diseases were problematic in theater, primarily short-lived diarrheal and respiratory conditions.

However, two comparatively novel infections—viscerotropic leishmaniasis and mycoplasma

fermentans—have emerged as issues of concern in relation to Gulf War service. It is important to

determine whether these or other infectious conditions may have contributed to the chronic health

problems affecting Gulf War veterans.

Infectious Disease in the Gulf War

As military operations geared up for the massive deployment of troops to Southwest Asia in 1990, there

was concern among military medical officials about the potential health threat posed by infectious

diseases endemic to the region. Historically, infectious diseases had caused widespread problems among

troops deployed to the region.596,666,1249 Medical officials were aware of the potential for diverse types of

vector-borne infections such as sandfly fever and leishmaniasis.475,664 Diarrheal diseases due to viral

agents, shigella, E. coli, and other agents were also thought to pose a threat,475 a concern born out in the

early months of troop deployment.

Several published reports have documented rates of infectious diseases detected in Gulf War personnel

during the war. It is one of the few areas for which surveillance data were collected during deployment.

A surveillance system was established in theater to monitor injury and disease rates, including infectious

diseases, in the nearly 40,000 Marine Corps personnel stationed in northeastern Saudi Arabia. Data were

collected from most Marine and Seabee unit aid stations and analyzed on an ongoing basis throughout the

deployment period.1607 In the early months of Operation Desert Shield, the U.S. Navy established a stateof-the-art laboratory facility, the Navy Forward Laboratory, headquartered in Al Jubayl, Saudi Arabia.

The work of this laboratory was to identify infections in clinical samples and to assist in detection of

biological warfare agents.661,1607 In addition, health surveys were administered to nearly 900 Marines in

three front-line units prior to deployment and immediately after their return to the U.S. five months later.

Blood samples were also collected pre- and post-deployment to identify rates of seroconversion resulting

from a variety of pathogens in theater.1280

Previous summary reports from the RAND Corporation and the Institute of Medicine have evaluated, in

some detail, the likelihood that Gulf War veterans developed chronic health problems as a result of

infectious diseases acquired in theater. These reports focused most specifically on infectious organisms
188  Effects of Gulf War Experiences and Exposures

endemic to the region and/or those that have the potential to cause chronic illness.608,687 These included Q

fever, hepatitis, malaria, brucellosis, West Nile virus, malaria, shigellosis, and leishmaniasis, among

others. Both reports generally concluded that there is little persuasive evidence indicating that a large

number of Gulf War veterans have suffered long-term adverse effects due to infectious diseases. The

IOM report did identify a number of chronic conditions for which scientific evidence supports an

association with infectious agents. However, the conditions identified have not been associated with Gulf

War service. The RAND report called for further characterization of mycoplasma infection in Gulf War

veterans and did not rule out the possibility that an as yet undetected chronic infection may underlie the

illness of some symptomatic veterans.

Gastrointestinal infections in theater. The most common infectious conditions affecting troops

during deployment were diarrheal diseases. In the early months of Operation Desert Shield, when large

numbers of troops were just arriving in theater, multiple diarrheal disease outbreaks were reported. These

early outbreaks appeared to be largely related to consumption of fresh produce purchased from countries

in the region, since the incidence of diarrheal diseases fell dramatically when those foods were banned.664

Surveys conducted during this period indicated that nearly 60 percent of ground troops had experienced at

least one episode of diarrhea. Twenty percent reported that one or more diarrheal episodes had been

severe enough to interfere with their work and had required them to seek medical attention.662,665 In

addition, nearly half of over 700 surveyed shipboard personnel reported having at least one diarrheal

episode during Operation Desert Shield.1167 Laboratory tests from all branches indicated that the major

causes of diarrheal diseases in theater were enterotoxigenic E. coli and shigella sonnei.

662

Although the rate of diarrheal diseases dropped after local produce was removed from troops’ diets,

gastrointestinal infections resulting from a variety of pathogens continued to affect personnel throughout

the deployment period.662 Late in 1990, gastroenteritis outbreaks due to Norwalk virus infection were

identified in units throughout theater.665 Spread of these infections was thought to relate to crowded

living quarters during some phases of deployment and with rugged living and sanitary accommodations in

units deployed in the desert. However, parasitic diseases were reported to be uncommon, with only nine

cases of giardia lamblia identified among 422 Marines tested, and no cases of amebiasis or other

intestinal parasitic infections.960

Respiratory infections during deployment. Acute upper respiratory infections were also

commonly reported during the war. Results of an in-theater survey of over 2,500 ground troops stationed

in northeastern Saudi Arabia between November 1990 and January 1991 indicated that over forty percent

had experienced respiratory symptoms.1279 Smokers and those with a history of respiratory disease were

at highest risk for developing upper respiratory conditions. Respiratory conditions were also more

common among troops housed in air-conditioned buildings than those living in tents. Surveillance of

Marine Corps troops indicated that respiratory conditions continued to affect troops throughout the

deployment period, particularly during periods of initial deployment and at other times when troops were

most crowded together.664

A self limited respiratory condition associated with persistent cough was commonly reported by troops

early in their deployment. This condition was given various names, including the “Kuwaiti cough” and

the “Kuwaiti crud.” It continues to be reported among personnel serving in the region today, and is

thought to be a reaction to high levels of particulates associated with the fine, blowing sand in the

region.1349

One of the earliest mentions of an unusual Gulf War-related illness described an upper respiratory

condition that affected troops who occupied long-abandoned housing units near the village of Al Eskan,

Saudi Arabia.832 The condition, termed Al Eskan disease, was initially described as a pneumonitis that

resulted from exposure to the fine sand, in combination with infectious agents, pigeon droppings, and

other possible contaminants. Most of the initial cases were described as self-limited, resolving with
Infectious Diseases in Gulf War Veterans  189

antibiotic treatment. This condition is considered further in relation to particulates, discussed later in the

report.

Sandfly fever. Sandfly fever was a particular concern for military medical planners for personnel

deploying to the region. This disease is caused by an arbovirus transmitted by sand flies, and had been a

serious problem for military troops in the region during World War II.596,1149,1249 Acute symptoms of

sandfly fever can include headache, fever, malaise, nausea, pain in limbs and back, and leucopenia.687

Acute infection can be followed by persistent symptoms of fatigue, weakness, and depression.395,475,687

About 80 percent of a group of captured Iraqi soldiers tested for sandfly fever were found to be

positive.1592,1593 But no cases of sandfly fever were identified among U.S. personnel during the 1990-

1991 Gulf War deployment.664 In addition, serological testing of the nearly 900 Marines in front-line

units after their return home did not identify a single positive case.1280

Leishmaniasis. Leishmaniae are intracellular trypanosome protozoa transmitted by the bite of the

same sand flies that carry sandfly fever. There are different presentations of leishmaniasis that result

from infection by different leishmania species. Cutaneous leishmaniasis is very common in the region,

typically the result of infection by L. tropica or L. major. Only twenty cases of cutaneous leishmaniasis

were identified among U.S. troops who served in the Gulf War, however, all resulting from L. major

infection.666,838,953,1142

Systemic infection by leishmania, visceral leishmaniasis, is usually the result of infection by L. infantum

or L. donovani. Symptoms of this condition, referred to locally as kala-azar, typically include fever,

diarrhea, weakness, and hepatosplenomegaly.1142 No cases of kala-azar were identified in U.S. troops

during the Gulf War.953 However, diagnosis of leishmaniasis is difficult since there are no validated

blood tests for this infection. Definitive diagnosis requires that the parasite be cultured from lymph node

or bone marrow biopsies, an invasive process that involves highly specialized laboratory techniques.1142

A form of visceral leishmaniasis that had not previously been recognized in the region was identified in

12 Gulf War veterans after their return from theater, as will be described in detail below. This condition,

referred to as viscerotropic leishmaniasis, was associated with infection by L. tropica. The total number

of Gulf War veterans affected by this atypical leishmaniasis is not known. Some infectious disease

specialists have speculated that it is unlikely that there were large numbers of undetected cases666 because

sandfly fever, an infection transmitted by the same vector as leishmaniasis, was not identified in Gulf War

personnel during the war. In addition, reports from entomological surveys of the Gulf War theater

indicated that relatively few sand flies were in open desert areas where many troops were located.275

Other infections in theater. Another infectious disease of potential concern was brucellosis, which is

endemic to the region30,346 and transmitted primarily through contact with infected animals or ingestion of

contaminated dairy products or meat. Chronic brucellosis has been described in the medical literature for

over sixty years,414 and is characterized by persistent and/or delayed onset of symptoms that resemble

those of Gulf War illness—fatigue, cognitive difficulties, muscle and joint pain, and respiratory

symptoms. Several reports have indicated that no cases of brucellosis were reported during deployment,

but the extent to which veterans were tested for this infection in theater is not clear from available

reports.660,1278

There were seven reported cases of malaria in Desert Storm troops,664,666 three cases of Q fever identified

in theater664 and one case of Q fever identified in a Gulf War veteran shortly after his return.432 Seventyfive Gulf War personnel were hospitalized for chicken pox during deployment.1431 Only a few cases of

viral hepatitis were identified by clinicians in theater,664 and 16 cases were identified among specimens

submitted to the Armed Forces Institute of Pathology.1460 Just one case of West Nile virus infection was

detected in theater,664,1278 although an analysis of samples taken from 865 Marines found that 30 had
190  Effects of Gulf War Experiences and Exposures

positive antibody titers to this virus, in both pre- and post- deployment sera.1280 One death due to an

infectious disease, meningococcal meningitis, was reported during the Gulf War.1813

All told, the impact of infectious diseases during the Gulf War was much less extensive than had been

expected based on previous U.S. and U.K. deployments to the region.664 Various preventive measures

taken by the military can be credited for this success, including vaccinations for infections endemic to the

region, extensive spraying and personal use of pesticides, repellants and other protective measures, rapid

identification and response to identified infectious agents, and broad efforts to provide clean water and

food to troops in theater.666

Infectious diseases in current military operations. Infectious diseases have been more

problematic for troops serving in the region for Operation Iraqi Freedom (OIF) and Operation Enduring

Freedom (OEF).67,687 Respiratory and diarrheal conditions during deployment were reported by about 70

percent of surveyed OIF personnel.1344,1345 Over 60 percent reported diarrheal episodes severe enough to

seek medical treatment.1345

Cutaneous leishmaniasis has also been more frequently identified in OIF personnel. As of 2005, over

1000 cases had been verified, most due to L. major.

399,687,954 A survey of troops reporting diagnosed

conditions suggests that the actual number of cutaneous leishmaniasis cases may be more than twice that

number.1344 Five cases of visceral leishmaniasis have also been verified.67 Additional concerns have

been raised in relation to acinetobacter infections in veterans injured in theater, principally in association

with wound contamination.67,1833

Early in Operation Iraqi Freedom, 19 cases of a serious idiopathic eosinophilic pneumonia were reported.

Affected patients required intubation and mechanical ventilation, and two individuals died from the

disease.222,802,1405,1833 No causative infectious agent has ever been determined. In addition, about 2.5

percent of personnel who have served in OIF and OEF have been reported to have acquired tuberculosis

(TB) infections during deployment, although no active disease cases have been identified.687,802 Over fifty

cases of malaria had also been diagnosed among personnel serving in Afghanistan, as of 2005.67,802

Chronic Symptoms and Syndromes Associated with Infectious Disease

Most familiar infectious diseases produce an identifiable acute illness that is self-limited, and resolves in a

matter of days or weeks. Some infections, however, can be associated with subclinical disease that is not

readily apparent or clearly identified.430,953 In addition, some infectious conditions may not resolve in the

usual time span, instead leading to a post-infectious chronic illness associated with persistent symptoms,

or a chronic infection with symptoms that come and go as the infection vacillates between latent and

active states.209,796,875,1144,1777 Other organisms produce illness that does not become evident for months, or

even years, after the initial infection.83,475,725 A number of organisms found in the Middle East can

produce subclinical and/or persistent infections of these types, including leishmaniasis, Q fever, and

brucellosis.44,430,432,475,725,955,1563

Symptoms associated with chronic infection or post-infectious conditions can be similar to those of Gulf

War illness—fatigue, muscle and joint pain, impaired cognition, gastrointestinal problems, and skin

rashes. Such problems have been well described in studies of symptoms and syndromes that develop

after diverse types of infections, including respiratory infection, central nervous system infection, and

gastrointestinal infection.150,201,209,348,796,1144,1718,1776 Postinfectious symptoms of fatigue, pain, malaise, and

diarrhea are associated with increased production of central and peripheral proinflammatory cytokines in

both animals and humans.784,953,1777
Infectious Diseases in Gulf War Veterans  191

Evaluation of Infectious Diseases in Gulf War Veterans Since the War

Despite the potential for infection in theater by a variety of unfamiliar organisms and the many

epidemiologic studies of Gulf War veterans, surprisingly few studies have evaluated infectious diseases

among Gulf War veterans since their return from the war. With the exception of one study of Air Force

veterans conducted by the U.S. Centers for Disease Control and Prevention (CDC), 464 most attention to

infectious disease in Gulf War veterans has focused on two very different types of organisms associated

with intracellular infection: leishmania protozoa and mycoplasma, a single celled bacteria-like organism.

Leishmania infection in Gulf War veterans. As previously described, 12 cases of viscerotropic

leishmaniasis due to L. tropica infection were verified in Gulf War veterans after their return to the U.S.

Cases were identified by infectious disease specialists at Walter Reed using rigorous methods.955,956 None

of the affected individuals had symptoms of cutaneous leishmaniasis, the more common manifestation of

L. tropica infection. Affected veterans presented with diverse, nonspecific symptoms including fatigue,

abdominal pain, cough, headache, swollen lymph nodes, and hepatosplenomegaly. Some had fever, some

did not; one patient was completely asymptomatic.953,955,956 Estimated incubation times for the earliest

identified infections ranged from 1 to 14 months, but one case was not verified until two years after

deployment.956 About half of the cases were evaluated for leishmania infection because of veterans’

presenting symptoms, others were identified when serologic surveys were conducted in their units. Five

of the initial eight cases described in a published study occurred in just two units.955

The number of undetected cases of viscerotropic leishmaniasis in Gulf War veterans is unknown, as is the

potential for persistent undetected infection to have contributed to Gulf War illness. As summarized in

Table 1, only limited assessment of leishmania infection has been carried out since veterans returned from

theater. No systematic studies, using well-validated testing methods, have assessed the prevalence of

leishmania infection in Gulf War veterans. This is likely due, in part, to the lack of well-validated

screening blood tests for this infection. Identification and verification of L. tropica infection requires

bone marrow aspirates or lymph node biopsies and rigorous laboratory methods.220,954,1142 The 12

identified cases were characterized as a result of referral to infectious disease specialists at Walter Reed

Army Medical Center and active screening of their units. Systematic evaluation of a larger sample of

defined groups of Gulf War veterans is required to determine the rate at which Gulf War veterans, or

particular subgroups, are affected by L. tropica or other leishmania infections.

Table 1. Post-War Assessment of Infection in Gulf War Veterans: Leishmaniasis

Study Method Key Findings

DeFraites327 Serology 2 of 78 symptomatic GWV had elevated titers to L. tropica

Magill955 Culture 12 cases of viscerotropic leishmaniasis due to L. tropica infection

Kreutzer838,954 unknown 20 cases of cutaneous leishmaniasis identified in GWV

Bourdette159 ELISA assay under

development

9% of 200 GWV tested positive for L. tropica: 10% of GWI cases vs. 4%

of controls (p = 0.15)

Fukuda464 Serology 5% of 158 GWV tested positive for L. tropica or L. donovani, no difference

by CMI case status

Koch824 Serology None of 24 GWV with chronic gastrointestinal symptoms tested positive

for leishmaniasis (species not identified)

Abbreviations: GWV = Gulf War veterans, CMI = chronic multisymptom illness
192  Effects of Gulf War Experiences and Exposures

The most informative research of this type comes from an unpublished study conducted by VA’s Portland

Environmental Hazards Research Center. The study assessed the prevalence of L. tropica infection in a

random sample of 200 Gulf War veterans, using an assay that was being developed and tested in a

collaborative effort between DOD and a private company. The Portland study was funded in 1994 by the

Department of Veterans Affairs. Results were reported at the 1998 federal Gulf War research

conference159 and also shared in detail with the Committee.1478 The enzyme-linked immunoassay

(ELISA) test used to detect evidence of L. tropica infection had previously been shown to detect

reactivity to this organism in Gulf War veterans with culture-verified viscerotropic leishmaniasis, and in

patients with cutaneous leishmaniasis.345

Results of the Portland study indicated that, overall, nine percent of 200 Gulf War veterans tested positive

for L. tropica, with values more than three standard deviations above the mean found in healthy,

nonveteran controls. Among the 167 veterans identified as either Gulf War illness cases or controls using

the Oregon case definition, the infection rate was somewhat higher for cases. Ten percent of Gulf War

illness cases tested positive, compared to four percent of Gulf War veteran controls (exact p value =

0.15).1478 This trend for a possible association of illness with infection was intriguing, but not statistically

significant in this small sample. No follow up studies were conducted, and no additional efforts to

validate the ELISA assay used in the study have been reported. Like the 12 Gulf War veterans

determined to have viscerotropic leishmaniasis using more rigorous methods,955 no Gulf War veterans in

the Portland study exhibited signs of cutaneous leishmaniasis.

The Committee looks forward to reviewing results from an ongoing VA study that will assess the

prevalence of occult leishmania infection in Gulf War veterans using an assay being developed by

investigators at the Omaha VAMC.

Mycoplasma infection in Gulf War veterans. Mycoplasma are small bacteria-like organisms that

lack a cell wall but are capable of independent self-replication. Various mycoplasma species are known

to produce human diseases affecting different organ systems.107,1730 Beginning in the middle 1990s, Dr.

Garth Nicolson and colleagues reported that a sizable proportion of symptomatic Gulf War veterans were

infected by a particular mycoplasma species, mycoplasma fermentans (incognitus).

1118 This organism had

first been described in the late 1980s by Dr. S.C. Lo, who identified it in patients infected with

HIV.920,922,924 Subsequent studies, however, called into question the uniqueness of the incognitus strain,

indicating that it was not distinct from other M. fermentans.

1339,1351

Questions have been raised about whether M. fermentans is pathogenic in humans,107,381 although serious

illness has been described in persons with well-characterized infections.118,921,925 One study has reported

that a large proportion of adults (44%) have M. fermentans in their saliva,244 suggesting this organism

may be a common constituent of human saliva. M. fermentans is less commonly found in the blood of

healthy individuals, however, with studies generally detecting it in 5-10 percent of non-diseased controls

and adults in the general population.381,525,772,835,1114,1116,1123

Dr. Nicolson reported that M. fermentans infection in Gulf War veterans could not be reliably detected

using conventional serological methods, since the infection was intracellular and not, over the long term,

associated with an identifiable antibody response.1117 He identified the infection in Gulf War illness

patients using specialized DNA detection methods developed in his laboratory.1118 A high proportion of

symptomatic family members of ill Gulf War veterans were also reported to test positive for M.

fermentans.

1113,1117,1118 In case series reports, Dr. Nicolson indicated that treating mycoplasma-infected

veterans with multiple extended courses of antibiotics successfully improved or eliminated their

symptoms.1118,1119 Speculation concerning possible sources of this infection included naturally acquired

infection, exposure to bioweapons in theater, and vaccine contamination.589,608,1112,1113,1115
Infectious Diseases in Gulf War Veterans  193

Table 2. Post-War Assessment of Infection in Gulf War Veterans: Mycoplasma

Study Assay Key Findings

Nicolson

19961118

1998

1111

20021116

20031114

Nucleoprotein

gene tracking

Nucleoprotein

gene tracking

Forensic PCR

Forensic PCR

14 (47%) of 30 symptomatic GWV tested positive for mycoplasma; 0 of 21 healthy

controls tested positive for mycoplasma

76 (46%) of 170 GWV with GWI tested positive for mycoplasma; 2 (5%) of 41 healthy

controls tested positive

8 of 8 GWV with ALS tested positive for mycoplasma, 7 for M. fermentans; 22/28

civilian ALS patients tested positive for mycoplasma, 3 for M. fermentans

45 (41%) of 110 GWV with GWI tested positive for mycoplasma, 37 for M.

fermentans; 6 (9%) of 70 healthy controls tested positive for mycoplasma, 2 for

M. fermentans

Donta263,355

2004

PCR 546 (39%) of 1,387 GWV with GWI screened for VA antibiotic clinical trial tested

positive for at least one of three mycoplasma species

Vojdani1732

1999

Multiplex PCR 33 (55%) of 60 GWV with GWI tested positive for mycoplasma, 20 for M. fermentans;

24 (15%) of 160 healthy controls tested positive for mycoplasma, 13 for

M. fermentans

Gray525

1999

Serologic testing 7(11%) of 64 GWV were mycoplasma positive prior to deployment and 11 (19%)

developed new mycoplasma infection after deployment; 3 (9%) of 32

nondeployed era veterans were mycoplasma positive prior to the war and 4

(14%) developed new mycoplasma infection after the war. No sign. association

between mycoplasma infection and development of symptoms.

Lo923

2000

Serologic testing 34 (5%) of 718 GWV referred to Phase II of the CCEP had antibodies to

M.fermentans prior to deployment, 8 (1%) seroconverted after deployment; 116

(5%) of 2233 GWV who were not in CCEP had antibodies to M. fermentans prior

to deployment, 26 (1%) seroconverted after deployment.

Abbreviations: PCR = polymerase chain reaction, CCEP = DOD Comprehensive Clinical Evaluation Program,

GWV = Gulf War veterans, GWI = Gulf War illness, ALS = amyotrophic lateral sclerosis, sign. = statistically significant

These reports stirred considerable interest and controversy, and several studies have now been conducted

to determine rates of mycoplasma infection in Gulf War veterans. (Table 2) Dr. Lo indicated that

evidence of M. fermentans infection should be detectable in most individuals using serological methods.

His large study found no difference in M. fermentans seropositivity or wartime seroconversion rates in ill

Gulf War veterans examined in DOD’s Gulf War registry program compared to veterans not evaluated in

the program.923 Similarly, a large study of Navy Seabees reported no difference in rates of detectable

antibodies to mycoplasma between Gulf War and nondeployed era veterans, and no association of

mycoplasma antibodies with symptoms.525

In contrast, three research groups have identified evidence of mycoplasma infection in a substantial

number of ill Gulf War veterans using specialized DNA detection methods. Dr. Nicolson and colleagues,

in several studies, have reported DNA evidence of mycoplasma infection in 40 to 45 percent of

symptomatic Gulf War veterans, but less than 10 percent of healthy controls.1111,1116-1118 Similarly, a study

evaluating samples submitted to a clinical laboratory indicated that 55 percent of symptomatic Gulf War

veterans tested positive for mycoplasma, compared to 15 percent of healthy controls.1732 In addition, 39

percent of symptomatic Gulf War veterans screened for participation in VA’s large antibiotic clinical trial

tested positive for mycoplasma infection using polymerase chain reaction (PCR) methods.263,355

The general consistency of studies that have detected mycoplasma DNA in Gulf War veterans appears

compelling. But inconsistencies between PCR results from several laboratories that tested for

mycoplasma infection for VA’s antibiotic trial raises some doubt about whether the methods used to
194  Effects of Gulf War Experiences and Exposures

Table 3. Post-War Assessment of Infection in Air Force Gulf War Veterans: CDC Study

Method Organism Tested: Key Findings

Serologic testing for

antibodies in 158 Gulf

War veterans

Anthrax protective antigen: 9% positive, no difference by CMI case status

Botulinum toxin: 6% positive, no difference by CMI case status

Coxiella burnetii: 4% positive, no difference by CMI case status

Dengue virus: 10% positive, no difference by CMI case status

E. chaffeensis: 3% positive, no difference by CMI case status

Leishmania: 5% positive, no difference by CMI case status

Sandfly fever virus: CMI cases 9% positive, controls 2% positive

Toxoplasma gondii: 19% positive, no difference by CMI case status

Yellow fever virus: 83% positive (due to vaccine), no difference by CMI case status

No veterans tested positive for Shistosoma species or S. stercoralis, or for West Nile, Sindbis,

Toscana, Karimbad, or Ishafan viruses

Stool specimen

cultures in 158 Gulf

War veterans

Blastocystis hominis: 8% positive, no difference by CMI case status

Enteroviruses: 9% positive, no difference by CMI case status

Giardia lamblia: 1% positive, no difference by CMI case status

No veterans tested positive for Salmonella, Shigella, Campylobacter, Yersinia, pathogenic E. coli,

Microsporidia, Cryptosporidium parvum, Cyclospora cayetanensis, Isopora belli, or Entamoeba

histolytica.

Source: Fukuda;

464 CMI = chronic multisymptom illness

detect mycoplasma infection—prior to and throughout the trial—were reliable, as discussed in the

Committee’s 2004 report.353,403 As a result, it is not possible to say with certainty whether mycoplasma

infection is associated with Gulf War illness. Uncertainties stem from questions about the reliability of

the DNA methods used, the lack of replication of DNA findings reported from undefined samples, and

conflicting information provided by serological testing.

Still, it is important that three different research teams, using somewhat different methods, have found

that 39-50 percent of symptomatic Gulf War veterans show evidence of mycoplasma DNA in their blood,

particularly studies that found rates in symptomatic Gulf War veterans to significantly exceed those of

healthy controls.263,1111,1732 Mycoplasma infection is one of a limited number of objectively-measured

parameters reported to distinguish symptomatic Gulf War veterans from healthy controls. It is therefore

important to learn, more definitively, whether it is a factor in even a subset of Gulf War illness cases.

If M. fermentans infection rates were shown more definitively to be elevated in ill Gulf War veterans,

important questions would still remain, however.353,1730 It would be important to determine if identifiable

illness or deployment subgroups have higher or lower rates of mycoplasma infection. It would also be

necessary to clarify whether mycoplasma is a causal factor in Gulf War illness or an opportunistic

infection, perhaps associated with general debilitation. Studies using PCR methods similar to those used

in Gulf War studies have reported elevated rates of mycoplasma infection in civilian patients with CFS,

fibromyalgia, ALS, and rheumatoid arthritis.552,1095,1114,1116,1123,1731 Investigators have suggested that

mycoplasma infection may underlie some of the symptoms common to these conditions,1732 perhaps

acting as a cofactor that may stimulate increased production of proinflammatory cytokines.1081,1730

Reports have documented recovery from symptoms of persistent fatigue and debilitation in civilian

patients with elevated levels of M. fermentans who were successfully treated with antibiotics.118,921
Infectious Diseases in Gulf War Veterans  195

It is important to determine more conclusively if mycoplasma infections occur at excess rates in Gulf War

veterans, if they are associated with Gulf War illness, and to further characterize the nature of any

identified association. Unanswered questions about detection methods requires that more conclusive

studies be conducted to determine if testing results in blinded samples obtained from symptomatic and

healthy veterans can be independently confirmed by more than one laboratory. Available evidence does

not provide a clear indication of whether mycoplasma infection does or does not have a role in Gulf War

illness. If such an association is confirmed, it will be important to ascertain if mycoplasma infection

represents an initiating, perpetuating, or opportunistic infection in relation to veterans’ symptoms, and if

its detection provides a useful objective marker that identifies a subset of ill veterans.

CDC evaluation of infection in Air Force veterans. The most extensive assessment of diverse

types of infection following Gulf War service comes from a study conducted by the U.S. Centers for

Disease Control and Prevention (CDC).464 Results are summarized in Table 3. The study evaluated

serum and stool samples in 158 Gulf War veterans from a single Air Force National Guard unit: 99 who

met criteria for chronic multisymptom illness (CMI) and 59 controls. Although laboratory testing of Gulf

War personnel in theater and immediately after their return had identified no cases of sand fly fever, six

percent of veterans in the CDC study tested positive. Veterans with CMI had a five-fold higher rate of

seropositivity than controls, but this excess was not statistically significant in this small sample. Other

identified infections generally occurred at low rates and affected similar proportions of veterans with CMI

and controls.464

Table 4. Post-War Assessment of Infection in Gulf War Veterans: Herpes Viruses

Study Method Key Findings

Carver214

1994

Serology in 37 Gulf

War veterans with

CFS

EBV viral capsid IgG and nuclear antigen antibodies:100% positive

EBV early antigen and nuclear antigen antibodies: 68% positive

EBV viral capsid IgM: 5% positive

Milner1050

1994

Serology in 85

symptomatic Gulf

War veterans

49% positive for recent or reactivated EBV

39% positive for recent or reactivated CMV

Wallace1746

1999

PCR of PBMCs of 46

GW veterans with

CFS, 32 healthy GW

veterans

HHV6 DNA detected in 0 sick, and 0 healthy GW veteran

HHV7 DNA detected in 48% of sick and 44% of healthy GW veterans

EBV DNA detected in 1 sick, 0 healthy GW veterans

No CMV DNA detected in sick or healthy veterans

Vojdani1734

2004

Serology in 100 GW

veterans with GWI,

100 healthy controls

Veterans with GWI had significantly elevated IgM titers for EBV viral

capsid antigen and IgG titers for CMV, HSV1,HSV2, HHV6 and VZV.

Abbreviations: EBV = Epstein-Barr virus, CMV = cytomegalovirus, HHV = human herpes virus, HSV = herpes simplex virus,

VZV = varicella zoster virus, PCR = polymerase chain reaction, PBMC = peripheral blood mononuclear cells

CFS = chronic fatigue syndrome, GWI = Gulf War illness

Herpes virus infection in Gulf War veterans. Herpes viruses are known to produce chronic

infection that can lie dormant or become reactivated under a variety of conditions. In the large U.S. Gulf

War clinical study, veterans who reported having mononucleosis, Epstein-Barr virus (EBV) infection,

prior to the war had nearly three times the rate of chronic multisymptom illness as veterans who had not

had mononucleosis.142 Several herpes viruses have been associated with persistent symptoms and

syndromes similar to those affecting Gulf War veterans.7,186,828,887 One year after their return from theater,

73 percent of 37 Indiana reservists who met criteria for chronic fatigue syndrome (CFS) showed evidence

of either active EBV infection or reactivation of a previous EBV infection.214 Investigators speculated that
196  Effects of Gulf War Experiences and Exposures

this activation may have resulted from deployment-related factors such as reduced sleep, prolonged

exposure to sun and high temperatures, or psychosocial factors.

Findings from studies that have evaluated rates of herpes virus infections in Gulf War veterans are

summarized in Table 4 and, as shown, have been variable. A 1994 clinical series reported by a VA

investigator indicated that, among 85 symptomatic Gulf War veterans, 49 percent showed evidence of

recent or reactivated EBV infection and 39 percent had evidence of cytomegalovirus (CMV) infection. A

later study from New Jersey investigators evaluated antibody titers for human herpes virus six (HHV6)

and EBV in 46 Gulf War veterans with CFS, and tested sick veterans and controls for PCR evidence of

infection by multiple herpes viruses. No serological or PCR differences were found between veterans

with CFS and healthy controls.1746 In contrast, a study that compared clinical laboratory samples from

100 symptomatic Gulf War veterans and 50 healthy controls found that Gulf War veterans had

significantly higher antibody titers to multiple herpes virus antigens, including EBV viral capsid antigen,

CMV, HHV6, herpes simplex types 1 and 2, and varicella zoster virus.1734

Very little additional information is available concerning infectious diseases in Gulf War veterans.

Clinical evaluation of a sample of over 350 Gulf War veterans from the Pacific Northwest identified none

with HIV, hepatitis B, hepatitis C, or syphilis, and only one with an elevated Lyme disease titer.160 Gulf

War registry programs have provided limited information, since registry protocols did not require

veterans to be screened for specific infectious diseases. The most frequently identified infections in both

registries were fungal infections of the feet, nails, and groin area.1651 In addition, a 1992 Army

epidemiologic investigation of unexplained symptoms in an Indiana Army Reserve unit included a limited

number of tests for infectious diseases. Serologic testing was conducted on six symptomatic soldiers for

brucellosis and two for Borrelia burgdorferi, but none tested positive. Stool samples were analyzed for

seven soldiers with diarrhea: none were positive for enteric pathogens, but two were positive for

Blastocystis hominis.

327

Antibiotic Treatment of Gulf War Illness

A 48-year old U.S. Marine Corps officer, attached to the Central Command staff, was

deployed in Saudi Arabia at ODS Central Command Headquarters. He examined SCUD (SS1) missile impact sites. Within 10 months after his return to the United States he presented

with chronic fatigue, skin rashes, diarrhea, headaches, aching joints, muscle pain, fevers,

sleep problems, nausea, vision problems, memory loss, and dental problems. ..... After two

cycles of doxycycline, he completely recovered.

- Case report, antibiotic treatment of Gulf War veteran1118

In theory, insights concerning a possible link between infectious disease and Gulf War illness could be

provided by results obtained when ill veterans are treated with antibiotics. As detailed in the first section

of this report, two case series and two clinical trials have assessed the effectiveness of prolonged and/or

high-dose antibiotic therapy for the chronic symptoms of Gulf War illness. The two case series reports

from Dr. Nicolson and colleagues both indicated that repeated courses of antibiotics provided substantial

improvement for symptomatic Gulf War veterans.1118,1119 In response to these reports, VA conducted a

large multi-center randomized trial of a 12 month course of doxycycline treatment for Gulf War illness in

veterans who tested positive for mycoplasma infection.355 Study results indicated that doxycycline

therapy provided, at most, short term benefit, but no sustained improvement in veterans’ functional status

or symptoms. However, as described in the Committee’s 2004 report, a number of methodological issues

raised questions about the degree to which the study reliably addressed questions concerning detection

and treatment of mycoplasma infection in symptomatic veterans.1268

A second federally-funded trial of antibiotic therapy was conducted by the Louisiana Medical Foundation,

directed by Dr. Edward Hyman.670 Results of this randomized, placebo-controlled trial of an
Infectious Diseases in Gulf War Veterans  197

unconventional, high dose antibiotic regimen were never published. As presented to the Committee by

Dr. Hyman’s collaborators, however, the treatment appeared to provide marked improvement for veterans

with Gulf War illness.332 But questions surrounding the theory underlying the treatment,672,1455 as well as

the lack of peer review and publication of study results also leave major uncertainties about the utility of

this protocol for Gulf War illness. So, although reports suggesting that antibiotic treatments provide

benefit for ill Gulf War veterans are intriguing, they have not thus far provided clear insights regarding a

potential role for infections in the pathophysiology of Gulf War illness.

Biological Warfare Agents in the Gulf War

Questions have been raised about whether Gulf War veterans might have been exposed to biological

weapons during deployment, and if such exposures could account, at least in part, for veterans’ persistent

symptoms.1559,1688 Government and research reports that have reviewed the issue have generally

considered this to be unlikely, based on information available from DOD, the Central Intelligence Agency

(CIA), The United Nations Special Commission (UNSCOM), and other sources.666,1227,1616,1690,1749 The

Committee has identified little information—scientific or anecdotal—that suggests any association

between biological weapons exposure and Gulf War illness. But evidence that directly addresses this

issue is limited, due in part to limits in biological detection capabilities in theater and the postwar loss of

military logs that recorded suspected biological events during the war.1602

No cases of acute or persistent disease due to identified biological warfare agents in the Gulf War have

been reported. Therefore, the central outstanding question is whether exposure to still-unidentified

biowarfare agents in theater could account for any cases of Gulf War illness. Determining if this is a

reasonable possibility requires two types of information. The first relates to whether Iraq possessed one or

more bioweapons that could potentially cause chronic symptoms similar to those of Gulf War illness.

The second concerns the likelihood that Gulf War veterans were exposed to such agents.

Iraqi biological weapons. Iraq denied having biological weapons after the Gulf War, and actively

concealed evidence related to its biological weapons program.693 Iraqi officials were forced to

acknowledge these weapons in 1995, when information came to light from U.N. inspections and the

defection of Husayn Kamil, who had overseen Iraq’s biological weapons program.693 It has now been

documented that Iraq had an active biological weapons program prior to and during the Gulf War. The

program involved multiple types of pathogens—bacterial, viral, and fungal, as well as toxins—that were

in various stages of research, production, and weaponization.693,1301,1494,1839

Prior to the Gulf War, bombs and missiles used for chemical weapons were adapted as delivery systems

for biological weapons, and pesticide sprayers were adapted for dispersion of biological agents and

installed on aircraft and land vehicles. These delivery systems have been described as inefficient and

inaccurate, but capable of causing harm.693,1839 Information obtained after the war from United Nations

inspectors and Iraqi informants indicates that Iraq had loaded anthrax, botulinum toxin, and aflatoxin into

missiles and bombs in preparing for the Gulf War1697,1749 and that Sadam Hussein had authorized the use

of biological weapons in relation to certain circumstances and targets.693,1616 Central Intelligence Agency

reports indicate that during the war, warheads containing anthrax were deployed to four locations in

Iraq.693,1749

As described in relation to chemical weapons, biological weapon exposures might conceivably have

occurred as a result of Iraq’s offensive use of biological agents or inadvertently as a result of Coalition

troops’ handling or destruction of Iraq’s biological weapons. Government investigations have

consistently concluded, however, that it is unlikely that biological agents were released during the war,

either as a result of Iraq’s offensive use or due to Coalition bombing of biological weapons

sites.1589,1616,1749
198  Effects of Gulf War Experiences and Exposures

Anthrax causes an acute and serious upper respiratory condition that is often fatal; it is unlikely that an

anthrax exposure event of any size would go undetected. Further, anthrax infection is not known to be

associated with a persistent constellation of symptoms similar to those of Gulf War illness. Botulinum

toxin is a neurotoxin, one of the deadliest poisons known. Exposures in theater, even at very low levels,

would likely have caused noticeable casualties. Botulinum toxin is also not known to cause a persistent

multisymptom condition in those who survive acute disease following exposure.

Iraq’s development of aflatoxin as a bioweapon was not known until after the war and has puzzled

observers.693,1494,1616,1839 Although long-term exposure can cause cancer and adverse effects on liver and

kidney function, aflatoxin has little identified utility for killing or disabling an enemy during war. The

Iraq Survey Group speculated that Iraq may have overstated its development of aflatoxin to conceal

production of other agents. It also indicated that Iraq had tested aflatoxin in combination with

incapacitating chemical agents—CS (tear gas) and CN (chloroacetophenone)—as well as mustard. No

evidence was identified, however, that combined biological/chemical weapons were produced or

fielded.693

Two additional biological agents that were potentially available to Iraq are known to cause chronic

problems that have similarities to Gulf War illness. T-2 mycotoxin, a type of trichothecene mycotoxin,

was developed by the Soviets after World War II.1616 Reports have suggested it may have been used by

communist forces in Laos, Cambodia, and Afghanistan during the 1970s and possibly by Iraq, in

combination with mustard gas, in the Iraq/Iran War in the 1980s.605,736,1301,1561 Acute symptoms include

skin redness and blistering, eye irritation, respiratory problems, vomiting and diarrhea, fatigue, and

muscle pain. Long term sequelae include immune suppression, cognitive problems and diarrhea.298 The

RAND report on chemical and biological weapons concluded that acute exposures would not likely have

gone undetected, however, due to the extreme sensitivity of skin and eyes to this substance.74

Brucella species are also known to have been developed as biological weapons by the Soviet Union.881

Iraq was known to possess cultures of at least two species, and to have conducted research specifically on

B. abortus.

693 Brucella can cause a subclinical infection or a delayed symptom complex that resembles

Gulf War illness. Symptoms may include fever, headache, weakness, fatigue, joint pain, gastrointestinal

symptoms, altered mood and cognition, and respiratory problems.574 However, there has been no reported

evidence, obtained prior to or after the war, indicating that Iraq mass-produced or weaponized brucella.

Detection of biological agents in theater. A number of measures were taken to detect and identify

biological agents during the Gulf War. These focused primarily on anthrax and botulinum toxin, the two

agents believed by military planners to have been weaponized by Iraq. Vaccines for both agents were

provided to U.S. troops, as supplies allowed. In theater, biological teams were stationed in 12 locations,

equipped with air sampling and biological detection equipment.1616 Monitoring units collected airborne

particulates and tested samples for the presence of anthrax and botulinum toxin. Identification of other

agents required samples to be submitted to laboratories in theater or the states. Field samples were also

collected from dead animals, water, and soil. Of 943 air samples taken in the field, 14 were initially

identified as being positive for anthrax and three for botulinum toxin. All were later determined to be

false positives after more definitive testing at military laboratories in Saudi Arabia.1616 Other samples

testing positive for chemical or biological agents in theater were sent to Fort Detrick for more definitive

testing. Although specific results of these tests were not made available to OSAGWI investigators, DOD

has reported that the samples “yielded no red flags identifying or confirming biological warfare

agents.”1616

The Coalition’s ability to detect biological agents in theater was limited, however. Air sampling was

done primarily during night time hours in the 12 selected areas, and only anthrax and botulinum toxin

could be detected in the field.1616 Even for those agents, detection capabilities have been described as

rudimentary.1227,1670,1688,1690 For example, monitoring equipment could not reliably detect aerosols
Infectious Diseases in Gulf War Veterans  199

containing anthrax or botulinum toxin, the form that would be expected in relation to an exploding missile

used in a biological attack.1839 The OSAGWI investigation concluded that it was not possible to

categorically rule out any use of biological weapons in theater. However, data and information from

multiple sources had not provided any confirmed evidence that biological agents had been released nor

that any troops had been exposed.1616

It is not certain that Iraqi disclosures and subsequent investigations have provided a complete picture of

Iraq’s biological program. In addition, U.S. capabilities for detecting biological agents in theater were

limited. But available results from air monitoring, environmental samples, and clinical testing provide no

indication that Gulf War veterans were exposed to, nor that they became ill as a result of, biological

weapons during deployment. It also appears unlikely that undocumented exposure to biological agents

that may have been present in theater would have resulted in the types of chronic symptoms associated

with Gulf War illness. So, although it is not possible to rule out the possibility of discrete incidents

involving exposure to unknown agents, there is currently no basis for suggesting a link between

biological weapons and Gulf War illness.

Summary. Infectious diseases in Gulf War Veterans. Acute respiratory and diarrheal diseases

affected a sizable proportion of military personnel during the Gulf War. However, Gulf War personnel

were minimally affected by diseases endemic to the region that had historically been problematic for

troops deployed to the Middle East. No evidence has indicated that Gulf War veterans were exposed to

biological weapons during the war, or that Gulf War illness is the result of such exposures. Some

pathogens to which veterans may have been exposed in theater can produce chronic conditions similar to

Gulf War illness. But relatively few studies have systematically evaluated Gulf War veterans for

evidence of active or latent infection by those organisms. Primary interest has focused on two

intracellular infections: an atypical systemic leishmaniasis caused by L. tropica and infection by

mycoplasma fermentans.

Viscerotropic leishmaniasis has been confirmed in 12 Gulf War veterans, but the total number of cases is

not known. This infection is difficult to identify and its prevalence in Gulf War veterans or association

with Gulf War illness has not been systematically evaluated. Several studies have identified evidence of

mycoplasma DNA in about 40 percent of symptomatic Gulf War veterans, a rate significantly higher than

that found in healthy controls. But uncertainties about test reliability and conflicting results from other

studies have called these findings into question. Therefore, questions remain concerning rates of infection

by both leishmania and mycoplasma and their potential association with Gulf War illness.
200  Effects of Gulf War Experiences and Exposures

Recommendations

Because of unanswered questions related to possible associations between Gulf War illness and persistent

infections in Gulf War veterans, the Committee recommends the following research:

 Using the most reliable assay methods available, determine the rate of leishmania infection,

particularly L. tropica infection, in veterans with Gulf War illness and healthy controls

 Using the most reliable DNA and serological assay methods available, determine the rate of

mycoplasma infection, particularly M. fermentans, in veterans with Gulf War illness and healthy

controls
Other Exposures in Theater  201

Other Exposures in Theater

Sand, Tent Heaters, Solvents, Jet Fuel, CARC,

and Contaminated Food and Water

In the 17 years since Desert Storm, many possible causes or contributors to Gulf War illness have been

suggested. In addition to the Gulf War-related exposures previously described, the Committee reviewed

available information on the health of Gulf War veterans in relation to sand and particulates,

petrochemical exposures other than oil well fires (tent heaters, solvents, jet fuel), chemical agent resistant

coating (CARC paint), and contaminated food and water. Each of these exposures have the potential to

cause adverse health effects, some chronic, and may have relevance to Gulf War veterans’ multisymptom

illness. They are considered in aggregate here in considerably less detail than exposures previously

discussed for a number of reasons. For some, there was little systematically-collected information

concerning their relationship with chronic symptoms or multisymptom illness in Gulf War veterans. In

addition, some of the exposures considered here, despite their potential for causing adverse effects, are

unlikely to have contributed to Gulf War illness for most ill veterans based on what is known about the

pattern and extent of veterans’ exposures during deployment. This would include exposures with known

toxic effects that were encountered by a very limited number of Gulf War veterans, and exposures widely

encountered during deployment, but in patterns similar to those associated with other deployments or

military service at home.

The general approach used in evaluating each of these exposures, although described in less detail, was

the same as that used for other Gulf War exposures. The Committee reviewed available information

about the extent and patterns of the exposure in theater, what is known generally from human and animal

studies about toxic effects of the exposure, and information from studies of Gulf War veterans concerning

associations between the exposure and symptom complexes, multisymptom illness, and other health

outcomes.

Sand and Particulate Exposures in the Gulf War

Images of the dense, black smoke generated by burning oil well fires in Kuwait are quite familiar, but

veterans also returned home with dramatic stories of blinding sandstorms in the desert that could last for

many hours, sometimes days. On some days, sandstorms were extreme enough to drastically reduce

visibility and require personnel to don protective goggles and/or tie cloths over their noses and mouths to

continue their duties.1349,1625 Levels of airborne particulates in Kuwait are among the highest in the

world,1578 and rates of asthma and other respiratory conditions in the local population are substantially

higher than in the U.S.1621 Newly arriving troops often developed what is commonly called the “Kuwaiti

crud,” a limited-duration cough or flu-like condition resulting from breathing in high levels of

particulates.903,1349 Airborne particulates were especially a problem during the spring and summer

months, due to the intensity of the shamal winds blowing in the region.

1625

Military personnel in the Gulf War were exposed to particulates from multiple sources, including the

high, naturally occurring background levels in the region, particulates in the smoke generated from

burning oil well fires, particulates in tents when tent heaters were in use, and additional particulates

associated with engine exhaust and industrial pollution in the region. Air quality monitoring conducted

by the Army at locations throughout Kuwait and Saudi Arabia beginning in May 1991 indicated that

levels of particulates smaller than 10 microns were many time higher than those considered safe by U.S.

air quality standards.1587,1625 The Department of Defense estimated that troops in the region would have

been exposed to elevated levels of particulates for an average of 153 days.1625 Air monitoring indicated
202  Effects of Gulf War Experiences and Exposures

that, during the months that oil fires were burning, 75 percent of measured particulates were due to

sand.1587

Health effects of particulates vary with the concentration and duration of exposure, and with the physical

and chemical properties of particles—their size, shape, and chemical composition. A number of health

concerns relate particularly to smaller size particulates. Those between 2.5 and 10 microns in diameter

can be inhaled into and accumulate in the lungs; those between 0.1 and 2.5 microns can lodge more

deeply into the alveoli; and those smaller than 0.1 microns (also known as ultrafine particulates) can cross

the pulmonary epithelium and enter the general circulation. The sand in the Kuwait region is extremely

fine—almost powder-like—and has often been described as being more like dust than the types of sand

more familiar to Americans. It also has a relatively low silica content. A 2000 report commissioned by

DOD concluded that exposure to airborne particulates in the region was not expected to produce long

term silica-related health effects.1536

Exposure to high levels of particulates have most commonly been associated with acute and chronic

respiratory and cardiovascular effects, including exacerbation of preexisting conditions.1045,1201,1220

Temporary spikes in urban levels of airborne particulates result in increases in emergency room visits and

mortality for individuals who are most vulnerable.

109,626,856

Recent animal studies also indicate that inhaled ultrafine particulates are associated with systemic

immune and inflammatory effects.492,1703 After entering the circulation from the lungs, ultrafine

particulates access a variety of tissues, including the liver and the brain.1107,1135,1136 Airborne ultrafine

particulates may also enter the brain directly through the nose via olfactory neuronal pathways, where

they can accumulate and, according to several recent studies, produce neuroinflammatory

effects.147,206,397,1135,1719 This is particularly of interest in light of research presented to the Committee

indicating that DU entry into the brain through the nose was enhanced in the presence of nasal

inflammation,896 presumably a common condition in Kuwait as a result of the high levels of airborne

particulates.

In 1992, the first published report of an unexplained illness in Gulf War veterans described a condition

that affected troops housed in abandoned apartment buildings in Al Eskan village, Saudi Arabia, which

had not been inhabited for the previous decade.832 The report indicated that about two-thirds of the

soldiers became ill with respiratory and gastrointestinal symptoms within 72 hours of arriving in

quarters. Although most recovered with antibiotic treatment, some relapsed and were subsequently

unresponsive to treatment. Investigators hypothesized that the condition had resulted from troops’

exposure to the mix of fine dust and pigeon droppings that covered their living area, triggering

immunopathologic reactions and a unique pneumonitis dubbed “Al Eskan disease.” Their analysis of the

sand in the area identified it as a very fine dust (0.1 – 0.25 microns) from which bacteria and fungi were

isolated. Investigators hypothesized that this dust may have acted as a carrier, enhancing delivery of

pathogens and/or chemical exposures during deployment and exacerbating their effects.831,833 No data

were provided, however, specifically demonstrating this carrier effect nor identifying health effects

related to the combined particulate/toxin exposure. More recently, scientists at the Naval Medical

Research Center have undertaken detailed investigations of the characteristics and composition of the

sand in the Kuwait region, and its potential to cause adverse health effects.942 It is hoped these data will

provide additional insights regarding the “dirty dust” hypothesis put forward in the wake of the Gulf War.

As described, sand and particulate exposure were ubiquitous throughout the Gulf War theater.

Consequently, very limited useful information can be obtained from epidemiologic assessment of

associations between particulates and multisymptom conditions. About half of Navy Seabees and

Australian veterans who served in the Gulf War reported they experienced sandstorms during

deployment,524,790 and a similar proportion of Air Guard troops reported they spent considerable time

sandbagging or digging in sand while in theater.1124 As shown in Appendix A-10, these variables were
Other Exposures in Theater  203

associated with elevated rates of chronic symptoms and multisymptom illness in unadjusted analyses but,

after adjustment for multiple exposures, sandstorms remained a significant risk factor for Gulf War illness

only for Navy Seabees.527 The location-related pattern of Gulf War illness observed in several

studies692,1236,1476 is inconsistent with the widespread presence of blowing sand and high levels of

particulates throughout the region. In addition, if blowing sand and particulates were a primary cause for

Gulf War illness, high rates of unexplained multisymptom conditions would be expected among

personnel serving in the current Iraq War, which has thus far not been the case.631

In summary, Gulf War veterans were exposed to extremely high levels of airborne particulates from

multiple sources during deployment. Most particulates, including fine and ultrafine particles, were due to

the high levels of fine, blowing sand in the region. Animal studies have recently found that inhaled

ultrafine particulates may have immune and inflammatory effects that were previously unrecognized, both

systemically and in the brain. Many questions remain, however, concerning what implications these

findings may have with respect to chronic brain and behavioral effects. Specific to the Gulf War

experience, little is known about the potential for synergistic effects between inhaled particulates and

other inhaled toxicants during the war. Given the many unanswered questions related to possible

neuroinflammatory and synergistic effects of inhaled ultrafine particulates, it is unknown whether they

may have contributed to chronic ill health in veterans in combination with other Gulf War exposures.

However, given the widespread of exposure to sand and particulates in the Gulf War and in the current

Iraq War, the Committee concludes they are unlikely to be a primary cause of Gulf War illness for most

affected veterans.

Exposure to Combustion Products from Tent Heaters in the Gulf War

Troops in the Gulf War theater experienced diverse living conditions during deployment. Some

personnel, for varying periods of time, might have slept under the stars or under their tanks in the desert,

been housed in tent cities erected for U.S. troops, camped in abandoned—sometimes waste infested—

housing areas in Southern Iraq, or housed in relatively comfortable accommodations in apartment

buildings or hotels. For those in tents during the colder months, November 1990 through April 1991, tent

heaters were used to keep warm. Different fuels were burned in these heaters—jet fuel, diesel fuel, and

kerosene—and reports indicate that heaters were typically unvented, allowing potentially harmful exhaust

to accumulate inside tents. Current policy directs that only Army-approved, vented tent heaters are to be

used in areas where people sleep and specify kerosene as the preferred fuel.1580

Fuel burned in heaters emits a complex mixture of gaseous compounds and particulates, similar to those

described in relation to oil well fires—carbon monoxide (CO), carbon dioxide (CO2), nitrous oxides

(NOx), sulfur oxides (SOx), volatile organic compounds, polycyclic aromatic hydrocarbons, and

particulates of varying composition and size. Actual exposure levels experienced by troops inside tents

would have varied with the type of heater used, the fuel burned, and the duration of time the heater was

used. In cold weather, typical exposures might have occurred for a continuous 8 hours each day, for

weeks to months. Two studies from Lovelace Respiratory Research Institute characterized emissions

associated with three types of unvented heaters and three types of fuels used in the Gulf War, in

simulation experiments conducted using vinyl-backed Army tents.238,1838 Results indicated that when tent

doors were closed, CO, NOx and SOx exceeded established air quality standards.1838 Particulates, mostly

in the ultrafine range (0.2 – 0.3 microns), were also in excess of established standards and contained high

levels of sulfur, ammonium, and carbon.238

Adverse health effects potentially resulting from prolonged inhalation of fuel combustion products were

previously described in relation to oil fires and particulates. Briefly, high levels of inhaled particulates

can have adverse respiratory effects and ultrafine particulates may also be associated with neurological

effects.147,1136 Carbon monoxide impairs oxygen delivery to organs and tissues and can lead to
204  Effects of Gulf War Experiences and Exposures

neurological and cardiovascular effects, even death at extremely high levels. Other combustion-related

pollutants such as NOx and SOx are also associated with respiratory effects. The Institute of Medicine’s

report on Fuels, Combustion Products, and Propellants found that evidence supports an association

between fuel combustion products and lung cancer,

684 but no excess of lung or other respiratory cancers

have been reported in Gulf War veterans. Four individuals are reported to have been hospitalized for

carbon monoxide poisoning during the Gulf War.1813

Epidemiologic studies indicate that a large proportion of Gulf War veterans used tent heaters during

deployment. Fifty to seventy percent of U.S. Army veterans1239,1708,1804 but only 21 percent of Navy

Seabees reported using tent heaters.524 Several studies have evaluated rates of symptom complexes and

multisymptom illness among veterans who reported using tent heaters during the war, as summarized in

Appendix A-5. In analyses that did not adjust for effects of other exposures in theater, use of tent heaters

was associated with higher rates of multisymptom conditions in three studies, with odds ratios ranging

from 1.9 for multisymptom illness to 2.8 for multiple chemical sensitivity.1264,1466,1698 Three studies

assessed this association, in two veteran populations, after adjusting for additional exposures in theater.

Studies of the Fort Devens Army cohort found that the use of tent heaters was significantly associated

with both cardiovascular and pulmonary symptoms,1239 and also with a modest excess of multisymptom

illness (OR = 1.4).

1804 There was no association between use of tent heaters and Gulf War illness in the

Navy Seabees study.527

Taken together, this information indicates that a substantial proportion of personnel who served in the

Gulf War were potentially exposed to excess levels of particulates and air contaminants for varying

periods of time as a result of using unvented tent heaters. This exposure was more prevalent in Army

than Navy personnel and any effects resulting from tent heaters might be more pronounced in Army

veterans. It is unknown whether exposure to particulates and other contaminants produced by tent heaters

may have interacted synergistically with other exposures in theater, including other sources of particulates

and airborne pollutants in theater. The very limited amount of information available from epidemiologic

studies does not provide a clear indication of whether tent heaters may have contributed to Gulf War

illness for some individuals, but indicates that if there is an association, it is likely to be modest.

Organic Solvents in the Gulf War

The term “solvents” refers to a broad range of compounds of different types that have the capacity to

dissolve or dilute other chemicals. Organic solvents are widely used in the military and throughout

society. There are no government reports documenting the specific types of solvents used or the degree

of solvent exposures that occurred during the Gulf War. In the Institute of Medicine’s Gulf War and

Health, Volume 2: Insecticides and Solvents, the IOM panel reports that it gathered information from

veterans and the Department of Defense to generate a list of 53 individual solvents likely used during the

Gulf War.682 The list includes a diverse array of compounds used in painting, vehicle maintenance,

equipment repair, and cleaning and degreasing. There is little information concerning whether or how the

solvents used by military personnel during the Gulf War might have differed from solvents used in other

deployments or stateside, with the exception of jet fuels and CARC paint, which are discussed separately.

In epidemiologic studies and registries, at least half of Gulf War veterans have consistently reported some

exposure to “solvents,” as a general category, during deployment.751,788,839,1698

Toxic effects of individual solvents vary with the specific type of compound, exposure route, and dosage.

Solvent exposures often involve mixtures of multiple compounds, the combined effects of which are not

well understood. The central nervous system is a primary target of solvents, although some solvents are

known to have hematological effects or are associated with liver disease, renal toxicity, reproductive

effects, and cancers.89 Excess solvent exposure has long been associated with reports of toxic

encephalopathy, and specifically with a neurasthenic-type syndrome that resembles Gulf War
Other Exposures in Theater  205

illness.61,532,578,913,1110 Symptoms typically include chronic headache, memory impairment, balance

problems, fatigue, and mood changes. Subtle indications of neuropathology may also be identified with

neurocognitive testing and brain imaging studies.33,595,1781 The existence of a unique syndrome (e.g.

“painters’ syndrome”) associated with chronic solvent exposure remains somewhat controversial,

however.31,940,1554,1555 Encephalopathy associated with solvent exposure is typically described in workers

exposed to relatively high levels of solvents for many years, as opposed to the briefer-duration exposures

associated with Gulf War service.1781 In its review of the occupational literature on solvent exposure, the

IOM concluded there was sufficient evidence to indicate that solvents are associated with leukemia and

suggestive evidence of an association between solvents and chronic neurobehavioral effects.682

Solvent exposure during the war, as a risk factor for chronic symptomatic illness, has been evaluated in

four Gulf War veteran populations. As shown in Appendix A-11, each study identified significant

associations between solvents and chronic symptom complexes in analyses that did not adjust for effects

of other exposures in theater.692,788,1264,1698 Solvents were not associated with chronic symptomatic illness,

however, in the one study that did control for effects of other exposures.695 Additional information

relevant to solvent exposures is provided by a population-based study of Gulf War veterans from the

Pacific Northwest. The study reported that veterans whose work in theater involved degreasing

machinery or repair of vehicles, generators, or batteries, had a 2-3 fold higher rate of multisymptom

illness than those with other occupations.1466 While interesting, these results are from crude analyses that

did not consider effects of other work activities or exposures, so it is not possible to determine whether

they are indicative of a true association.

In summary, chronic exposure to high levels of solvents has been associated, in occupational studies, with

a chronic encephalopathy that resembles Gulf War illness. It is likely that a large proportion of Gulf War

veterans were exposed to solvents of various types and at varying concentrations and durations during

deployment. There is little information, however, indicating that solvent exposure patterns in the Kuwaiti

Theater of Operations were either unique or excessive. The Committee identified no studies that

identified solvent exposure as an independent risk factor for chronic symptoms in Gulf War veterans.

The Committee also did not identify any reported incidents related to unusual or excess solvent exposure,

with the exception of fuels and CARC painting operations, and no testimony or anecdotal reports from

veterans describing the development of symptoms in relation to solvent exposure. Therefore, the

Committee concludes that solvent exposures during the Gulf War are not likely to have caused Gulf War

illness.

Jet Fuel in Relation to Gulf War Illness

Veterans in all areas of the Gulf War theater were commonly exposed to fuels of different types during

deployment. Government estimates indicate that nearly two billion gallons of fuel were used by the U.S.

military between August 1990 and May 1991 in the Gulf War.1506 About 75 percent of that was jet fuel,

used to power not only jets but vehicles on the ground—tanks and trucks. Jet fuel, along with kerosene,

was also burned in tent heaters, cook stoves, and generators, used to incinerate trash and human waste,

and burned to generate smoke as a method of obscuring troops and equipment. Uncombusted fuels were

also commonly sprayed or dumped on the ground to suppress dust and blowing sand, and used as solvents

in cleaning weapons and equipment. Twenty-four percent of the fuel used in theater was diesel, used for

many of the same purposes as jet fuel. Only one percent of the fuel used was regular gasoline.1506 The

majority of the fuel used by the U.S. during the war was obtained from local sources, primarily Saudi

Arabia.

The chemical and physical properties of uncombusted fuels differ from those of burning fuels and

exhaust. The present discussion focuses on health effects potentially associated with exposure to

uncombusted fuels; effects of combusted fuels are addressed in sections of the report related to oil well
206  Effects of Gulf War Experiences and Exposures

fires and tent heaters. During the Gulf War, the highest-level exposures to uncombusted fuels would have

occurred among personnel whose work related to the supply and storage of fuels, those who fueled and

worked with aircraft, those who fueled, maintained, or drove ground vehicles, and those exposed to fuels

that were sprayed or dumped onto the ground to suppress the blowing desert sand. In national studies,

about 80 percent of both U.S. and U.K. Gulf War veterans report being exposed to fumes from diesel or

petrochemicals during deployment, and 57-67 percent report dermal exposure to fuels.751,1698

He described one brigade dumping 30,000 gallons of diesel fuel on the roads daily, and said

U.S. service members living in tents near the roads—and particularly truck drivers carrying out

the spraying—complained of nausea from breathing the resulting fumes. As a result, the

preventive medicine person to whom they reported obtained respirators for the drivers’ use.

-- Report on testimony of Gulf War Army Sanitary Engineer,19961227

Petroleum-derived fuels are complex mixtures of organic compounds—hundreds of aliphatic and

aromatic hydrocarbons, other toxic solvents (e.g. benzenes, toluenes, xylenes) and various performanceenhancing additives.1287 The most widely-used fuel in the Gulf War was jet fuel and several types were in

use in theater. JP-4, a kerosene/gasoline mix, was used but was being phased out in 1991. JP-5,

primarily kerosene, was the Navy’s primary jet fuel. JP-8, a military version of the commercial jet A-1

fuel with additional additives, was designated the primary fuel for use in Army and Air Force aircraft and

ground vehicles. These generalizations did not always hold in the actual circumstances of war when, for

example, Air Force units were located on bases where only JP-4 was available, or Army vehicles used

diesel fuel due to operational problems. Different types of fuels have different toxicity profiles that relate

to the source and type of petroleum used, variability in refinery processes, and specific compounds and

additives contained in the fuel. JP-8 was designated as the primary military fuel of choice to replace JP-4

because it is less volatile, reducing the risk of explosions and fires, and contains lower levels of the toxic

chemicals n-hexane and benzene.1506,1579 However, JP-8 carries greater potential for dermal toxicity than

JP-4. In 2003, the National Research Council, citing uncertainties related to adverse effects of exposure

to JP-8, recommended that the military no longer use JP-8 for desert sand control or for obscuring troops

and equipment.1103

As with other classes of hazardous exposures, toxic effects of fuels depend on the specific type of fuel,

the physical state of the fuel, the dosage, and the route of exposure. Fuel exposure can occur through

inhalation of vapors and aerosols, through dermal absorption, and through ingestion. Despite their

widespread use, uncertainties remain concerning toxicological effects of jet fuels, particularly chronic

effects. The U.S. Air Force has sponsored a number of research initiatives in the past decade to address

questions relating to biological and behavioral health effects of jet fuels, particularly JP-8.792,1287 Health

effects described in association with jet fuel exposure include pulmonary effects, dermal effects,

neurobehavioral effects, and immune effects. People acutely exposed to high levels of JP-8 report

symptoms that include nausea, dizziness, fatigue, memory impairment, headache, respiratory distress, and

skin irritation, but are not reported to have excess healthcare visits or diagnosed medical

conditions.792,1221,1287

Studies evaluating effects of jet fuel exposure on the central nervous system are of particular interest in

relation to the chronic symptoms affecting Gulf War veterans. Human studies conducted more than

twenty years ago indicated that chronic exposure to jet fuel was associated with a multisymptom

syndrome (dizziness, headache, nausea, fatigue, memory difficulties, respiratory problems) accompanied

by shortened attention span, reduced auditory evoked cortical potentials, electroencephalogram

abnormalities, and psychiatric symptoms.817-819,1504 More recently, several studies have demonstrated

subtle central nervous system (CNS) effects in relation to lower-dose jet fuel exposure.1287,1290 For

example, exposure to JP-8 among workers at an Air National Guard base, some of whom had no direct
Other Exposures in Theater  207

contact with fuels, was associated with significant neurocognitive impairment on the day of exposure.1557

Deficits were observed on measures of information processing and executive function and were most

pronounced in relation to more complex tasks. In a large study of Air Force personnel, workers with

higher level exposure to jet fuel continued to exhibit deficits in cognitive capacity (digit span, symbol

digit tests), and simple motor skills (tapping tests) 14-72 hours after exposure.792 Other studies have

demonstrated balance abnormalities1430 and alterations in blink response in workers exposed to jet fuel.1002

Although these studies have provided important insights regarding short-term effects of exposure to jet

fuels, they did not determine whether jet fuel can produce longer-term CNS effects in humans.

In animal studies, inhalation of jet fuel has been shown to modulate behavior and CNS neurotransmitters

as long as 85 days after exposure, resulting in reduced dopamine levels and increased levels of serotonin

metabolites HVA and 5-HIAA.

1131,1317 Animal studies have also indicated that repeat inhalation of jet

fuel produces impaired learning of complex tasks, but not simple tasks, that persists for up to 180 days

post exposure.1289 In addition, inhalation of jet fuel vapors has been associated with genomic alterations

related to neurotransmitter signaling pathways.904 Also of possible relevance to chronic symptoms

affecting Gulf War veterans, animal studies have demonstrated diverse effects of jet fuel on

immunity367,582-585,782,1691 and on pulmonary function.363,1298,1492,1796

In discussions with the Committee, Dr. Glenn Ritchie, a neurotoxicologist with expertise in neurological

and behavioral effects of jet fuel, suggested that jet fuel exposure, when combined with other Gulf Warrelated exposures, might have unexpected consequences that are relevant to Gulf War illness.

1288 This

could include, for example, adverse effects from inhalation of “sand aerosols” formed by the mix of fuel

vapors with fine airborne particulates in the region, or unanticipated effects of other exposure

combinations. Few studies have evaluated interactions between jet fuel and other Gulf War-related

exposures, however. One study identified limited immune alterations (suppressed plaque-forming cells,

decreased delayed hypersensitivity) in mice exposed to a mixture of jet fuel, PB, and DEET. 1187 In

addition, jet fuel has been shown to enhance the absorption of permethrin in a porcine skin model,

1295 and

to inhibit metabolism of DEET and carbamate pesticide in a liver cell culture model.391,611

The Institute of Medicine’s Gulf War and Health report on Fuels, Combustion Products, and Propellants

reviewed hundreds of studies related to the human health effects of fuels. The report concluded that there

was insufficient evidence to determine whether there is an association between exposure to uncombusted

fuels and any of the health outcomes evaluated.684 This conclusion relied on results of human studies, but

the studies considered did not include the human studies of neurological effects referred to above.

Studies of Gulf War veterans have provided information on the relationship of veteran-reported exposures

to fuels in theater and rates of chronic symptoms and multisymptom conditions, as shown in Appendix A5. Five studies specifically evaluated the association of skin contact/direct contact with fuels with chronic

symptom complexes in Gulf War veterans.695,1264,1466,1507,1698 All reported significant associations in

analyses that did not consider effects of other exposures in theater, with one suggesting a dose-response

effect. 1466 Two studies found that fuel contact was not associated with chronic symptoms, when effects

of other exposures in theater were considered.695,1507 In addition, four studies specifically assessed

whether veterans who were exposed to fuel sprayed on the ground had higher rates of multisymptom

conditions. Three found no association between fuel sprayed on the ground and chronic symptoms in

analyses that controlled for effects of other exposures,527,695,1507 and one reported no association between

this exposure and defined syndromes in unadjusted analyses.564

In summary, fuel exposures during the Gulf War were widespread. Most Gulf War veterans were likely

exposed to some level of uncombusted petroleum fuels during deployment, predominantly jet fuel, and

subgroups experienced higher-level exposures related to their work activities. There is no information

indicating that fuel exposures associated with Gulf War service differed markedly from those of other

military deployments or service in the U.S., with one exception. That exception is the use of fuels to
208  Effects of Gulf War Experiences and Exposures

control blowing sand, which may have resulted in high levels of inhalation and dermal exposure for some

individuals, and lower level, repeat inhalation exposures for others. Multiple studies in humans have

suggested that inhalation exposure to uncombusted fuel is associated with acute neurobehavioral effects.

In studies that assessed chronic symptoms or multisymptom conditions in relation to uncombusted fuel

exposure in the Gulf War, however, no significant associations were identified. In addition, the

Committee identified no incident reports or anecdotal reports from veterans indicating that they

developed acute or chronic illnesses that they attributed to exposure to fuels. As a result, the Committee

concludes that, although uncombusted petroleum-based fuels may have the potential to cause health

effects similar to the chronic health problems affecting Gulf War veterans, it is unlikely that they are a

primary cause of Gulf War illness for the majority of affected veterans.

CARC Paint: Exposure to Chemical Agent Resistant Coating in the Gulf War

In addition to the hundreds of thousands of troops mobilized to the Middle East during Operation Desert

Shield, thousands of military vehicles were brought into theater for the war effort. Prior to their arrival,

most military vehicles were painted in the familiar green “woodland” camouflage, necessitating a massive

effort to repaint them a tan color more appropriate for desert warfare.1619 Large painting operations were

set up in theater to paint incoming vehicles prior to the initiation of Operation Desert Storm. After the

ceasefire in February 1991, similar operations repainted many vehicles with woodland camouflage colors

before they were shipped back to the United States.

Because of prewar concerns regarding Iraq’s arsenal of chemical weapons, many of the newly arriving

vehicles were painted with a special compound, chemical agent resistant coating, or CARC paint. CARC

paint is a heavy polyurethane coating that, when applied to tanks and other vehicles, provides protection

from chemical warfare agent penetration, facilitates decontamination from chemical agents, and extends

the service life of the vehicle. CARC contains multiple potentially hazardous compounds, including

toluene, benzene, crystalline silica, and ketones. The compound in CARC considered most hazardous is

hexamethylene diisocyanate (HDI), which hardens the paint. In addition, large amounts of potentially

hazardous solvents (paint thinners, cleaners, etc.) were used in painting operations. Exposure to

aerosolized CARC paint, at sufficiently high levels, causes respiratory problems, dizziness, fatigue,

headache, skin rashes, nausea and vomiting, and chemical hypersensitivity.326,1577,1619 CARC is not

considered particularly hazardous after it dries, however, unless it is aerosolized by sanding or chipping,

or heated to high temperatures.

Military occupational safety guidelines require personnel applying CARC paint to use respirators, wear

protective gear that covers all exposed parts of the body including head and hands, and work in properly

ventilated areas.1585,1619 DOD reports indicate that CARC paint was used almost exclusively for Army

vehicles during the Gulf War. Inadequate CARC paint supplies required the Marine Corps to paint their

vehicles with other types of tan paint that did not contain isocyanates. The Air Force and Navy routinely

use other types of paint for their vehicles and aircraft.1619

The most concentrated and sustained exposures to CARC paint occurred among personnel who worked in

painting operations established for mass painting of vehicles. In September of 1990, the first painting

operation involving CARC paint was set up at the Port of Ad Dammam, Saudi Arabia, where painting

was initially done by experienced civilian contractors who had proper protective equipment. Two

additional major CARC spray painting operations were established by the Army at Ad Dammam and Al

Jubayl.1619 These sites were operated by a Florida Army National Guard unit, the 325th Maintenance

Company, which had not been trained in CARC painting operations. The 325th began painting vehicles in

December, 1990. Members of the unit worked around the clock in tents erected to spray paint vehicles.

Reports indicate that they lacked both proper personal protective gear and the required air circulation

equipment. According to a December 1990 memo from a safety officer with the Army Central
Other Exposures in Theater  209

Command, personnel began reporting health problems—dizziness, rashes, vomiting, and nausea—within

a very short time.1584 Onsite investigations were conducted at Ad Dammam and Al Jubayl between

December 1990 and June 1991. Painting operations were temporarily shut down at times, due to safety

concerns.1573,1619 Eventually, protective gear and respiratory equipment were provided to members of the

unit but, in some situations, not until many months after painting operations began.1619

A report from DOD’s Special Assistant for Gulf War Illnesses indicates that other, smaller CARC

painting operations were established throughout theater, but that these operated for shorter periods of time

and generally applied CARC using brushes and rollers, rather than by aerosol spray painting.1619 In

addition, CARC was used on a smaller scale by individual units in painting and touching up vehicles.

The DOD report also indicates that their office had received word, in 2000, of medical problems reported

by civilian painting contractors that they attribute to their use of CARC paint during the Gulf War.1619

I served nine months in the Persian Gulf in the 325th Maintenance Combat Support Unit, a

Florida Army National Guard Company. I have chemically induced asthma, experience

allergic reaction to various substances from cigarette smoke to household cleaners. I have

shortness of breath, muscle aches and cramps, reappearing sores, cognitive dysfunction,

numbness in my face and hands, and extreme fatigue. Fourteen months after returning from

the Gulf I was forced to take a medical disability from a job of 11 years and I’m not able to do

the physical labor nor the mental work I did before my Gulf War service.

- 1996 testimony, Gulf War veteran1229

Members of the 325th Maintenance Company continued to report health problems, some of them severe,

after their return from theater. Despite concerns raised by military authorities and Congressional offices,

no systematic evaluation of the health of members of this unit was ever conducted. In addition, the

Committee identified no other reports systematically documenting short or long-term health effects of

personnel who used CARC paint during the war. To find out more about possible long-term health

effects related to CARC exposure, Committee staff obtained information from memos and reports

describing the health of members of the 325th Maintenance Company during and after the war, from

DOD’s report on the use of CARC paint during the war, from testimony presented to Congress and the

Presidential Advisory Committee, from a Congressional office that assisted veterans in the 325th, from

physicians who evaluated and assisted ill veterans in the unit, and from the regional VA office that

processed disability claims for veterans in the unit.

In the years since the war, media reports have continued to describe chronic health problems among

members of the 325th Maintenance Company.279,1772 In 1993, Dr. William Johnson testified to Congress

that personnel he had examined from the 325th had a number of symptoms commonly seen in Gulf War

veterans—headache, dizziness, fatigue, and neurocognitive problems—as well as asthma-like

symptoms.

719 An occupational medicine physician who had evaluated about 20 veterans in the unit

reported to DOD that the paint fumes from the Al Jubayl operations had permeated the entire camp,

affecting eating, sleeping, and administrative areas. He indicated that the air was so permeated with

solvent vapor that lights had to be replaced with a type that resisted explosions.1611 Dr. Bruce Pettyjohn

was medical officer for the 325th, and examined many of those in the unit both before and after they

deployed to the Gulf War. He reported that, in addition to the respiratory problems he observed, most of

the ill veterans he examined after the war had memory problems, skin rashes, muscle pain, and

gastrointestinal problems. He told Committee staff that many of the veterans had been seriously ill, but it

had not been possible for him to determine whether their ailments had stemmed from the CARC paint

exposures, other Gulf War-related exposures, or a combination.

Because of the large number of personnel from the 325thwho were reporting health problems, claims

representatives from the Department of Veterans Affairs (VA) met with members of the unit at their

annual training in Fort Stewart, Georgia, after the unit returned from Saudi Arabia. As of 2000, a DOD
210  Effects of Gulf War Experiences and Exposures

report indicated that of the approximately 200 members of the 325th that had participated in painting

operations, 163 had been evaluated in DOD or VA Gulf War registries. Findings from registry

examinations of these individuals were never compiled and summarized, according to the DOD report,

due to medical privacy issues.1619 Officials with the VA Regional Office in St. Petersburg, Florida,

recalled that close to 200 disability claims had been filed in connection with CARC exposures by

members of the 325th but that disposition of those claims had not specifically been tracked. No numbers

regarding final claim adjudication were available. News articles and Congressional staffers described

stories of individual veterans who had difficulties getting their medical problems service connected.279,1772

Few epidemiologic studies of Gulf War veterans queried veterans about their use of and exposure to

CARC paint during the war. In the U.S. national study of Gulf War veterans, just over 20 percent of

veterans reported being exposed to CARC paint. A higher proportion of those enrolled in the CCEP and

VA Gulf War Registries—35 to 48 percent—reported CARC exposure.751,839 As shown in Appendix A-1,

CARC exposure was identified as a significant risk factor for multisymptom illness in two of the three

studies that addressed this question,564,752,1466 but neither determined if CARC was an independent risk

factor, controlling for effects of other exposures. Unadjusted analysis of data from the U.S. national study

indicated that veterans who reported CARC exposure had a 5-fold greater risk than unexposed veterans

for the unique neurological symptom complex identified by that study.752

In summary, it appears that some exposure to CARC paint, before or after it dried, was fairly common

among troops serving in the Gulf War and that a limited number of personnel involved in intensive

painting operations were exposed to excessive levels of fresh CARC paint. The greatest concern in

relation to long-term effects of CARC is for personnel who had the highest-level exposure to this toxic

substance, particularly those for whom protective measures were inadequate. Available information

indicates that some individuals in the Florida Army National Guard’s 325th Maintenance Company

suffered acute and chronic health effects consistent with known effects of CARC paint. Without a

systematic evaluation, however, it is not possible to determine the extent of health problems affecting

members of this unit, or if those problems are uniquely the result of CARC exposure or may be related to

other exposures in theater.

The committee concludes that, overall, the limited extent of exposure to fresh CARC paint during the

Gulf War is not consistent with the high prevalence of Gulf War illness, or its pattern of occurrence. It is

therefore unlikely that CARC paint caused or contributed to Gulf War illness for the majority of ill

veterans. However, CARC paint may have had adverse health effects in the limited number of personnel

with more intensive and sustained exposure.

Contaminated Food and Water in the Gulf War

Rapid deployment of American military personnel to the Middle East in the fall of 1991 presented many

logistical challenges, including those related to providing living accommodations and safe food and water

supplies for hundreds of thousands of arriving troops. In the early months of the troop buildup, canned

and frozen food and prepackaged meals were shipped from the U.S. and were supplemented with fresh

produce and dairy products obtained from countries in the region.662 Throughout the deployment period,

potable water was obtained from reverse-osmosis purification units run by the U.S. military, from local

commercial bottled water suppliers, and from local municipal systems that supplied chlorinated water.662

Despite extensive efforts by the military to provide safe food and water to the troops, widespread

outbreaks of diarrheal disease occurred in the early months of Operation Desert Shield. In September

1991 this posed a serious threat, when over 50 percent of troops surveyed in theater reported diarrheal

episodes and 20 percent reported they had been temporarily unable to perform their duties due to

diarrhea.662 The primary pathogens identified were e. coli and shigella species, and the primary source of
Other Exposures in Theater  211

contamination in those months was believed to be the produce supplied by regional countries, since rates

of diarrheal diseases dropped after these items were banned in late September. 664 Diarrheal diseases

continued to occur, at reduced rates, throughout the deployment period. Additional outbreaks were

reported to occur most commonly in relation to interpersonal transmission of enteropathogens in field

units and when food was supplied or prepared by foreign food handlers.664

In addition, there were difficulties obtaining sufficient supplies of potable water and some units had to

rely on water supplied by host nations, delivered in tanker trucks.1618 Policy at the time allowed for the

use of petroleum transport tankers to carry drinking water, once the tanks had been superchlorinated and

thoroughly flushed.1618 Although water supplies were regularly monitored by U.S. personnel, testing

results were typically not available for 18-24 hours.1618 The Department of Defense’s report on water use

during the Gulf War also indicates that there were occasions when non-potable water was used for

drinking and food preparation.1618 In addition, personnel located close to the spewing and burning oil

wells experienced another source of food and water contamination resulting from the “oil rain.” Troops

in those areas described being completely soaked with oil and having their food and water taste like

oil.1688

Exposure to contaminated food and water during deployment appears to have been fairly widespread.

Twenty-one percent of veterans in the CCEP reported eating contaminated food and 20 percent indicated

they had bathed in contaminated water during deployment.839 In addition, 30 percent of veterans in the

U.S. National Study of Gulf War era veterans indicated they had eaten food contaminated with oil or

smoke.751 Overall, 75 percent of Gulf War veterans said they ate food and 34 percent drank water that

had not been supplied by the military.751,988

Some enteric pathogens have the potential to cause chronic illness,268,970 but reports from field medical

units indicate that most diarrheal episodes and outbreaks of gastroenteritis during deployment were brief

and resolved within days.662 Still, persistent digestive disturbances, including chronic diarrhea, are

frequently reported problems among ill Gulf War veterans.370,393,695,751,824,1451,1565

Several epidemiologic studies have evaluated rates of chronic symptoms and multisymptom illness in

relation to veterans’ reports of exposure to contaminated food and water in theater (Appendix A-3). In

unadjusted analyses, eating food contaminated with petroleum or oil was associated with an elevated risk

for multisymptom illness in two studies.564,752 This was a particularly strong risk factor in the U.S.

national study, in which veterans who reported eating food contaminated with oil had a 10-fold higher

rate of the unique neurological symptom complex defined in that study.752 These data come from

unadjusted analyses, however, and it is not possible to determine whether this excess risk resulted from

ingestion of the oil-contaminated food or if eating oil-contaminated food may reflect, more generally, risk

resulting from being in close proximity to the spewing oil wells. In addition, two studies, after adjusting

for effects of multiple exposures, reported that bathing in or drinking contaminated water was a

significant risk factor for chronic symptomatic illness.527,1507 Among Danish veterans, this association

was with water contaminated with oil or fumes, so may have reflected proximity to the oil well fires.

In summary, exposure to contaminated food and water appears to have been fairly common during Gulf

War deployment, and acute diarrheal diseases commonly occurred among Gulf War personnel.

Relatively little clear information is available concerning their association with chronic symptomatic

illness in Gulf War veterans, however. It is also not known if exposure to contaminated food and water

was more or less common during the Gulf War than in other military deployments to the region. Overall,

it appears unlikely that food and water contamination were major causes of Gulf War illness for most ill

veterans.
212  Effects of Gulf War Experiences and Exposures

Other Potential Hazards Encountered by Military Personnel in the Gulf War

A variety of additional exposures have been suggested as possible contributors to the development of

chronic symptoms affecting Gulf War veterans. These include sources of electromagnetic radiation in

theater, industrial pollution, exposure to the decontaminating agent DS2, and exposure to hydraulic fluids,

among others. Almost no information is available concerning the extent of exposure to these substances,

or their likely health effects. The Committee therefore has no basis on which to draw conclusions

regarding any health effects potentially attributable to these exposures, although most were likely to have

been encountered by a limited number of Gulf War veterans. They are mentioned here, in brief, for the

sake of completeness and to indicate the Committee’s awareness of veterans’ concerns regarding these

exposures.

Sources of electromagnetic radiation. Veterans have expressed concern about possible adverse

effects of electromagnetic radiation for individuals who may have had particularly high exposure during

the war. Several sources have been described. These include radio and microwaves in locations at which

high-level communications towers and equipment were located. Veterans have also indicated that new

weapons systems that utilized energy beams, while not in wide use, were being tested during the 1991

Gulf War.1269

There has been extensive research exploring possible adverse effects of exposure to electromagnetic

radiation, of various types, in other settings. While individual studies have reported that exposure to radio

waves, microwaves, and other types of electromagnetic radiation may be associated with increased risk of

cancers and other health outcomes, findings have been equivocal, and no clear consensus has emerged

concerning long-term effects of higher-level exposures.401,498 Studies have not specifically assessed

adverse effects of short term, concentrated exposure to radiation frequencies emitted by microwave

communications equipment comparable to those that may have been encountered by military personnel

during the Gulf War.

Between 20 and 30 percent of U.S. veterans reported being exposed to “microwaves” in the U.S. National

Survey and federal registry programs,751,1505,1651 but the sources of those exposures were not queried or

identified. In unadjusted analyses, exposure to “ionizing or non-ionizing radiation” was associated with

higher rates of cognitive and fibromyalgia symptoms in Iowa veterans, but not in Canadian veterans.511,692

No government documents or veteran reports were identified that provide additional information

concerning individuals potentially exposed to electromagnetic radiation during the Gulf War in

connection with the testing or use of energy weapons.

Sources of industrial pollution. During the Gulf War, U.S. troops were frequently stationed in

industrial areas where operating chemical plants and refineries were located. Government reports have

routinely identified industrial pollution as a source of airborne particulates and other contaminants during

the Gulf War.1625 Almost no information is available, however, about the specific types of pollution in

those areas or the extent of exposures to contaminants associated with local industry.

There are incident reports describing chemical exposures of unknown type and origin, however, the best

known of which is the “purple T-shirt event.” On March 19, 1991, Navy Seabees camped in an industrial

sector of Al Jubayl, in northern Saudi Arabia, described being enveloped in a cloud of noxious fumes that

contained a purple colored dust. They experienced symptoms that included burning in their eyes, noses,

and throats, nosebleeds, and choking. At the same time, their brown T-shirts turned purple, as did

portions of their combat boots. Some of the soldiers sought medical attention, and their symptoms are

reported to have resolved in a short time. Despite a later environmental hazard investigation, and

chemical testing of some of the affected shirts, no specific chemical or source of the fumes was identified.

Military investigators have generally concluded that the unknown chemical likely came from an

unidentified incident at one of the industrial plants located near the camp.1627
Other Exposures in Theater  213

Chemical decontaminating agent. Decontamination Solution 2, or DS2, is a solution used by the

military to decontaminate vehicles following exposure to chemical warfare agents. This solution contains

ethylene glycolmonomethyl ether (2ME), a type of solvent widely used in industry that has been

associated with adverse reproductive and hematological effects.1615,1690 Although it is known that DS2 was

used during the Gulf War,675 no documentation is available concerning the extent of its use. The

Committee identified only one report of an incident involving the use of DS2 during the Gulf War, in

which a group of soldiers were said to have developed rashes after exposure.1690

Airplane hydraulic fluid. In recent years, studies have suggested that inhalation exposure to fumes

produced by hydraulic fluids used in aircraft may have adverse neurological effects. Airline crew

members flying certain aircraft have reported nonspecific symptoms such as headache, cognitive

impairment, and fatigue that some have attributed to fumes from hydraulic fluid and engine oil

leaks.287,1794 Several types of hydraulic fluid were used in military aircraft during the Gulf War, some of

which contained tricresyl phosphates (TCPs),978 organophosphate esters that have been associated with

neurotoxic effects.1067,1570 However, no information is available on the extent of exposure to these

substances during the Gulf War, or on adverse effects potentially attributable to them. One U.S. Gulf

War study, in unadjusted analyses, found that veterans whose work activities during the war included

cleaning “hydraulic leaks” had an elevated rate of Gulf War illness.1466

Summary. Other exposures in theater. The Committee reviewed information on a variety of Gulf

War exposures that have the potential to cause adverse effects but for which there is relatively little

information concerning individual exposures and/or associations with Gulf War illness. This includes

sand/particulates in theater, tent heaters, solvents, jet fuel, CARC paint, and contaminated food and water.

Several of these exposures are unlikely to have been primary causes of Gulf War illness for the majority

of ill veterans based on what is known about their distribution during deployment. Gulf War illness

affects between 25 and 30 percent of those who served in the 1990-1991 Gulf War, and occurs in a

nonrandom distribution pattern—that is, its prevalence differs by branch of service and by location in

theater. Primary causes of Gulf War illness, therefore, would have to have been widespread enough to

affect a substantial number of individuals, but not equally distributed in all sectors of theater. This

suggests that exposures such as solvents, fuels, and particulates, encountered throughout theater by most

units, are unlikely candidates as primary causal factors in Gulf War illness. It also suggests that freshly

sprayed CARC paint, encountered by relatively few veterans in very limited areas, is also an unlikely

cause of Gulf War illness for most veterans. These observations are generally supported by

epidemiologic studies that have assessed rates of multisymptom illness in relation to these exposures.

Descriptive reports during and after the war, however, indicates that some military personnel involved in

intensive CARC painting operations, particularly those who had inadequate training and protective

equipment, have suffered chronic health problems since the war. In different individuals these problems

have resembled Gulf War illness, adverse consequences of CARC exposure, or both. Systematicallycollected information is needed to understand the degree to which these individuals have been affected by

persistent adverse effects of CARC or other Gulf War-related exposures.

Less commonly-encountered exposures such as these raise questions about the potential for various

substances to have contributed to Gulf War illness in some as-yet-unknown way, as part of a “cocktail”

effect resulting from combinations of exposures. As described here in relation to particulates, scientists

are just beginning to identify neurotoxic effects of substances not previously associated with diagnosed

neurological diseases. Little is currently known about how some of these exposures, particularly when

combined with other neurotoxic substances, might contribute to adverse effects that are currently

unknown.
214  Effects of Gulf War Experiences and Exposures

Recommendations

A number of exposures in theater are unlikely to have been primary causes of Gulf War illness in the

majority of ill veterans, but may have contributed to illness risk in identifiable subsets of Gulf War

veterans. To better understand the potential contributions of two of these exposures, CARC paint and

unvented tent heaters, the Committee recommends the following:

 Conduct an epidemiologic investigation to determine if personnel who served with the Army

National Guard’s 325th Maintenance Company in the Gulf War suffer excess health problems in

comparison to nondeployed personnel, to describe the nature of any excess problems, and to

evaluate the degree to which problems are associated with veterans’ exposure to CARC during

deployment, alone or in combination with other Gulf War exposures.

 In existing and future epidemiologic studies of Gulf War veterans, analyze data collected relating

to exposure to unvented tent heaters during the Gulf War using analytic methods that control for

the effects of other exposures in theater, to determine whether tent heaters contributed to the risk of

Gulf War illness, particularly among Army veterans in theater during winter months.
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  215

Synthesis: What the Weight of Evidence Tells Us

About the Causes of Gulf War Illness

The 1990-1991 Gulf War was unique in many respects. Although the combat period was brief, military

personnel encountered a variable mix of chemical, biological, psychological, and physical exposures

during deployment. For many years, complexities related both to what occurred in theater and the

multisymptom illness resulting from the war have given rise to widespread uncertainty and debate.

Different deployment-related factors have been put forward by individuals from different sectors—

government officials, veterans, clinicians, scientists, and members of the public—as the cause or most

important cause of Gulf War illness. As viewed through different lenses, detailed and sometimes

persuasive cases have been made that different exposures—stress, oil well fires, depleted uranium,

vaccines, nerve agents—appeared, at least in theory, to be the most likely cause of Gulf War illness.

Seventeen years after the war, the extensive body of scientific research on the health of Gulf War veterans

and the large number of government investigations related to exposures in theater permit a more in-depth,

evidence-based evaluation. Earlier observers have suggested that it might not be possible to determine

the cause of Gulf War illness so many years after the war. Based on its broad review of available

information, however, the Committee found that evidence of different types from different sectors points

consistently to a limited number of factors as the most prominent and likely causes of Gulf War illness.

The Committee believes it is extremely important to understand why Gulf War veterans became ill.

Veterans and their healthcare providers need this information to inform appropriate treatment strategies.

Scientists need this information to design research studies that most accurately characterize pathological

processes, tests, and treatments for Gulf War illness. Government officials need this information to

improve programs that care for ill Gulf War veterans and to prevent similar problems in the future.

Seventeen years after the Gulf War, answers to the question of what caused Gulf War illness are long

overdue.

Scientific determination of disease causality is neither routine nor straightforward. There is no general

agreement, from a scientific perspective, on how best to characterize or determine disease causation,

especially when considering links between chronic disease and environmental factors.1321 Unlike

infectious disease, there are no accepted criteria, like Koch’s postulates, used to judge if an

exposure/disease causal relationship exists. Understanding such relationships in human populations is

often complicated by factors such as the potential for multiple “causes” to contribute to disease,

uncertainties related to exposure levels, latency of observable clinical effects, and variability in individual

susceptibility to hazardous exposures. Multiple factors must be considered and weighed in making

scientific judgments about disease causation, based on a variety of indicators that have been suggested as

important.609,1321,1516 These typically include the overall consistency of epidemiologic findings relating an

exposure to a disease, the biological plausibility of the association, the presence of a dose/response effect,

and whether the exposure/illness link is consistent with other knowledge in the field.

The Committee considered factors such as these in reviewing the broad spectrum of evidence related to

each of the putative risk factors for Gulf War illness. For each exposure topic, the Committee

systematically considered three general types of information: (1) what was known about the extent and

patterns of the exposure in theater, (2) what was known, overall, about adverse effects of the exposure

from human and animal studies, and (3) what studies of Gulf War veterans have determined about

associations between the exposure and Gulf War illness. Available information in all three categories was

reviewed in a similar way for the different wartime experiences and exposures of interest. For example,

evidence related to psychological stressors as a possible cause of Gulf War illness was considered in the

same way as evidence related to exposures such as depleted uranium and oil well fires. The types and

strength of evidence in each area were then compared, to allow the Committee to determine where
216  Effects of Gulf War Experiences and Exposures

evidence of an association was strongest, where there appeared to be no association, and where there was

insufficient information to support firm conclusions.

General Patterns of Exposure in the Gulf War

Gulf War illness, that is, the complex of chronic symptoms consistently found at excess rates in Gulf War

veterans, affects between 25 and 32 percent of veterans who served in the 1990-1991 Gulf War. Its

primary cause or causes would therefore be expected to have been commonly encountered by Gulf War

personnel during deployment. General insights about the causes of Gulf War illness might also be

provided by comparing what is known about the extent and patterns of exposures during the 1990-1991

Gulf War with the distribution of Gulf War illness in different veteran subgroups. Gulf War illness has

been shown to affect ground troops, particularly Army personnel, at significantly higher rates than other

personnel in theater, and to be most prominent among troops who served in forward areas. In addition, a

similar pattern of widespread multisymptom illness, unexplained by identifiable medical or psychiatric

diagnoses, has not been reported in veterans who served in Bosnia in the 1990s or in personnel returning

from current conflicts in the Middle East. This suggests that insights into the cause or causes of Gulf War

illness might also be provided by comparing the circumstances and exposures of the 1990-1991 Gulf War

with those of more recent deployments.

Overall, it would generally be expected that the most prominent etiologic factors for Gulf War illness

should be widespread enough to have affected a large number of troops during the 1990-1991 Gulf War,

and most frequently experienced by ground troops, particularly those serving in forward areas. And,

based on currently available evidence, the most prominent causes of Gulf War illness should also have

been widespread in the 1990-1991 Gulf War, but not in current Middle East deployments. Information of

this type, summarizing key aspects of what is known about general patterns of Gulf War exposures, is

provided in Table 1.

General information on exposure patterns in the 1990-1991 Gulf War indicates that a number of

exposures were widespread during Gulf War deployment, and most prominent among ground troops who

were in forward locations at some time during the war. These include psychological stressors, oil well

fire smoke, depleted uranium (DU), use of pyridostigmine bromide (PB) pills, and pesticide use. Two of

these, psychological stressors and DU, have also been prominent among personnel serving in Operations

Iraqi Freedom (OIF) and Enduring Freedom (OEF), although reports have not identified a widespread

Gulf War illness-type problem in veterans of those conflicts. Major vaccine exposures of interest do not

generally distinguish the Gulf War from current conflicts, since all personnel serving in recent

deployments were to have received the six-shot anthrax vaccine series, and multiple other vaccines for

deployment. Anthrax vaccine was administered to a lower proportion of 1990-1991 Gulf War troops, and

preferentially given to those in fixed locations in support areas during the war.

Overall, there is sufficient information on exposure patterns in theater to indicate that two exposures of

interest are generally compatible with what is known about the distribution of Gulf War illness in Gulf

War veterans. Exposure to oil well fire smoke and the use of PB pills were both widely experienced,

most prominently in forward areas of theater and by ground troops. Neither have affected troops in

current Middle East conflicts to a significant extent, although isolated exposures might have occurred.

The general patterns summarized in Table 1 also suggest that four other exposures of interest are not

“good fits” with the patterns in which Gulf War illness affects veterans. These include the fine, blowing

sand in the region, exhaust from tent heaters, fuel exposures, and freshly-applied chemical agent resistant

coating (CARC) paint. Exposures to sand and military fuels were ubiquitous throughout the Gulf War
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  217

Table 1. General Patterns of Exposures in the 1990-1991 Gulf War

and Current Middle East Deployments

Was Gulf War exposure

widespread, and most

prominent among ground

troops in forward areas?

Was exposure more

prominent in the 1990-1991

Gulf War than in current

Middle East deployments?

Veterans’ Experiences and Exposures in Theater

Pyridostigmine bromide Yes Yes

Pesticides Yes

Psychological stressors Yes No

Chemical weapons Yes

Oil well fires Yes Yes

Number of vaccines No No

Anthrax vaccine No No

Tent heater exhaust No

Sand/particulates No No

Depleted uranium Yes No

Solvents No No

Fuel exposures No No

CARC paint No

Abbreviation: CARC = freshly applied chemical agent resistant coating

Note: Blank cells indicate that available information is insufficient to characterize pattern of interest.

theater, and would be generally similar in the current Iraq War. The most intensive exposures to freshlyapplied CARC paint in the 1990-1991 Gulf War occurred in limited areas, at vehicle spray painting

operations located in Saudi Arabia.

There is insufficient evidence on patterns of exposure to clearly indicate whether two Gulf War exposures

of concern—chemical agents and pesticides—are supported by this type of general analysis. Although

DOD models indicate that about 100,000 troops were potentially exposed to low levels of nerve agents in

relation to munitions demolitions at Khamisiyah, Iraq, in 1991, the full extent and locations of low-level

chemical weapons exposures during the 1991 Gulf War is unclear. Concern about chemical weapons

exposures was very prominent early in the current Iraq War, but there have been no indications that a

substantial number of troops were exposed to chemical agents in current Middle East deployments. There

is also no detailed information available as yet on patterns of pesticide use in current deployments.

Several pesticide products of concern during the 1990-1991 Gulf War are no longer used by the military,

however, and there are multiple indications that, overall, pesticides have been used at lower levels in

current deployments, in keeping with current military pest control policies.

It is important to emphasize that this type of general assessment can provide only preliminary indications

of which exposure patterns are consistent with exposures likely to have been most prominently associated

with Gulf War illness. Firm conclusions cannot be based on this type of general assessment for a number
218  Effects of Gulf War Experiences and Exposures

of reasons, including the well-recognized limitations of ecological inferences of this type.811 However,

this information can help to narrow the broad field of exposures in question, particularly by identifying

exposures that are unlikely to have been primary causes of Gulf War illness. Such insights can add to an

overall assessment of evidence, when considered with the more detailed types of information provided by

research on biological effects of exposures in humans and animals, as well as epidemiologic and clinical

studies of Gulf War veterans.

General Information on Health Effects of Exposures

As detailed in earlier sections of the report, a large number of diverse types of research studies have

provided information on health and biological effects of many of the exposures associated with Gulf War

service. These include studies of human populations exposed to psychological stressors and chemical

hazards. It also includes multiple types of laboratory studies that have evaluated biological effects of

these exposures in animals. The Committee reviewed research of these types to determine what insights

they provide concerning likely causes of Gulf War illness.

Evidence from animal studies evaluating biological effects of exposures. There is no clear

animal model for Gulf war illness, in part because there are not objective measures to determine if

animals experience many of the symptoms associated with Gulf War illness. As described in previous

sections, however, a large number of studies have evaluated effects of Gulf War-related exposures in

animals, and have identified effects that are compatible with Gulf War illness-type symptoms. These

include adverse effects on brain structure and neurobiological measures, as well as effects on memory and

behavior. Most such studies have evaluated effects in animals over relatively brief time periods. For

example, animal studies have demonstrated that stressors can produce short-term changes in behavior and

hypothalamic-pituitary-adrenal (HPA) axis measures. Little information is available, however, about the

potential for time-limited stressors to produce adverse effects that persist for an extended period in adult

animals.

Animal studies have demonstrated persistent neurological effects of exposure to pyridostigmine bromide,

fuels, solvents, and receipt of multiple vaccines that include neurobehavioral effects and changes in brain

waves, neurotransmitters, and sleep patterns. Low-level sarin exposures have also been found to have

persistent effects on the brain and behavior, including EEG effects and alterations in cholinergic receptors

in brain areas associated with learning and memory, as well as long-term effects on HPA parameters and

autonomic function. In addition, research in animal models indicates that different classes of pesticides

used during the Gulf War can have long-term effects on the brain, including effects on learning and

behavior. Repeat, low level exposures to organophosphate pesticides have been shown to have persistent

effects that differ from effects of single exposures, even at higher dosage levels.

Animal studies have also demonstrated that soluble forms of DU, when ingested or injected, and DU

pellets implanted under the skin can have effects on the brain and behavior. Little information is

available, however, concerning persistent central effects of short-term DU exposure, in forms and dosages

most commonly encountered by Gulf War veterans. There is also little information from animal studies

to indicate whether time-limited exposure to stressors, smoke from oil well fires, anthrax vaccine, sand,

tent heaters, or CARC paint produce persistent effects that are compatible with symptoms associated with

Gulf War illness.

Research in animal models has also identified significant neurological effects resulting from different

combinations of neurotoxicant exposures associated with the Gulf War—organophosphate pesticides,

permethrin, DEET, PB, and low-level sarin—and from combinations of these exposures with stress.

Diverse findings have been reported in relation to chemical absorption, metabolism, and biological

effects of mixtures of these neurotoxicants, effects that differ from those of single exposures.
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  219

Evidence from studies evaluating effects of occupational and environmental exposures

in human populations. An extensive number of research studies have described human health effects

of many of the types of exposures encountered by military personnel in the Gulf War. Relatively few,

however, have evaluated rates of persistent symptoms and symptom complexes in relation to these

exposures. As catalogued in some detail in the Institute of Medicine’s Gulf War and Health series of

reports, research on humans occupationally exposed to diverse types of chemical exposures such as

petroleum exhaust or uranium dust have primarily evaluated rates of cancers and limited other diagnosed

conditions. Therefore, general research on the effects of Gulf War-related exposures in human

populations provides only limited insights concerning possible links between exposures and persistent

symptomatic illness.

The Committee identified human population studies that evaluated chronic symptoms and symptom

complexes in relation to only three types of chemical exposures associated with Gulf War service:

pesticides, nerve agents, and organic solvents. Community studies have identified significant associations

between low level exposure to agricultural pesticides and increased rates of symptoms similar to those of

Gulf War illness—chronic cognitive problems, headaches, gastrointestinal problems, sleep disturbances,

and mood alterations. Persistent symptoms similar to those of Gulf War illness have also been described

in occupational studies of British sheep farmers regularly exposed to organophosphate sheep dip, and in

other pesticide-exposed workers. In both community and occupational settings, chronic symptoms of this

type have been reported in individuals with no history of pesticide poisoning, generally in relation to lowlevel exposures over a prolonged period. Long-term follow up of individuals exposed to sarin in terrorist

attacks in Japan in the 1990s also indicates that some individuals developed persistent symptoms, balance

irregularities, neurocognitive decrements, and alterations in brain structure that parallel those observed in

Gulf War veterans. Individuals evaluated in these studies, however, had higher-level sarin exposures than

those generally believed to be associated with Gulf War service.

In addition, chronic neurocognitive and mood symptoms have been described in workers occupationally

exposed to organic solvents. Acute neurological, respiratory, and skin symptoms have also been reported

in relation to fuel exposures, but studies have not reported on chronic symptomatic outcomes. No studies

were identified that provide information on persistent symptoms or symptom complexes in relation to

other types of Gulf War exposures. That is, human studies have not provided information on chronic

symptomatic illness, unrelated to diagnosed conditions, that persists for many years after time-limited

exposure to psychological stressors, petroleum smoke, uranium dust, vaccines, PB, sand and particulates,

exhaust from tent heaters, or CARC paint.

In summary, studies in animal models have demonstrated delayed or persistent neurological effects

following short-term exposure to a number of compounds associated with Gulf War service—PB, lowlevel sarin, pesticides, fuels and solvents, and multiple vaccines—effects that could plausibly relate to

symptoms of Gulf War illness. Animal studies also indicate that some combinations of neurotoxicant

exposures, at levels comparable to those experienced by Gulf War veterans, can produce neurological

effects that differ from those of individual exposures. Research in human populations indicates that lowlevel exposure to pesticides, sublethal exposure to sarin, and exposure to organic solvents can be

associated with chronic symptoms and symptom complexes similar to those of Gulf War illness. These

chronic symptom complexes develop, in some cases, after exposure to neurotoxicants at levels that do not

cause acute symptoms.

Overall, research in animal models has provided information essential for understanding the biological

effects of Gulf War exposures. Recent studies that have identified persistent effects of low level

exposures have been especially useful in this regard. General research on health effects of exposures in

human populations has also been important in identifying exposed populations in whom elevated rates of

persistent symptoms similar to those of Gulf War illness have been reported. Although both types of

research provide valuable insights related to the cause or causes of Gulf War illness, application of these
220  Effects of Gulf War Experiences and Exposures

findings to the Gulf War experience is limited in some respects. It is important, therefore, that general

research findings related to biological and health effects of Gulf War exposures be considered in the

context of what is known about the extent and patterns of exposures during the Gulf War, as well as

associations between Gulf War exposures and Gulf War illness identified in studies of Gulf War veterans.

Evidence from Studies of Gulf War Veterans

Although informative, research in animal models and general findings from studies of human populations

cannot precisely characterize the impact of Gulf War exposures on military personnel who served in the

1990-1991 Gulf War. Associations between Gulf War illness and the diverse psychological, biological,

and chemical exposures experienced during Gulf War deployment, at different levels and in different

combinations, can only be directly evaluated in Gulf War veterans themselves. In light of the complex

exposure scenario of the Gulf War, understanding the cause or causes of Gulf War illness requires careful

consideration of findings from research on Gulf War veterans. The Committee reviewed, in detail, results

from the large number of studies that have evaluated associations between chronic symptomatic illness in

Gulf War veterans and experiences and exposures during the Gulf War. These include epidemiologic

studies that have assessed risk factors for multisymptom illness in Gulf War veterans, as well as clinical

studies that have evaluated measurable health outcomes in relation to Gulf War exposures.

Major findings from Gulf War epidemiologic studies. As detailed in previous sections of the

report, epidemiologic studies have evaluated many possible risk factors for Gulf War illness. These have

included hundreds of evaluations of persistent symptoms and multisymptom illness, variously defined, in

relation to numerous exposures assessed by diverse variables. Exposure-illness associations have been

assessed in many different populations of Gulf War veterans, with some veteran groups evaluated by

multiple studies. Appendix A provides detailed findings from these studies, listed by type of exposure.

For example, identified associations between symptomatic illness and variables related to chemical agents

(e.g., being put on chemical alert, DOD-modeled proximity to the Khamisiyah demolitions) are listed

together in a single table, Appendix A-2.

In reviewing epidemiologic findings related to risk factors for Gulf War illness, the Committee sought to

determine the overall strength of evidence related to each exposure of interest. This required an

assessment of whether Gulf War epidemiologic studies consistently indicated that an exposure was or was

not significantly associated with symptomatic illness in Gulf War veterans, and whether there was

evidence of a dose/response relationship. Table 2 summarizes findings from all epidemiologic studies

that evaluated associations between Gulf War exposures and multisymptom illness in Gulf War veterans.

As shown, the table identifies both the number of different Gulf War veteran populations in which each

type of exposure was assessed, and the number of populations in which each exposure was significantly

associated with symptomatic illness. Detailed results for all exposure variables are provided in Appendix

A. For purposes of the summary in Table 2, findings related to each type of exposure in a given veteran

population were counted only once. For example, some studies evaluated many different psychological

stressors as risk factors for symptomatic illness in a given population of Gulf War veterans. Table 2

reports the number of different Gulf War veteran populations in which at least one psychological stressor

was significantly associated with symptomatic illness.

Consistency of associations between exposures in theater and Gulf War illness. Epidemiologic

studies have evaluated an extensive number of risk factors for Gulf War illness in numerous Gulf War

veteran populations. As previously described, epidemiologic studies that reported only results of

preliminary analyses—that is, analyses that did not adjust for confounding effects of multiple

exposures—were not useful in identifying risk factors for Gulf War illness. As shown in Table 2,

preliminary analyses of this type identified nearly all Gulf War exposures as significant risk factors for

Gulf War illness in all Gulf War veteran populations. Illogical findings of this type are an expected result
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  221

of confounding in epidemiologic research, that is, the result of confusing the effects of multiple exposures

with one another. For example, most Gulf War personnel who served in combat also took PB pills and

used personal pesticides. In assessing exposure-illness associations, effects of serving in combat would

be “mixed in” with, or confounded by, the effects of PB and pesticides, unless effects of each exposure

are assessed independently, while controlling for the effects of other exposures.

Given the large number of exposures in theater and the high degree of correlation among exposures,

epidemiologic studies that did not control for the confounding effects of multiple wartime exposures

invariably produced results that were not helpful, and even misleading, for determining the causes of Gulf

War illness. As detailed in Appendix A, the magnitude of associations identified by these preliminary

analyses also provided little basis for distinguishing between effects of Gulf War exposures. These

measures, typically odds ratios (OR) or risk ratios (RR), reflect the degree of increased illness risk

associated with a given exposure. Individual OR and RR values for different exposures varied in

different studies, but median values across studies were generally similar. For the majority of Gulf War

exposures, median values indicated a three-to-four times greater risk for exposed, compared to unexposed

personnel, in unadjusted analyses. Anthrax vaccine was consistently the weakest of identified risk factors

in these analyses. That is, Gulf War illness risk for veterans who reported receiving the anthrax vaccine

was usually less than twice that of veterans who did not recall receiving the vaccine, in unadjusted

analyses.

In contrast, Gulf War epidemiologic studies that controlled for confounding effects of multiple wartime

exposures provided clear distinctions between the many Gulf War exposures of interest. Across all

studies that adjusted for effects of multiple exposures, only two exposures—the use of pyridostigmine

bromide (PB) pills and the use of pesticides—were consistently identified as significant risk factors for

Gulf War illness. As shown in Table 2, use of PB was significantly associated with multisymptom illness

in six of six Gulf War veteran populations, and pesticide use was significantly associated with

multisymptom illness in five of six veteran populations, in studies that controlled for effects of other

wartime exposures.

Epidemiologic studies that controlled for effects of multiple exposures also identified factors that were

not significantly associated with Gulf War illness. The largest number of risk factor variables assessed in

Gulf War epidemiologic studies related to diverse psychological stressors during deployment. These

included experiences that may have been extremely traumatic, (e.g. seeing soldiers maimed or killed),

experiences associated with prolonged and intense stress (e.g., being in combat), and other types of

psychological stressors not directly related to combat (e.g., change in marital status).

Results of adjusted analyses consistently indicated that psychological stressors during deployment were

not significantly associated with Gulf War illness. Psychological stressor variables were assessed in

seven different Gulf War veteran populations, using analyses that controlled for effects of other wartime

exposures. As shown in Table 2, no stress-related variables were identified as significant risk factors for

multisymptom illness in six of the seven Gulf War populations, after controlling for effects of deployment

exposures. In addition, two of three studies that evaluated effects of sand exposures, and two studies that

evaluated fuel exposures found they were not significant risk factors for Gulf War illness, after adjusting

for effects of other exposures.

Epidemiologic findings related to exposure to smoke from oil well fires and possible exposure to

chemical agents were not consistent, as indicated in Table 2. Oil fire smoke was identified as a

significant risk factor for Gulf War illness by two of four studies that controlled for effects of other

deployment exposures. In three of five populations, variables potentially indicative of exposure to

chemical agents (e.g. hearing chemical alarms, exposure to nerve gas), were found to be significant risk

factors for Gulf War illness, after adjusting for effects of other exposures. For several other deployment
Table 2. Gulf War Illness in Relation to Experiences and Exposures During the 1990-1991 Gulf War:

Summary of Evidence from Studies of Gulf War Veterans

Epidemiologic Studies of Gulf War Veterans:

Association of Deployment Exposures With Multisymptom Illness

Preliminary Analyses*

(no controls for other exposures)

Adjusted Analyses*

(controlling for effects of other exposures) Clinical Evaluations of Gulf War Veterans:

GWV populations in

which association

was assessed a

GWV populations in

which association

was sign.b

GWV populations in

which association

was assessed a

GWV populations in

which association

was sign.b

Doseresponse effect

identified?

Association of Deployment Exposures

with Measured Clinical Outcomes

Pyridostigmine bromide 10 9 6 6 Yes associated with sign. neurocognitive and HPA

differences in Gulf War veterans

Pesticides 10 10 6 5 Yes associated with sign. neurocognitive and HPA

differences in Gulf War veterans

Psychological stressors 14 13 7 1

Chemical weapons 16 13 5 3

associated with sign. neuroimaging and

neurocognitive differences in Gulf War veterans

Oil well fires 9 8 4 2 Yes

Number of vaccines 2 2 1 1 Yes

Anthrax vaccine 5 5 2 1

Tent heater exhaust 5 4 2 1

Sand/particulates 3 3 3 1

Depleted uranium 5 3 1 0

Solvents 4 4 1 0

Fuel exposures 5 4 2 0

CARC paint 3 2 0 0

Abbreviations: GWV = Gulf War veterans, sign. = statistically significant, HPA = hypothalamic-pituitary-adrenal axis, CARC = chemical agent resistant coating

Notes: *Detailed results for all exposure variables are provided in Appendix A; Preliminary analyses refer to methods that did not adjust for effects of other exposures during deployment.

a Indicates total number of Gulf War veteran populations in which an association of multisymptom illness with the exposure of interest was evaluated

b Indicates number of Gulf War veteran populations in which one or more variables reflecting the exposure of interest was sign. associated with multisymptom illness
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  223

exposures, there was insufficient information from Gulf War epidemiologic studies to assess their

contributions as independent risk factors for Gulf War illness. These included DU, vaccines, exhaust

from tent heaters, and CARC paint.

Evidence of dose-response effects in relation to Gulf War illness. A parameter commonly used to

evaluate the likelihood of a causal relationship between an exposure and a health outcome is whether

there is evidence of a dose-response pattern of association. This refers to a graded relationship between

increasing levels of exposure and greater degrees of illness risk or severity. As indicated in Table 2, Gulf

War epidemiologic studies have reported dose-response associations between multisymptom illness and

several deployment exposures. Dose-response effects have been identified in relation to PB use, pesticide

use, oil well fires, and the number of vaccines received, both by Gulf War studies that controlled for

effects of confounding by other exposures, and by studies that did not.

A dose-response pattern of association between PB and Gulf War multisymptom illness has been

identified by multiple studies, both in relation to the number of days PB was used, and the total number of

pills taken during deployment.241,788,789,938,1466,1804 Dose-response effects associated with pesticide use

have also been identified, both in relation to the number of days that pesticides were used241 and the

amount of DEET used.564 In addition, several studies provided indications that veterans who were closest

to the Kuwaiti oil well fires, or were exposed to oil fire smoke for longer periods of time, have higher

rates of symptomatic illness than veterans with less exposure.241,564,752,1466,1687 A dose-response effect is

also reflected in the observed association between Gulf War illness and the number of vaccines received

for deployment.241,641,788,789,1698

Association of Gulf War exposures with clinical findings in Gulf War veterans. In addition

to epidemiologic research on risk factors for multisymptom illness in Gulf War veterans, a variety of

studies have assessed measurable clinical outcomes in Gulf War veterans in relation to Gulf War

exposures. As summarized in Table 2, these studies have identified significant findings in Gulf War

veterans on brain scans, neurocognitive testing, and measures of hypothalamic-pituitary-adrenal axis

(HPA) function, which differ in relation to exposures during the Gulf War. Objectively-measured

differences have been identified in association with veterans’ reported use of PB and pesticides, as well as

modeled estimates of exposure to nerve agents.

A recent collaborative study by investigators from the Army, the Boston VA, and Boston University

School of Public Health, identified structural differences in the brains of Gulf War veterans in association

with possible nerve agent exposure. Reduced white matter volume, identified using magnetic resonance

imaging (MRI) scans, was significantly correlated, in a dose-response manner, with DOD-modeled

estimates of nerve agent exposures resulting from the Khamisiyah weapons demolitions in March of

1991.599,1780 In an earlier study, this research team also identified neurocognitive decrements in Gulf War

veterans, which also differed in a dose-response manner with modeled levels of nerve agent exposure.1237

Boston investigators had previously identified measurable differences on tests of memory and attention

among symptomatic Gulf War veterans, which were significantly associated with veterans’ reported use

of PB during the war.1512 They have recently reported results from a DOD-funded project that evaluated

neurocognitive function in a sample of Gulf War veterans who worked with pesticides during

deployment.836 Findings indicated that veterans with the highest level exposures to both pesticides and

PB exhibited significantly increased rates of multisymptom illness, as well as significantly greater

memory and motor function decrements, compared to veterans with low or no exposures. In addition,

investigators from the Bronx VA have identified significant differences between Gulf War and

nondeployed era veterans on multiple measures of hypothalamic-pituitary-adrenal (HPA) function. HPA

differences were significantly associated with veterans’ symptoms and with their reported use of PB and

pesticides during deployment, but were not associated with psychological stressors or other Gulf War

exposures.501-503
224  Effects of Gulf War Experiences and Exposures

Overview of the Evidence Linking Gulf War Illness with Experiences and Exposures

During Gulf War Deployment

An extensive amount of information is available that contributes to understanding what caused Gulf War

illness. Individually, single studies or types of information might suggest the possibility that an 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. Studies of

Gulf War veterans consistently implicate only two wartime exposures as significant risk factors for Gulf

War illness: use of pyridostigmine bromide 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

significant risk factors for 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.

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
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  225

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 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 during the war. 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 is unclear,

however. 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 at

Khamisiyah, Iraq, but serious 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
226  Effects of Gulf War Experiences and Exposures

War illness and low-level nerve agent exposure cannot be ruled out, for whatever subgroup 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 airborne

particulates, 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. General 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 significant correlations between use of different types of pesticides and between use of PB and

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
What the Weight of Evidence Tells Us About the Causes of Gulf War Illness  227

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 mixtures of PB,

multiple pesticides, low-level nerve agents, oil and dense smoke from burning wells, depleted uranium

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.

Summary: 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 indicates that use of

pyridostigmine bromide (PB) pills and pesticides are significantly associated with increased rates of 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 depleted uranium

or anthrax vaccine to Gulf War illness. The prominence of both exposures in more recent deployments,

in the absence of widespread unexplained illness, suggests that they are unlikely to have been major

causes of Gulf War illness for the majority of ill 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.

Limited evidence from Gulf War studies does not support 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.
228  Effects of Gulf War Experiences and Exposures
The Nature of Gulf War Illness  229

3| The Nature of Gulf War Illness

As described throughout this report, Gulf War illness refers to the complex of chronic symptoms that

affect veterans of the 1991 Gulf War at excess rates. The Committee was charged with assessing the

degree to which federally-funded Gulf War research programs have been effective in answering questions

related to the nature, causes, and treatments of Gulf War-related conditions. Previous sections of the

report have reviewed evidence related to the causes of Gulf War illness, and the limited amount of

information available on its treatment. This section provides information related to the nature of Gulf

War illness, that is, scientific research on biological and clinical characteristics of Gulf War illness, and

the relationship of Gulf War illness to symptom-defined medical conditions in the general population. It

also provides the Committee’s recommendations for additional research to improve understanding of

pathophysiological mechanisms associated with Gulf War illness.

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 biological parameters

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.

Most of these biological differences have been identified by research methods and protocols not routinely

used in healthcare settings. They span a wide variety of findings that provide diverse indicators of

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 nature of Gulf War

illness, important work remains in identifying the specific pathophysiological processes that underlie

veterans’ symptoms.

Understanding the biological nature of Gulf War illness and the specific physiological processes that

contribute to veterans’ symptoms is of great importance. Veterans have long sought answers to questions

about the nature of Gulf War illness, as have their healthcare providers. Government policymakers also

need this information to improve healthcare and benefits programs that serve Gulf War veterans. But

identifying the specific biological mechanisms that contribute to Gulf War illness is most essential in

order to identify processes that can be targeted for treatment and improved diagnostic testing.

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-related multisymptom illness.

That information is summarized in the pages that follow, with the Committee’s recommendations for

research needed to better understand the physiological nature of Gulf War illness. Preliminary

information is also provided in connection with the current emphasis of the Committee’s work, exploring

biological processes not yet studied in Gulf War veterans that may contribute to a better understanding of

Gulf War illness. Additional information is provided from the Committee’s review of research on

multisymptom conditions in the general population, conditions that include chronic fatigue syndrome,

fibromyalgia, and multiple chemical sensitivity. These conditions are often compared to Gulf War

illness, and have frequently been studied in Gulf War veterans. As will be described, studies indicate that

Gulf War illness has both similarities and differences with multisymptom conditions found in the general

population. Research related to these conditions can potentially provide useful insights concerning the

biological mechanisms associated with Gulf War illness, and contribute to identifying beneficial

treatments.
230  The Nature of Gulf War Illness

Biological and Clinical Characteristics of Gulf War Illness

In its 2004 report, the Committee provided findings and recommendations on the major areas of research

reviewed to that time. This included the Committee’s finding that a growing body of evidence indicated

that Gulf War Illness had an important neurological component. Since that time, the Committee has

reviewed more recent studies of neurological findings in Gulf War veterans, as well as a wide range of

studies evaluating other biological and clinical parameters.

The majority of studies of Gulf War veterans have historically provided broad assessments of population

patterns of symptoms, hospitalization, and mortality, or have focused on psychiatric assessments in

smaller, clinical samples. Studies that provided clinical evaluations of Gulf War veterans usually found

that physical examinations and standard clinical testing methods identified a limited number of medical

diagnoses, but few objective abnormalities in symptomatic veterans who did not have diagnosed

conditions.160,393,464,879,1651 This sometimes led investigators to conclude that there are no unusual or

abnormal medical problems in Gulf War veterans. The absence of consistent diagnostic indicators from

routine clinical testing methods suggested to some that Gulf War illness was not a medical problem with

identifiable biological abnormalities. An alternate interpretation was that the biological abnormalities that

underlie veterans’ symptomatic illness were unfamiliar, and could not be detected by clinical tests

routinely used to diagnose more familiar conditions.

Results from a diverse spectrum of research studies that are now available support the second perspective,

that is, that veterans are medically ill, but that the physiological abnormalities that contribute to their

illness are not captured by tests routinely used in clinical practice. This view has long been supported, in

a broad sense, by the large number of population studies documenting consistent symptom profiles

affecting substantial numbers of Gulf War veterans from different units and regions. This pattern of

medically unexplained symptoms distinguished Gulf War veterans from contemporary veterans who did

not serve in the Gulf War, and from veterans who have since served in hostile engagements in Bosnia and

Iraq. Moreover, veterans’ illnesses have not been linked to combat or deployment stress, but are

consistently associated with neurotoxic exposures in the 1990-1991 Gulf War. The view of Gulf War

illness as an organic illness is further supported by more recent studies that have identified diverse

biological alterations in symptomatic veterans. Overall, available evidence consistently indicates that

veterans with Gulf War illness are medically ill, but that clinicians have lacked the diagnostic tools

needed to determine the nature of veterans’ symptomatic illness.

For the first 10 years after Desert Storm, before most research described in the present report was

available, the view of Gulf War illness as a stress-related psychological problem was more common.

Limited research was conducted during those years to assess unfamiliar biological abnormalities in

symptomatic veterans, that is, abnormalities not detected by routine clinical examination and testing.

When the Committee issued its last major report, nearly all scientific findings that provided objective

evidence of biological alterations in veterans with Gulf War illness came from studies of neurological

parameters in symptomatic veterans. In the last several years, a growing number of studies have provided

more detailed evaluations of biological parameters in relation to Gulf War illness, using research methods

not previously used in Gulf War veterans and, in some cases, methods that have only recently been

developed.

As will be described in the following pages, multiple studies have now reported diverse biological

findings that distinguish symptomatic Gulf War veterans from control groups. These differences relate to

a variety of biological systems, and include findings related to brain structure and function identified by

neuroimaging scans and neurocognitive studies, alterations in autonomic function, findings associated

with the immune system and hypothalamic-pituitary-adrenal axis, as well as novel findings related to the

body’s ability to protect itself from neurotoxic exposures. Recent studies that have relied on more routine
Biological and Clinical Characteristics of Gulf War Illness  231

clinical testing methods, however, have continued to identify only limited differences between

symptomatic Gulf War veterans and comparison groups.

In reviewing existing research on biological characteristics of Gulf War illness, the Committee has

identified several methodological issues that appear to have played a role in whether studies identified

clear distinctions, or raised additional questions as a result of inconclusive or conflicting results. Overall,

the most informative studies have compared symptomatic Gulf War veterans to healthy controls, rather

than combining all deployed Gulf War veterans into a single group—symptomatic and healthy veterans

together—and comparing them to referent groups. Different Gulf War illness case definitions also appear

to affect the clarity of study findings, with fewer distinctions identified by studies that use less specific

case definitions of “ill” versus “well” veterans. Studies that distinguish Gulf War illness subgroups of

importance appear to be particularly informative, for example, subgroups of veterans with different

clinical characteristics, symptom profiles, and/or exposure histories.

Important progress has been provided by the growing body of research studies that have identified

diverse, objectively measured biological alterations in veterans with Gulf War illness. These studies have

provided insights into the biological systems and processes affected by Gulf War illness. Significant

work remains, however, in characterizing the precise pathophysiological processes that underlie veterans’

symptoms. It is important to determine if differences identified by individual studies are replicable in

other veterans affected by Gulf War illness or are most relevant to identifiable Gulf War illness

subgroups. A clearer understanding is needed of how identified biological abnormalities contribute to

veterans’ persistent symptoms, and how findings in different areas interrelate with one another. Most

importantly, additional research is needed to determine how biological findings in veterans with Gulf War

illness can be most usefully applied to identifying diagnostic tests and beneficial treatments.
232  Biological and Clinical Characteristics of Gulf War Illness

Brain and Central Nervous System Alterations in Gulf War Veterans

I had never had headaches before the war, but now I was having them frequently and they

were getting worse. My dizziness was getting worse but wasn’t bad enough yet to make me

nauseous or to make me fall. By the summer of 1992, I was having violent and explosive

vertigo attacks, and it was becoming more difficult to focus on anything. My concentration

was so poor that I would forget how to reach my projected destination ...

--Army Colonel, Gulf War veteran716

As described in detail in the Committee’s previous report, a growing body of evidence available in 2004

indicated that an important component of Gulf War illness is neurological in character. From the earliest

years that veterans first returned from the Gulf War with symptoms of persistent headache, problems with

memory and concentration, and balance and mood disturbances, clinicians have suspected that veterans’

symptoms could be associated with central nervous system abnormalities. Clinical examinations,

however, typically provided few indications of identifiable neurological disorders in Gulf War veterans.

Today, multiple lines of research have supported early clinical and research indications that service in the

Gulf War, for many veterans, has had persistent adverse effects on the central nervous system, as

summarized in Table 1.

Table 1. Summary of Research Findings Indicative of Persistent Central Nervous System

Effects Associated with Gulf War Service

Area of Research Major Findings in Gulf War Veterans

Symptom evaluations in large

population-based studies

All epidemiologic studies have identified prominent neurological symptom

complexes affecting Gulf War veterans at significantly excess rates. Characteristic

symptoms include persistent headache, memory and concentration difficulties,

dizziness, mood, and visual disturbances.

Diagnosed neurological diseases ALS affects Gulf War veterans at twice the rate of nondeployed veterans; Gulf War

veterans downwind from 1991 Khamisiyah demolitions have died from brain

cancer at twice the rate of other veterans in theater.

Neuroimaging research Studies utilizing MRI, MRS, and SPECT scans have identified abnormalities in

basal ganglia, brain stem, hippocampus, white matter volume, and cerebral blood

perfusion that distinguish symptomatic from healthy veterans. MRI studies have

identified reduced white matter volume in relation to the Khamisiyah demolitions.

Neuropsychological research Multiple differences in neurocognitive function sign. distinguish symptomatic Gulf

War veterans from healthy controls, after controlling for effects of psychological

status. Neurocognitive abnormalities have also been identified in relation to

neurotoxic exposures in theater.

Abbreviations: ALS = amyotrophic lateral sclerosis, MRI = Magnetic Resonance Imaging, MRS = Magnetic Resonance Spectroscopy,

SPECT = Single Photon Emission Computed Tomography, sign. = statistically significant

All population-based studies have consistently identified symptom complexes suggestive of central

nervous system abnormalities at significantly elevated rates in Gulf War veterans. Identified rates of two

diagnosed diseases also suggest that Gulf War service led to neurological sequelae. Amyotrophic lateral

sclerosis (ALS), a rare and fatal neurodegenerative condition, has been shown to affect Gulf War veterans

at twice the rate of nondeployed era veterans.557,633,634,636 The mortality rate from brain cancer has also

been reported to be twice as high for veterans downwind from munitions demolitions at Khamisiyah, Iraq,

in March of 1991, compared to veterans in other areas of theater.105,192 Elevated rates of ALS and brain
Brain and Central Nervous System  233

cancer suggest the need for additional research to determine rates of other neurological disorders in Gulf

War veterans, research that has not yet been conducted. These diagnoses have been identified in a

relatively small number of Gulf War veterans, however, compared to the widespread problem of Gulf

War illness.

This section of the report provides information on research that has evaluated central nervous system

parameters in Gulf War veterans, with a particular focus on veterans with Gulf War illness. Several

research teams have identified objective indicators of central nervous system alterations in Gulf War

veterans using sophisticated brain scans and neurocognitive testing methods. Objectively measured

differences identified in these studies are not diagnostic of familiar neurological diseases, but have been

significantly associated both with veterans’ symptoms and with chemical exposures during the war.

Additional findings related to other aspects of neurological function, including autonomic regulation,

peripheral neuromuscular and sensory findings, and neuroendocrine alterations, are each considered in

separate sections.

Observers have sometimes commented, in reviews and editorials, that studies have not identified evidence

of neurological abnormalities in Gulf War veterans.101,686,1310 These comments have referred, most

generally, to the lack of neurological findings identified on standard clinical evaluation, or the

infrequency of peripheral neuromuscular and sensory abnormalities in Gulf War veterans. The

Committee’s review of findings from standard clinical examinations and peripheral nerve studies also

found that these types of evaluations provide little indication of abnormalities in Gulf War veterans. It is

important to distinguish the lack of findings in these areas, however, from the many significant findings

identified in relation to other aspects of neurological function in symptomatic Gulf War veterans,

including identified alterations in brain structure and function, and autonomic nervous system

dysregulation.

Neuroimaging Findings in Gulf War Veterans

Computed tomography (CT) scans and conventional MRI help rule out naturally occurring

disorders; they rarely show lesions specific for neurotoxic disease.

-- Experimental and Clinical Neurotoxicology, 20001359

Gulf War veterans have been evaluated with different types of neuroimaging scans, in research studies

and clinical practice, to determine if Gulf War illness is associated with discernable abnormalities in brain

structure or function. Several studies of this type were described in the Committee’s 2004 report, and

additional research has been reported in recent years, as summarized in Tables 2 and 3. The earliest

clinical reports evaluated symptomatic Gulf War veterans using electroencephalograms (EEG), as well as

standard computerized tomography (CT) and magnetic resonance imaging (MRI) scans of the head. As

has often been the case with more routine clinical testing methods, few abnormalities were identified in

these studies, and no significant differences between Gulf War illness cases and controls.46,563,878,893,1109

Early evaluations of Gulf War veterans at the University of Texas Southwestern (UTSW) also had not

identified differences between symptomatic and healthy veterans on MRI or SPECT (single photon

emission computed tomography) scans.563 In a later study, UTSW investigators assessed the same

veterans using long echo proton (1H) magnetic resonance spectroscopy (MRS).568 Results indicated that

veterans with the three Haley syndromes had significantly reduced N-acetyl-aspartate to creatine

(NAA/Cr) ratios compared to healthy controls, reflecting reduced functioning brain cell mass in the

brainstem and bilaterally in the basal ganglia. The specific regions affected differed for each of the three

Haley Syndromes, as detailed in Table 2. Investigators also reported that reduced brain cell mass was

associated with central dopamine activity in symptomatic veterans. Specifically, reduced neuronal mass
234  Biological and Clinical Characteristics of Gulf War Illness

Table 2. Published EEG and Brain Imaging Findings in Symptomatic Gulf War Veterans

Study Group Studied Method(s) Key Findings

Newmark1109

1995

65 active duty GWV evaluated in

the CCEP

EEG No EEG abnormalities identified

Haley563

1997

23 GWV with Haley Syndromes,

10 well GWV, 10 nondeployed

controls

MRI, SPECT No MRI differences between cases and controls. Similar

proportion of cases and controls had foci of T2 signal intensity in

subcortical white matter (26-30%). No SPECT abnormalities

identified.

Amato46

1997

20 GWV referred for

neurological evaluation

EEG, CT No abnormalities on EEG, CT scans of the head.

Haley568

2000

22 Navy Reserve GWV with

Haley syndromes, 2nd sample of

6 GWV with Haley Syndrome 2,

18 veteran controls (9 GWV, 9

nondeployed)

Proton MRS NAA/creatine ratio sign. lower in symptomatic GWV than controls:

Syndrome 1 in basal ganglia, Syndrome 3 in brainstem, and

Syndrome 2 in basal ganglia (14%) and brainstem (26%). Choline/

creatine ratio sign. lower in basal ganglia of Syndrome 1 GWV

than in controls. Syndrome 2 findings replicated in 2nd GWV

sample.

Meyerhoff1027

2001

11 GWV with CMI, 11

nonveteran controls

Proton MRS NAA/creatine ratio sign. lower in right basal ganglia of ill GW

veterans compared to controls. No differences in choline/creatine

ratio.

Lee878

2005

33 symptomatic GWV evaluated

in the UK GVMAP

EEG, CT or

MRI

Results reported as “no evidence of any neurological disorder”

specific measures not provided.

Menon1022

2004

10 symptomatic GWV, 5

nonsymptomatic GWV, Vietnam

veteran controls

Proton MRS NAA/creatine ratio in hippocampus was sign. lower in symptomatic

GWV than in GWV and Vietnam controls, and in younger GWV

than older GWV. No difference in choline/creatine ratios.

Levine893

2006

27 symptomatic GWV, 15 GWV

with PTSD, 11 symptomatic

nondeployed GWV, 4

nonsymptomatic GWV

EEG GWV had no abnormalities on EEG

Spence1462

2006

21 GWV with Haley syndromes,

17 veteran controls (9 GWV, 8

nondeployed)

SPECT Using a modified method to control for global signal effect,

Syndrome 2 GWV had sign. lower average intracerebral blood

flow and regional emission in areas of insula and frontal cortex.

Effects were not observed using standard global scaling measure.

Abbreviations: GWV = Gulf War veterans, CCEP = DOD’s Comprehensive Clinical Evaluation Program, EEG = electroencephalogram, MRI =

Magnetic Resonance Imaging, MRS = Magnetic Resonance Spectroscopy, CT = Computerized Tomography, GVMAP = Gulf Veterans’ Medical

Assessment Program (U.K. registry for GWV), NAA = N-acetyl aspartate, SPECT = Single Photon Emission Computed Tomography, CMI =

chronic multisymptom illness,464 sign. = statistically significant

in the left, but not the right, basal ganglia was significantly correlated with increased central dopamine

activity, estimated using the ratio of plasma homovanillic acid (HVA) to 3-methoxy-4-hydroxyphenylglycol (MHPG).562

The UTSW MRS findings were soon replicated, in part, in a pilot study conducted by investigators at the

San Francisco VAMC, in which 11 Gulf War veterans with chronic multisymptom illness (CMI) were

found to have a significantly reduced NAA/Cr ratio in the right basal ganglia, compared to healthy
Brain and Central Nervous System  235

Table 3. Preliminary Findings from Additional Neuroimaging Research

on Symptomatic Gulf War Veterans

Study Group Studied Method(s) Key Findings

Weiner1758

2005

52 GWV with CMI, 83 GWV with

inconsistent symptoms, 90 healthy

GWV controls (GWV include 25

with Haley Syndrome 2)

Proton MRS No sign. differences between groups in NAA/creatine ratios or

NAA/choline ratios in basal ganglia or brainstem.

Choline/creatine ratio in right basal ganglia sign. lower in

Syndrome 2 GWV than healthy controls.

Haley558

2006

21 GWV with Haley syndromes,

17 veterans controls (9 GWV, 8

nondeployed)

CBF response to

cholinergic

challenge, using

SPECT

Sign. differences in global CBF response to physostigmine

infusion in Syndrome 2 GWV compared to controls and

Syndromes 1 and 3; multiple regional differences identified

between Syndrome 2 and controls.

Abbreviations: GWV = Gulf War veterans, CMI = chronic multisymptom illness,464 CBF = cerebral blood flow, MRI = Magnetic Resonance

Imaging, NAA = N-acetyl aspartate, SPECT = Single Photon Emission Computed Tomography, sign. = statistically significant

controls.1027 More recently, researchers at the VAMC in Jackson, Mississippi, identified significantly

lower NAA/Cr ratios in the left and right hippocampus of symptomatic Gulf War veterans compared to

both healthy Gulf War veterans and Vietnam-era controls.

1022 And in 2006, UTSW researchers reported

that veterans with Haley Syndrome 2 had significantly reduced cerebral blood flow, both globally and

regionally in the frontal cortex and insula, compared to healthy controls. These findings were obtained

with SPECT scans using a newly developed analytic method to control for global signal effect.1462

As previously mentioned, an additional Gulf War neuroimaging study of interest comes from the Boston

VA Environmental Hazards Research Center, which did not specifically evaluate differences between

symptomatic and healthy veterans. The Boston study used MRI scans to assess the volume of brain

structures in 26 Gulf War veterans in relation to DOD-modeled exposure levels to sarin and cyclosarin

after the Khamisiyah weapons demolitions in March of 1991.599 Results indicated that Gulf War veterans

had significantly reduced white matter volume, and enlarged right and left ventricles that varied, in a dose

response manner, with increasing sarin and cyclosarin exposure. These results parallel findings of

regional reductions in white matter volume in sarin-exposed survivors of the Japanese subway attack in

1995.1816

One additional MRI study of Gulf War veterans comes from National Institutes of Health investigators,

but did not evaluate either multisymptom illness or exposures in theater. Rather, it compared brain

volume measures in 37 Gulf War veterans with and without PTSD to those of nondeployed reservists and

healthy civilians. Gulf War veterans, overall, as well as nondeployed reservists, had significantly smaller

hippocampal volumes than healthy nonveteran controls. There were no significant differences between

Gulf War veterans with and without PTSD.1739

Overall, accumulated findings from published studies have indicated that Gulf War illness is not

associated with abnormalities on EEG, CT, or standard MRI evaluations. In contrast, proton MRS studies

from three research teams have identified Gulf War illness-related alterations in three brain areas:

brainstem, basal ganglia, and hippocampus. Additional studies have identified significantly reduced

cerebral blood flow in the most severely ill Gulf War veterans, using specialized SPECT scan analyses,

and reduced white matter volume in relation to modeled levels of nerve agent exposure. Most published

imaging findings come from relatively small studies that assessed different types of abnormalities in

different areas. Therefore, additional research is needed to determine if these findings can be replicated

and/or further extended in larger samples.
236  Biological and Clinical Characteristics of Gulf War Illness

The Committee also reviewed preliminary results from three additional federally-funded Gulf War

neuroimaging projects. Although final results have not yet been published, early findings from two of the

studies have been presented at Committee meetings and research conferences, and are summarized in

Table 3. As shown, preliminary results from the San Francisco VAMC MRS project1758 do not appear to

support earlier findings from that group’s pilot project1027 and the initial UTSW MRS study.568

Symptomatic veterans in this study have not been found to have reduced NAA/Cr ratios in basal ganglia

or the brainstem.1758 The Committee will review additional information from this study and final results

when they are available, in order to gain a clearer understanding of the study’s findings and apparent

discrepancies with earlier projects.

Preliminary findings from an additional SPECT study of Gulf War veterans conducted by UTSW suggest

additional cerebral blood flow abnormalities in Gulf War veterans with Haley Syndrome 2. Specifically,

results indicate that symptomatic veterans differ from healthy controls in the magnitude and direction of

cerebral blood flow response to cholinergic challenge, globally and in several identified brain regions.558

In addition, early results from an additional MRI study of Gulf War veterans have been reported by

researchers from Boston VA and Boston University.1224,1780 Preliminary findings indicate that highly

symptomatic Gulf War veterans have significantly reduced total white matter volume, compared to

veterans with few or no symptoms.

Overall, a variety of neuroimaging studies have provided multiple indications of differences in brain

structure and function that distinguish symptomatic Gulf War veterans from healthy controls. Few Gulf

War illness-related brain abnormalities or case/control differences have been identified on tests routinely

used in clinical practice—EEGs, CT scans, and visual evaluation of MRI. More specialized brain

imaging studies, however, have consistently provided significant findings. Of the seven identified

projects that have compared symptomatic Gulf War veterans with healthy controls using proton MRS,

specialized SPECT analyses, and volume assessment of brain structures using MRI, six have identified

significant Gulf War illness-related differences with healthy controls. This includes findings from four

published studies and preliminary findings from two additional projects that have not yet been published.

No case/control differences have been identified in preliminary findings from one unpublished study. An

additional study has identified brain structure alterations in Gulf War veterans whose symptom profiles

were not considered, finding an overall reduction in white matter volume in relation to modeled nerve

agent exposures during the Gulf War.

The neuroimaging findings described have been an important step forward in documenting central

nervous system alterations in relation to Gulf War illness and, to a limited extent, Gulf War exposures.

Significant findings from the structural MRI and SPECT studies depended on technical methods

developed in recent years, and therefore could not have been identified when the earliest Gulf War studies

were conducted. Thus far, however, the variable methods used to evaluate different types of parameters

in different brain regions have, in effect, produced multiple one-of-a-kind findings. In most cases, there

have not been attempts to reproduce these results or integrate them with other findings in Gulf War

veterans. The Committee appreciates and encourages the ongoing efforts of different research teams to

carefully reexamine existing findings and to evaluate measures of brain structure and function in relation

to additional health, functional, and exposure parameters in order to provide a fuller understanding of the

nature of brain abnormalities in Gulf War veterans.
Brain and Central Nervous System  237

Neurocognitive Findings in Gulf War veterans

When I first came back from the war, I had a lot of problems remembering things. One day I

drove my kids to school and dropped them off, but then instead of driving home I just

wandered around for a couple of hours because I couldn’t remember where I was going.

-- SSgt PB, Gulf War veteran716

Prominent symptoms suggestive of neurological abnormalities in returning veterans—headache, memory

and concentration problems, balance abnormalities, mood alterations—prompted early use of

neuropsychological assessments in Gulf War veterans.78,499,624,1778,1779 Neuropsychological studies provide

objective measures of brain function, and constitute the largest body of research on central nervous

system function in Gulf War veterans. Neuropsychological testing assesses different cognitive domains,

which reflect function in areas of the brain that support different types of cognitive tasks. Executive

system tasks, for example, reflect frontal lobe functioning. A wide variety of specialized tests are used

clinically and in research studies to assess cognitive domains that include attention, executive system

functioning, motor skills, visuospatial functioning, memory, mood, and performance effort.

Neuropsychological testing has been used for many years to quantify neurocognitive deficits related to

chemical exposures.47 Evaluations can be used to assess damage in individuals who exhibit clinically

obvious effects of chemical poisoning and also to identify more subtle dysfunction in exposed individuals

without clinically obvious disease.48,939 For example, neuropsychological studies indicate that

agricultural workers chronically exposed to organophosphate pesticides exhibit identifiable decrements in

processing speed and mood.

1320,1483

There are two general categories of neuropsychological tests: (1) tests that characterize cognitive

measures that are relatively stable over time, used to estimate baseline abilities that predate the illness

condition being assessed, and (2) tests that have high specificity for detecting functions differentially

affected by particular diseases or neurotoxicants. Performance on neurocognitive tests can be affected by

a number of factors, which should be assessed and controlled for in well-conducted studies. These

include age, education, gender, medical conditions, and psychiatric conditions like PTSD and depression.

Motivational measures should also be assessed to ascertain if the examinee is exerting adequate effort to

ensure the test battery is a valid assessment of their cognitive functioning.

The impact of psychological parameters—as contributors, as cofactors, and as outcomes, are extremely

important considerations in neuropsychological testing, and can be complex. Changes in affect and

emotional functioning, for example, depression or abnormal mood swings, can be symptoms of brain

injury, and so are important to measure when assessing central nervous system function.1359,1779,1781 On

the other hand, posttraumatic stress disorder (PTSD) and other psychiatric conditions can directly affect

neurocognitive function and test measures. It is important, therefore, to adjust measured

neuropsychological outcomes for the effects of psychiatric conditions like PTSD or depression. But this

can be problematic if psychological factors, such as depression, are “overcontrolled,” reducing or

eliminating the effect of the brain injury being evaluated.1709,1779

The large number of projects that have evaluated neuropsychological parameters in Gulf War veterans

have used diverse tests to assess different aspects of brain function in studies of varying design, size, and

quality. One important distinction in this group of studies relates to whether neurocognitive function was

assessed in relation to Gulf War deployment overall (e.g., comparing outcomes in deployed and

nondeployed veterans), in relation to Gulf War illness (comparing symptomatic to healthy veterans), or in

relation to exposures during deployment (comparing Gulf War veterans who had a particular exposure in

theater to unexposed veterans). The first type of studies, those that assessed neuropsychological

outcomes in relation to Gulf War deployment, do not provide insights specific to Gulf War illness, since

they combine neuropsychological measures obtained in symptomatic veterans with those of healthy

veterans. Those studies are summarized in Table 4.
238  Biological and Clinical Characteristics of Gulf War Illness

Table 4. Neurocognitive Evaluation of Gulf War-Deployed Veterans Overall,

Not Differentiated by Veterans’ Health Status

Study Sample Key Findings

Goldstein499

1996

21 GWV, 38 nonveterans GWV had sign. lower overall test performance, as measured by global

impairment index based on 14 tests. No sign. differences on individual tests.

Adjustment for psychological covariates reduced or eliminated group

differences.

Axelrod78

1997

44 male GWV from Army

Guard unit

Compared to normative values, GWV had sign. deficits on measures of motor

speed and executive functioning.

Sillanpaa1409

1997

49 GWV from a single

Army reserve military

police unit

Neuropsych test performance sign. corr. with emotional dysfunction.

White1782

2001

Lindem/Heeren910

2003

Lindem/Proctor911

2003

Lindem/White912

2003

193 GWV, 47 Germany

deployed veterans

GWV scored sign. worse on tests of attention and executive functioning and

mood states. Only mood functioning scores differed sign. after controlling for

multiple comparisons and psychological diagnoses.

In GWV, sign. corr. between PTSD severity and poorer performance on tests of

intellectual ability, sustained attention, motor speed and coordination, verbal

learning, and mood. PTSD-related effects differed in veterans who did/did not

report exposure to chemical agents.

Sign. more neuropsych symptoms reported by GWV than Germany deployed

veterans. GWV neuropsych symptoms not sign. associated with performance

deficits but were correlated with mood measures.

In subset of 58 GWV and 19 Germany-deployed veterans tested for motivation

and effort, most had perfect or near-perfect scores; similar subset of GWV and

Germany deployed scored suboptimally.

David315

2002

207 British GWV, 78

nondeployed era veterans

GWV had sign. worse performance on tests of verbal and intellectual

performance, motor speed, and dexterity. Differences were reduced or

eliminated with adjustments for depression, multiple comparisons.

Gray527

2002

3,831 GWV Seabees,

4,933 Seabees deployed

elsewhere, 3,104

nondeployed Seabees

GWV had sign. higher (worse) scores than other two groups on Cognitive

Failures Questionnaire.

Vasterling1708

2003

72 GWV, 33 nondeployed

veterans

No sign. difference on neuropsych measures.

Proctor1240

2003

143 Danish GWV, 72

nondeployed veterans

No sign. differences on neuropsych tests. GWV reported sign. more mood

disturbances than nondeployed veterans.

Vythilingham1739

2005

14 GWV with PTSD, 23

GWV without PTSD, 22

nondeployed veterans, 29

healthy civilians

No neuropsych differences associated with PTSD or Gulf War deployment.

GWV with and without PTSD and nondeployed reservists had sign. worse

scores than healthy civilians on measures of visual and verbal memory.

Barrash102

2007

301 GWV, 99 era veterans

deployed elsewhere

Only 1% of GWV and 4% of era veterans had neuropsych test results judged to

be noncredible by independent reviews.

Abbreviations: GWV = Gulf War veterans, neuropsych = neuropsychological, PTSD = posttraumatic stress disorder, sign. = statistically

significant, corr. = correlated
Brain and Central Nervous System  239

As shown in Table 4, studies that assessed neuropsychological function in relation to Gulf War

deployment overall, but not specifically in veterans with chronic symptomatic illness, typically identified

limited, or no, differences with reference groups. Deployment-related differences most often were found

on tests of mood and emotional functioning, while identified differences in other neurocognitive domains

were often diminished or eliminated when adjusted for effects of psychiatric conditions or emotional

functioning.315,499,910,911,1782 In reviewing these studies, the Institute of Medicine suggested that several

may have overcorrected for depression and multiple comparisons, potentially masking subtle cognitive

deficits in several domains.686 Studies indicated that veterans’ subjective cognitive symptoms were often

not associated with objectively-measured performance deficits, and were more closely correlated with

reduced mood scores.78,911 Several studies reported that Gulf War veterans’ level of motivation and effort

during cognitive testing was similar to that of nondeployed era veterans, and that noncredible

neuropsychological examination due to insufficient effort or malingering was not a significant problem in

studies of Gulf War veterans.102,912,1782

Neurocognitive findings in Gulf War veterans with multisymptom illness. Studies that evaluated

neurocognitive measures in symptomatic Gulf War veterans provide information more specifically relevant to

Gulf War illness. Results of these studies are summarized in Table 5. As shown, neuropsychological

evaluations consistently identified significant differences in neurocognitive function between symptomatic Gulf

War veterans and healthy controls. These included differences in tests of attention and executive system

functioning, memory, visuospatial skills, psychomotor skills, and mood and emotional functioning. Identified

differences, while generally not large, were consistently significant and remained significant after adjustments

for emotional functioning and psychiatric disorders. Findings, in some cases, indicated that symptomatic

veterans display a slowing of response speed that affects their mental flexibility across multiple cognitive

domains. This was most apparent on tests that were timed and computerized, on which small differences in

reaction times could be detected.49,864

A potentially important distinction was first identified in a 1999 study of symptomatic Gulf War veterans

from the Pacific Northwest,49 confirmed in an expanded sample,1497 and generally supported by other

studies.1782 The Pacific Northwest study identified a subgroup of symptomatic veterans who had

significantly reduced neurocognitive performance on a variety of tests. These “slow cases” were similar

to other symptomatic veterans on measures of psychological distress but exhibited a unique profile of

objective deficits in memory, attention, and response speed. Investigators suggested that this subgroup

should be the focus of additional study,49,1497 supporting the broader point that subgroups of importance

can be obscured when all symptomatic veterans are considered as a single group.1709

Neuropsychological evaluation of symptomatic veterans again indicated that many who report cognitive

difficulties do not have objectively measurable neurocognitive deficits and that performance motivation is

not generally a problem in Gulf War studies.78,135,315,1497,1512,1708 And, although psychiatric and emotional

parameters are often associated with reduced cognitive function in symptomatic Gulf War veterans,

psychological factors do not account for or explain the neurocognitive deficits identified in symptomatic

Gulf War veterans.686,1709,1779

Neurocognitive function in relation to exposures in theater. In discussing results of their

studies of Gulf War veterans, some investigators have commented that identified neurocognitive deficits

resemble those associated with neurotoxic exposures.49,78,864 Several Gulf War studies have specifically

evaluated veterans’ neurocognitive function in relation to exposures they encountered during deployment,

and are summarized in Table 6. Most evaluated neuropsychological outcomes in relation to neurotoxic

exposures—nerve agents, pesticides, and pyridostigmine bromide (PB)—without specific reference to

multisymptom illness. The majority of these studies have been conducted by researchers from VA’s

Boston Environmental Hazards Research Center and Boston University. A 2001 study from Dr. Roberta

White and colleagues reported that, among veterans in the Fort Devens cohort, self reported pesticide use
240  Biological and Clinical Characteristics of Gulf War Illness

Table 5. Neurocognitive Evaluation of Symptomatic Gulf War Veterans

Study Sample Key Findings

Axelrod78

1997

17 GWV with neurocog

symptoms, 27 GWV with no

neurocog symptoms

Veterans with cognitive symptoms exhibited sign. lower scores on tests of motor

speed and executive functioning, and exhibited more psychological distress.

Haley563

1997

Hom624

1997

23 GWV with Haley Syndromes,

10 GWV and 10 nondeployed

veteran controls

26 GWV with Haley Syndromes,

10 GWV and 10 nondeployed

veteran controls

Symptomatic GWV, overall, scored sign. worse than controls on measures of

generalized brain function and on specific measure of executive system

functioning. Most sign. deficits were in veterans with Syndrome 2.

Symptomatic GWV had sign. lower scores on summary measures of intellectual

and cognitive function and performed sign. worse on tests of abstract reasoning

and problem solving, flexibility of thought, verbal and perceptual motor skills,

tactile and visual perception, psychological and emotional functioning.

Anger49

1999

Binder135

1999

Storzbach1496

2000

Storzbach1497

2001

Binder136

2001

66 GWV with unexplained

symptoms from WA and OR,

35 GWV controls

100 GWV with unexplained

symptoms

241 GWV with unexplained

symptoms, 113 GWV controls

239 symptomatic GWV, 112

GWV controls

32 GWV with CFS, 62 GWV

controls

Symptomatic GWV, overall, had sign. poorer performance on memory test. “Slow

case” subgroup of symptomatic GWV had sign. poorer performance on tests of

memory, attention, and response speed.

Subjective cognitive complaints sign. corr. with measures of response latency

and affective distress, but modestly corr. with other neuropsych measures.

Symptomatic GWV had sign. poorer performance on tests of memory, attention,

and response time, and sign. greater psychological distress.

In expanded sample, subgroup of “slow cases” were again identified who

performed sign. worse on tasks of memory, attention, and response time. Other

symptomatic GWV had very limited neuropsych differences from controls.

GWV with CFS performed sign. worse on measures of reaction time and forced

choice after controlling for effects of premorbid cognitive differences.

Bunegin193

2001

8 symptomatic GWV, 8 GWV

controls

Symptomatic GWV had sign. poorer performance on tasks of memory and

executive function on a computerized battery.

Lange864

2001

48 symptomatic GWV, 39 GWV

controls

Symptomatic GWV had sign. poorer performance on measures of attention,

concentration, information processing, and abstraction and conceptualization.

Sign. differences remained after controlling for concurrent psychopathology.

David315

2002

65 GWV with CMI, 33 GWV with

no symptoms

GWV with CMI performed sign. worse on multiple measures than healthy

controls. Sign. poorer performance on vocabulary and digit-symbol tests after

adjusting for depression, no sign. differences after Bonferroni correction.

Gray527

2002

845 GWV Seabees who met

study criteria for GWI, 2986 who

did not.

GWV with any of 4 multisymptom illnesses or more than 12 symptoms were sign.

more likely to score > 42 on Cognitive Failures questionnaire than GWV without

GWI (odds ratios between 3.3 and 12.7).

Sullivan1512

2003

207 treatment seeking GWV

(120 referred for neuropsych

evaluation), 53 treatment

seeking nondeployed veterans

GWV performed sign. worse on measures of attention, visuospatial skills,

memory, and mood. Differences remained sign. after controlling for effects of

PTSD.

Abbreviations: GWV = Gulf War veterans, corr=correlated, neurocog = neurocognitive, neuropsych = neuropsychological, WA = Washington

state, OR = Oregon, CFS = chronic fatigue syndrome, sign. = statistically significant
Brain and Central Nervous System  241

Table 6. Neurocognitive Evaluation of Gulf War Veterans in Relation to Exposures in Theater

Study Sample Key Findings

Sillanpaa1409

1997

49 GWV from a single Army

reserve military police unit

Neuropsych test performance not sign. associated with exposure score derived

from multiple exposures combined.

White1782

Lindem910

2001

Proctor1237

2006

193 Army GWV in Fort

Devens cohort

140 Army GWV with

modeled estimates of nerve

agent exposure

Self-reported pesticide exposure associated with sign. worse scores on all POMS

subscales; self-reported exposure to chemical weapons associated with sign.

worse scores on measures of memory, attention/executive functioning, and mood.

Modeled nerve agent exposure sign. associated, in dose-dependant pattern, with

poorer performance on tests of fine psychomotor dexterity and visuospatial skills.

Nerve agent exposure was not sign. associated with mood state.

Vasterling1708

2003

26 GWV with higher

exposure levels, compared to

46 GWV with lower level

exposures

Neuropsych test performance not sign. associated with higher level exposures (all

exposures combined into one measure).

Sullivan1512

2003

207 GWV seeking treatment GWV who reported using PB performed sign. worse than GWV who did not use

PB on measures of executive system functioning.

Abbreviations: GWV = Gulf War veterans, POMS = Profile of Mood States, DU = depleted uranium, PB = pyridostigmine bromide,

sign. = statistically significant

was significantly associated with measures of reduced mood functioning, and veterans who reported

exposure to chemical warfare agents had significantly greater deficits on tests of memory, attention, and

mood.1782 Dr. Kim Sullivan and colleagues later reported that Gulf War veterans who used PB during

deployment scored significantly worse on measures of executive system function than veterans who did

not use PB, after controlling for effects of PTSD.1512

In 2006, Dr. Susan Proctor and colleagues identified significant neurocognitive deficits in veterans

potentially exposed to sarin and cyclosarin following weapons demolitions near Khamisiyah, Iraq, in

March of 1991. In detailed analyses, slowed performance on psychomotor and visuospatial tasks was

significantly associated with modeled nerve agent exposure levels in a dose-response pattern, that is,

greater deficits were correlated with greater exposure levels. This study is noteworthy for a number of

reasons. In contrast to previous studies, exposure data were provided by DOD models that estimated

levels of sarin and cyclosarin exposure for troops in specific locations, rather than relying on veterans’

self-reported exposures. In addition, the neuropsychological testing had been done prior to veterans being

notified about the Khamisiyah demolitions, providing test results for which both veterans and

investigators were blind to veterans’ exposure status.1237 Study results parallel those from neurocognitive

studies of Japanese citizens exposed to sarin in the 1995 subway terrorist incident, in whom persistent

neurocognitive deficits were documented several years after exposure.1054,1128,1827,1828

Boston researchers are currently completing a project that involves neuropsychological testing of a large

cohort of Gulf War military pest control personnel. Results of preliminary analyses are available in a

DOD project report.836 Early findings suggest that Gulf War veterans who had the highest-level exposure

to both pesticides and PB during deployment have significantly worse performance in several

psychomotor domains than veterans with low exposures. This study is particularly noteworthy because it

evaluated a group of veterans who were highly knowledgeable concerning types and methods of pesticide

use during the Gulf War, and is evaluating combined effects of PB and pesticides in relation both to

neurocognitive measures and to multisymptom illness. The Committee looks forward to reviewing final

results from this study as they become available.
242  Biological and Clinical Characteristics of Gulf War Illness

As previously described, VA investigators have conducted periodic examinations of a small cohort of

Gulf War veterans with high-level exposure to depleted uranium (DU) resulting from friendly fire

incidents. The project did not specifically evaluate DU exposure, or compare outcomes in veterans

exposed vs. not exposed to DU. Investigators did report, however, that in several of the longitudinal

clinical evaluations, veterans with the highest levels of circulating uranium exhibited poorer accuracy on

automated neurocognitive tests than veterans with lower-level circulating uranium.994,997,998 Differences

were statistically significant only in the 1997 evaluation, and investigators indicated that identified

differences were driven by a subset of individuals who had suffered severe medical and psychiatric

complications from their injuries. Therefore, there is no clear indication of whether or not circulating

levels of DU are associated with identifiable neurocognitive deficits.

Two additional studies have assessed neurocognitive function in relation to a generalized “total exposure

burden” measure that combined self-reports of multiple different deployment exposures such as oil fire

smoke, combat, poor sanitation, and vehicle exhaust.1409,1708 Measured neurocognitive deficits were not

associated with exposure levels measured in this way. This supports other indications that identified

associations between neurocognitive deficits and self-reported exposure to PB, chemical weapons, and

pesticides are exposure-specific, that is, not attributable to greater endorsement of exposures, overall, by

symptomatic veterans.

In summary, neuropsychological studies in Gulf War veterans consistently indicate that symptomatic

veterans are affected by persistent, but subtle, "subclinical" central nervous system damage. Symptomatic

veterans exhibit decrements in attention and executive system functioning, memory, visuospatial skills,

psychomotor functioning, and mood. In some instances, study results reflected slowed response latencies

across several cognitive domains. Measured deficits are generally modest and are not identified in all

Gulf War veterans with cognitive symptoms. Characterizing Gulf war illness-related cognitive effects

requires careful testing and analytic methods, involving comparisons between symptomatic Gulf War

veterans and healthy controls, with appropriate adjustments for psychiatric and other confounders.

Neuropsychological research involving broad comparisons of deployed Gulf War veterans, overall, with

nondeployed veterans, has provided limited information relevant to Gulf War illness. In contrast,

comparisons between symptomatic and healthy Gulf War veterans consistently identify subtle

neurocognitive decrements not explained by PTSD or other psychological conditions. A number of

studies have indicated that research on identifiable veteran subgroups—those with more pronounced

cognitive impairment and those with differing exposure histories, is likely to be most informative. This

includes findings from several studies that neurocognitive decrements in Gulf War veterans are associated

with exposure to pesticides, PB, and nerve agents during Gulf War deployment.

Assessment of Audiovestibular Function and Postural Stability

Veterans with Gulf War illness consistently report multiple symptoms suggestive of central nervous

system alterations. Dizziness and balance difficulties are common, and figure prominently in two Gulf

War illness case definitions.565,752 Two research teams have conducted investigations to determine if

these problems relate to measurable organic irregularities associated with balance. University of Texas

Southwestern investigators identified a variety of audiovestibular abnormalities in symptomatic

veterans.563,1304 These included greater interocular asymmetry in saccadic velocity and rotation-induced

nystagmus, particularly among veterans meeting criteria for Haley Syndrome 2, the group in whom dizzy

spells were most frequent.

Symptomatic Gulf War veterans were also evaluated on measures of sensory organization and postural

sway by investigators at the East Orange, New Jersey, VA. Preliminary results were presented to the

Committee by Dr. Thomas Findley438 and additional details presented at the 2004 conference of the
Autonomic Nervous System  243

American Academy of Physical Medicine and Rehabilitation.27 Significant abnormalities related to

postural stability and sensory organization were identified in symptomatic veterans: over 50 percent

scored more than 2 standard deviations below normal on quantitative balance testing, compared to 10

percent of healthy controls. Only methodological papers related to this study have been published in the

peer reviewed literature, however.233,234

Autonomic Nervous System Alterations in Gulf War Veterans

The autonomic nervous system (ANS) is the part of the nervous system that regulates involuntary, or

“automatic” physiological activities. The body’s ability to maintain normal organ function and respond to

changing biological conditions depends on ANS regulation of processes such as circulation, breathing,

digestion, and temperature control. Autonomic neurons connect the brain and spinal cord with all major

organs and glands of the body via its three major components, the sympathetic, parasympathetic, and

enteric nervous systems. Signaling utilizes the neurotransmitters acetylcholine and norepinephrine, as

well as a variety of other chemical messengers. Autonomic pathology can be associated with diverse

symptoms such as dizziness, weakness, digestive abnormalities, and sexual dysfunction, and can also be

an important feature of conditions such as diabetes and Parkinson’s disease.457,537,935,1368 Different aspects

of autonomic function can be evaluated in different ways; no single test is all inclusive.936 Autonomic

tests frequently assess ANS regulation of cardiovascular function, by determining effects of different

types of physiological challenges on parameters related to heart rate and blood pressure.

A potential link between Gulf War illness and ANS dysregulation has been posited from several

perspectives. These include concern about effects of cholinergic exposures during the war,740,1071 the

possible relationship of many Gulf War illness symptoms to ANS dysregulation, and observed ANS

alterations in multisymptom conditions like chronic fatigue syndrome and fibromyalgia. One of the

earliest reports of a possible autonomic problem in Gulf War veterans came from a study presented at a

federal Gulf War research conference. Investigators from the Detroit VA identified an excess of gall

bladder disease requiring surgery in Gulf War veterans and hypothesized the condition could be the result

of bile stasis due to autonomic dysregulation.1049 Since then, multiple research teams have evaluated

autonomic function more directly in symptomatic veterans, using a variety of testing methods. Key

findings from published studies are summarized in Table 4.

Additional information on autonomic testing of symptomatic Gulf War veterans has been provided by

two federally-funded research projects. Preliminary results from a project conducted by Midwest

Research Institute were presented to the Committee by Dr. Antonio Sastre.1352 Findings from this and

additional Gulf War autonomic research conducted at Georgetown University are publicly available in

Department of Defense project reports, but have not been published in research journals.251,1353 Findings

are included in the summary discussion here because the projects were, in some respects, more

comprehensive than other Gulf War ANS studies and provide context for the published studies listed in

Table 4. Key findings from the two additional federal Gulf War ANS projects are summarized in Table 5.

As shown in the tables, studies have identified a variety of ANS measures that significantly distinguish

veterans with Gulf War illness from healthy controls, using different testing methods and evaluating

different Gulf War illness populations. The diversity of study approaches used and groups evaluated

make direct comparison of study results problematic, although a number of commonalities can be

identified.

First, it appears, from all but one of the studies listed, that veterans with Gulf War illness differ

significantly from healthy controls on multiple measures of autonomic function. Studies identified few or

no differences in baseline cardiovascular parameters, but significant differences in response to
244  Biological and Clinical Characteristics of Gulf War Illness

Table 4. Published Studies of Autonomic Function in Symptomatic Gulf War Veterans

Study Group Studied Autonomic Tests Key Findings

Davis321

2000

14 GWV with CFS or

ICF, 27 GWV and

nonveteran controls

NMH during 3-stage tilt table

testing (isoproterenol in

stages 2 and 3)

Sign. more symptomatic GWV had NMH response to

tilt in stage 1 and overall. Symptomatic GWV had

sign. greater systolic BP, HR, and change in HR with

stage 1 tilt.

Peckerman1184,1185

2000, 2003

51-55 GWV with CFS

or ICF (16 with

PTSD), 42-47 GWV

controls

BP responses to speech and

arithmetic stress tests, cold

pressor test, BP change

between supine and standing

positions

Symptomatic GWV had sign. less BP response to

cognitive stressors, responses correlated with

symptom severity and functional impairment. BP

differences were most pronounced in symptomatic

GWV with PTSD. No differences on cold pressor test.

Sharief1397

2002

39 symptomatic

GWV, 18 GWV

controls

Valsalva ratio, standing ratio,

sympathetic skin response

Findings reported as “no real differences” on any tests

(statistical results not provided).

Fiedler433

2004

12 GWV with CFS,

19 GWV controls

BP and HRV response to

diesel vapor exposure

Symptomatic GWV had sign. increased systolic BP

and respiratory variability response to diesel vapors.

They also had blunted reactivity to (less increase in

BP, HRV) and recovery from behavioral tasks in the

presence of diesel exposure, but not in the absence of

exposure.

Stein1481

2004

11 GWV with CMI (6

male/5 female), 26

FM patients, 36

controls

24 hour electrocardiogram GWV had sign. lower 24-hour short term high

frequency HRV than controls. Males and females

differed on multiple HRV measures over the 24 hour

period. Overall, female GWV and FM patients had

sign less. HRV than controls and male patients.

Haley569

2004

21 GWV with Haley

syndromes, 17

veteran controls

24 hour electrocardiogram

and BP, Valsalva ratio, tests

of sympathetic function

(silastic sweat imprint,

sympathetic skin response)

Symptomatic veterans had sign. less nighttime

increase in HRV high frequency power and less

decrease in nighttime HR than healthy controls. No

differences on measures of circadian BP, Valsalva

ratio, sympathetic function tests.

Lucas937

2005

49 GWV with CMI, 44

GWV, 45

nondeployed veteran

controls

BP, HR, respiratory rate, endtidal CO2

, symptoms, and

NMH in relation to 2 stage tilt

test (isoproterenol in stage 2)

Veterans with CMI had sign. more and faster onset of

symptoms during tilt than controls. Symptomatic

GWV had nonsign. higher rate of NMH, sign. higher

respiratory rate, and sign. lower tidal CO2 with stage 1

tilt.

Abbreviations: GWV = Gulf War veterans, CFS = chronic fatigue syndrome, ICF = idiopathic chronic fatigue, NMH = neurally mediated

hypotension, PTSD = posttraumatic stress disorder, FM = fibromyalgia, CMI = chronic multisymptom illness,464 BP = blood pressure,

HR = heart rate, HRV heart rate variability, sign. = statistically significant

physiological challenges. Findings most often indicated a blunted, or reduced, autonomic response to

those challenges.321,433,1185,1353 In addition, both published studies that monitored electrocardiograms over

a 24-hour period identified significantly diminished heart rate variability in the high frequency range in

symptomatic Gulf War veterans—observed over a 24-hour period in one study, and during nighttime

hours in the other.569,1481 Second, results of these studies indicate that methodology is extremely

important in understanding ANS function in Gulf War illness. All three studies that tested ANS function

using the Valsalva maneuver, for example, found no difference between cases and controls, indicating
Autonomic Nervous System  245

Table 5. Additional Results from Federally-Funded Gulf War Autonomic Research

Study Group Studied Autonomic Tests Key Findings

Clauw251

2001

17 symptomatic GWV,

31 controls

24 hour electrocardiogram

and effects of tilt testing on

HR and HRV

No differences in baseline HR and BP. GWV had sign. greater

diastolic BP increase response to tilt and sign. greater daytime

low frequency HRV than controls that, unlike controls, dropped

significantly during the night .

Sastre1353

2004

49 GWV with GWI

(KS), 19 GWV and 23

nondeployed veteran

controls

Continuous BP and

electrocardiogram during

deep breathing, sustained

hand grip, Valsalva

maneuver, arithmetic

stress, emotional stressor,

and tilt testing

Limited case/control BP and HR differences with breathing and

emotional stressors, no differences with Valsalva, arithmetic or

hand grip stress. Cases had sign. higher mean BP at baseline,

numerous sign. case/control HRV differences during and after

tilt. GWI cases had sign. less HR and HRV response to tilt in

both spectral and time domains (lower total power, low frequency

power, SDNN, and %NN).

Abbreviations: GWV = Gulf War veterans, GWI (KS) = Gulf War illness, defined using Kansas criteria,1476 BP = blood pressure, HR = heart rate,

HRV heart rate variability, NN = time interval between normal beats in electrocardiogram, SDNN = standard deviation of NN intervals, %NN =

the proportion on NN intervals greater than 50 msec., sign. = statistically significant

that pathways involved in this test are not associated with Gulf War illness.569,1353,1397 Alterations in

sympathetic skin response and simple assessments of cardiovascular changes with standing also were not

linked with Gulf War illness in several studies.569,1185,1397 The only study that found no ANS differences

between symptomatic Gulf War veterans and controls relied on three tests also shown by other studies not

to be informative.1397 In contrast, significant differences between cases and controls were demonstrated in

all studies that assessed ANS function using tilt table testing and/or 24-hour

electrocardiogram.251,321,569,937,1353,1481 It is important to emphasize, therefore, that ANS research in Gulf

War veterans requires the use of appropriate ANS testing methods, and that reliable conclusions about

ANS function cannot be based on tests that are not informative in this population.686,1310,1397

In addition, the specific ANS differences associated with Gulf War illness varied from study to study. In

general, it appears that more pronounced ANS differences were identified in studies that used more

symptomatic, narrowly-defined Gulf War illness “case” subjects. Gulf War veterans who meet case

criteria for chronic fatigue syndrome (CFS), for example, are required to be more highly symptomatic

than cases defined according to the less restrictively defined chronic multisymptom illness (CMI).465 In

tilt table testing, Gulf War veterans with CFS had significantly higher rates of neurally mediated

hypotension (NMH) than healthy controls.321 Using a similar tilt testing protocol, however, veterans who

met CMI criteria had only a nonsignificant excess of NMH, but did have a pronounced symptomatic

responses to tilt.937

In addition to differences associated with case definition, studies with small sample sizes generally

identified fewer significant ANS findings than larger studies. Studies have also indicated that ANS

function may vary in different veteran subgroups. Single studies have reported that some ANS findings

were more pronounced in symptomatic veterans who also had PTSD,1184 and in female compared to male

veterans.1481 This suggests that sample size and selection can have important effects on the types of ANS

findings obtained, and on whether Gulf War illness-related distinctions are identified at all. For example,

the study that identified pronounced ANS distinctions between male and female Gulf War veterans, but

less difference between Gulf War illness cases and controls, relied on a sample of just 11 Gulf War

veterans.
246  Biological and Clinical Characteristics of Gulf War Illness

Many of the research limitations described appear to have been addressed in the Midwest Research

Institute project, which identified the most extensive ANS differences between Gulf War illness cases and

healthy veteran controls.1353 The project administered a multifaceted ANS battery to a relatively large,

population-based sample of Gulf War-era veteran cases and controls, and identified Gulf War illness

cases using a validated case definition. Some ANS tests identified no differences between cases and

controls, while others identified multiple ANS differences that were internally consistent. The Committee

is troubled that these results have not yet been published, however. Still, the consistent and extensive

Gulf War illness-related ANS findings identified in this project support the importance of using more

thorough testing protocols in suitably-sized and defined Gulf War illness case and control groups. The

Committee urges these investigators to publish their findings at the earliest opportunity and looks forward

to reviewing them further at that time.

Despite consistent indications that symptomatic Gulf War veterans differ significantly from healthy

controls on ANS measures, the variability and limitations of current studies do not allow a clear

characterization of Gulf War illness-related autonomic dysfunction. Individual findings appear to suggest

alterations in central,1185 parasympathetic,569,1481 or sympathetic251,1481 ANS processes, or a combination of

these.1353 Understanding the physiological implications of these findings is also complex.

Neurophysiologists do not universally agree on how some ANS alterations are best interpreted, for

example, whether HRV frequencies in different ranges clearly reflect sympathetic tone, parasympathetic

tone, or aspects of both. 385,1169,1527 More comprehensive research is needed to better understand existing

ANS findings and further characterize autonomic function in symptomatic Gulf War veterans.

Neuromuscular and Sensory Findings in Gulf War Veterans

Symptoms reported by Gulf War veterans frequently include muscle pain and weakness and can also

include numbness, and tingling sensations in the extremities. Such symptoms potentially indicate

abnormalities in peripheral nerve function related to sensation and motor function. In addition to research

on central nervous system and autonomic function in veterans with Gulf War illness, multiple studies

have tested peripheral nerve parameters associated with sensory and neuromuscular function.

Theories concerning possible causes of muscle weakness and fatigue in Gulf War veterans have included

suggestions that exposure to acetylcholinesterase inhibitors may have had persistent adverse effects on

neuromuscular junctions. As previously described, peripheral neuropathy is a characteristic feature of the

delayed neurotoxic condition associated with organophosphate poisoning.934 One large survey of British

Gulf War veterans queried veterans in detail about the presence and severity of numbness and tingling in

each limb to identify patterns indicative of peripheral neuropathy. Ten percent of Gulf War veterans had

symptoms suggestive of peripheral neuropathy, with highest rates among veterans who reported handling

pesticides and experiencing side effects from pyridostigmine bromide pills during deployment.241

Several of the largest U.S. Gulf War studies that assessed peripheral nerve function compared measures

obtained in all deployed Gulf War veterans with those of veterans who did not serve in the Gulf War.

These studies, summarized in Table 6, combine clinical results from symptomatic and healthy Gulf War

veterans and so do not provide information specifically related to Gulf War illness. In the large VA

clinical study that compared Gulf War with nondeployed era veterans, Gulf War deployment was not

associated with excess rates of peripheral neuropathy.319 Similarly, two additional studies reported no

significant differences in peripheral nerve or muscle strength measures between Gulf War veterans, as a

group, and veterans who did not serve in the Gulf War.
Neuromuscular and Sensory Findings  247

Table 6. Studies Assessing Sensory and Neuromuscular Function

in Gulf War Veterans, Not Differentiated by Health Status

Study Groups Studied Parameter(s) evaluated Key Findings

Kaiser738

2000

527 GWV Seabees, 969

nondeployed GW-era

Seabees

Handgrip strength No differences in muscular strength between GWV and

nondeployed veterans. No associations between

muscular strength and use of PB or insecticides.

Joseph729

2004

56 GWV and 120 other

veterans referred to a

physical medicine/

rehabilitation clinic

Motor and sensory nerve

conduction tests, needle

EMG

GWV referrals had sign. fewer confirmed cases of

radiculopathy, no sign. difference in confirmed cases of

generalized peripheral neuropathy or mononeuropathy.

Davis319

Eisen393

2004,2005

1,061 Gulf War and

1,128 nondeployed GWera veterans

Neurological examination

(reflex and manual muscle

testing, sensory testing),

nerve conduction studies

Deployed GWV had sign. more symptoms of limb

numbness or tingling. No sign. difference in rates of

diagnosed peripheral neuropathy based on

abnormalities on exam or nerve conduction studies.

Group results for specific tests not reported.

Abbreviations: GW = Gulf War, GWV = Gulf War veterans, PB = pyridostigmine bromide, EMG = electromyography,

sign.= statistically significant

Most Gulf War studies in this area, however, have evaluated sensory and neuromuscular parameters

specifically in symptomatic Gulf War veterans. Results of these studies are more relevant to Gulf War

illness, and are summarized in Table 7. As shown, multiple studies used a variety of testing methods to

objectively measure sensory and motor nerve function and muscle strength in symptomatic Gulf War

veterans. Several studies focused specifically on Gulf War veterans who had pronounced symptoms of

muscle weakness, numbness, and pain.

Despite the prominence of symptoms of this type in Gulf War veterans, very few studies have identified

any objective indications of peripheral neuropathy or abnormal muscle function in symptomatic veterans.

Standard neurological examinations revealed very few abnormalities and no significant differences

between symptomatic and healthy veterans. This parallels the sparsity of neurological findings identified,

overall, in Gulf War studies that have included physical examinations.464,788,878,893 In addition,

electrodiagnostic testing using electromyography (EMG) and nerve conduction tests identified few

abnormalities or significant differences related to Gulf War illness.

Four studies identified measurable, but limited, peripheral nerve findings in symptomatic Gulf War

veterans.160,563,704,1186 Three indicated that symptomatic veterans have significantly higher (less sensitive)

sensory thresholds than well veterans. These included two early studies—one from the U.K. and one

from the University of Texas Southwestern—which reported that symptomatic Gulf War veterans had

elevated cold sensory thresholds.563,704 A third study from the East Orange, New Jersey, VA reported that

symptomatic veterans had elevated thresholds for detecting light touch.1186 The New Jersey study also

found that higher tactile thresholds in both symptomatic and healthy Gulf War veterans were strongly

associated with use of pyridostigmine bromide during the war.

Findings of small sensory fiber abnormalities in Gulf War veterans can only be considered preliminary,

however. The two studies that reported cold threshold abnormalities relied on very small,

nonrepresentative samples—14 symptomatic British veterans from a veterans’ organization704 and five

symptomatic U.S. Navy Seabees from a single reserve unit.563 The New Jersey study that identified

elevated tactile thresholds utilized a larger and more diverse sample of symptomatic Gulf War
248  Biological and Clinical Characteristics of Gulf War Illness

Table 7. Studies Assessing Sensory and Neuromuscular Function

in Symptomatic Gulf War Veterans

Study Groups Studied Parameter(s) evaluated Key Findings

Jamal704

1996

14 symptomatic GWV, 13

civilian controls

Heat, cold, and vibratory sensory

testing; motor and sensory nerve

conduction, needle EMG

Symptomatic GWV had sign. higher cold threshold, greater

sural nerve latency, and reduced median nerve sensory

action potential compared to controls. No case/control

differences on other measures.

Amato46

1997

20 GWV referred for

neuromuscular evaluation

with severe muscle

weakness or pain (no

controls)

Serum CK, muscle strength

tests, nerve conduction studies,

repetitive nerve stimulation,

quantitative and single-fiber

EMG, muscle biopsies

All GWV had normal muscle strength and tone, no evidence

of polyneuropathy. 6 GWV had mildly elevated CK, 2 had

abnormal nerve conduction. EMGs were normal except for 1

GWV with single-fiber jitter. 5 GWV had nonspecific

abnormalities on muscle biopsy.

Haley563

1997

23 male GWV with Haley

syndromes, 10 GWV

controls, 10 nonveteran

controls

Somatosensory evoked

potentials in all subjects. In 5

cases: nerve conduction studies,

quantitative and single fiber

EMG, sensory testing (heat,

cold, vibration)

Syndrome 2 cases had prolonged mean LP-P37 latency,

syndrome 3 cases had prolonged PF-LP latency. No

case/control differences in evoked potential abnormalities. All

5 cases tested had cold threshold abnormalities, 3 had

abnormal vibratory threshold. Normal nerve conduction,

EMGs.

Peckerman1186

1999

29 male GWV with CFS,

31 GWV controls

Tactile, thermal, and vibratory

sensory testing

Symptomatic GWV had sign. higher tactile thresholds than

controls. No case/control differences in thermal and vibratory

tests. In all GWV, elevated tactile thresholds were sign.

associated with using PB and burning human waste in

theater.

Bourdette160

2001

244 GWV with GWUI, 107

GWV controls

Handgrip strength in fatigued

cases, nerve conduction studies

and EMG in 13 veterans with

neurological exam abnormalities

Sign. more GWUI cases had reflex abnormalities. Cases with

unexplained fatigue had sign. less handgrip strength than

controls.15 of 23 GWUI cases with peripheral neurological

symptoms had abnormal findings on neuro exam (distal

sensory impairment, abnormal reflexes). None had nerve

conduction abnormalities,1 of 13 had EMG abnormality.

RiveraZayas1293

2001

12 GWV with 2 or more

symptoms of peripheral

neuropathy (no controls)

Reflex and manual muscle tests,

motor and sensory nerve

conduction studies, needle EMG

No reflex or muscle abnormalities on physical exam. 2 GWV

had nerve conduction abnormalities consistent with carpal

tunnel syndrome, all other test results normal.

Sharief1397

2002

49 male GWV with > 4

neuromuscular symptoms,

26 male GWV controls (< 2

neuromuscular symptoms)

Neurological exams, motor and

sensory nerve conduction

studies, thermal and vibratory

sensory tests, needle and

concentric single fiber EMG

No abnormalities on reflex or manual muscle testing. No

differences between ill GWV and controls on sensory or motor

nerve conduction or on sensory thresholds. All EMG results

within normal range, no differences between ill and well GWV.

Rose1311

2004

49 male GWV with > 4

neuromuscular symptoms,

26 male GWV controls (< 2

neuromuscular symptoms)

Myometric measures of muscle

strength and static and dynamic

fatigue in 8 muscle groups,

handgrip fatigue, muscle

biopsies, glycolytic activity

No sign. differences in quantitative measures of muscle

strength and fatigue. Measured muscle fatigue levels

generally were not correlated with veteran-perceived fatigue.

No case/control differences in muscle biopsies, fiber type

ratios, or muscle atrophy. Symptomatic GWV required sign.

more effort on exercise test, and had sign. higher plasma

lactate levels.

Blanchard142

2006

327 GWV with CMI, 708

GWV controls

Neurological exam, sensory and

nerve conduction studies

No association between CMI and peripheral neuropathy in

GWV or era veterans.

Abbreviations: GWV = Gulf War veterans, CMI = chronic multisymptom illness,

464 CFS = chronic fatigue syndrome, GWUI = Gulf War

unexplained illness (defined by study), EMG = electromyography, CK = creatine kinase, LP = lumbar potential, P37 = cerebral cortical potential,

PF = popliteal fossa potential, PB = pyridostigmine bromide, sign. = statistically significant
Neuroendocrine Findings  249

veterans.1186 Just one other study tested temperature thresholds—the King’s College study of British

veterans—and found no significant differences in symptomatic Gulf War veterans.1397

Studies of symptomatic Gulf War veterans have also identified very few abnormalities related to muscle

function, and none indicative of diagnosable muscle pathology. The most comprehensive muscle

function study found that symptomatic British Gulf War veterans required significantly more effort to

perform a subanaerobic exercise test than healthy veterans, and produced significantly higher plasma

lactate levels with exercise.1311 Investigators suggested that this indicated mitochondrial inefficiency in

symptomatic Gulf War veterans. Lactate levels were not as high as those associated with traditional

mitochondrial disease, however, and few mitochondrial and muscle fiber abnormalities were identified in

muscle biopsies.

Overall, the majority of research studies that have assessed peripheral sensory and neuromuscular

function in Gulf War veterans have not identified objective indicators of pathology. Standard clinical

examination, EMG, and nerve conduction tests consistently provide no indication that symptomatic

veterans are affected by generalized polyneuropathies or abnormal neuromuscular transmission. It is

important to note, however, that the one type of abnormality identified in several studies related to altered

sensory thresholds. These findings suggest that some symptomatic Gulf War veterans may have subtle

small sensory fiber neuropathies, abnormalities that would not be detected by methods (nerve conduction

studies, EMGs, neurological examinations) used in most of the studies listed in Tables 6 and 7. It is

possible that such abnormalities are more prominent in more highly symptomatic veterans, like the cases

evaluated in the Texas and New Jersey studies, or among veterans with specific exposures in theater, as

suggested by the New Jersey study.1186

Even if these more subtle sensory findings are confirmed by larger studies, consistent findings that Gulf

War veterans are not affected by generalized polyneuropathies or abnormal neuromuscular transmission

suggest that veterans’ neuromuscular symptoms are not attributable to overt muscle damage or peripheral

nerve pathology. Alternate explanations include the possible contribution of lower-level mitochondrial

insufficiency, suggested by one study, and alterations in central nervous system processing of peripheral

sensorimotor input.

Neuroendocrine Alterations in Gulf War Veterans

Elevated rates of diagnosable endocrine disorders such as diabetes and thyroid disease have not been

associated with Gulf War service.46,142,393,464,751,1476 Endocrine measures not routinely evaluated in

standard medical workups have only minimally been assessed, however. As previously described,

evaluations of the cohort of Gulf War veterans with high-level exposure to depleted uranium identified

first elevated, then reduced serum levels of prolactin in this group.992,997 One MR spectroscopy study of

symptomatic Gulf War veterans also reported a significant correlation between reduced neuronal function

in the left basal ganglia and elevated central dopamine activity.562

Function of the hypothalamic-pituitary adrenal (HPA) axis is known to be altered in several conditions

that have affected Gulf War veterans since the war, including posttraumatic stress disorder (PTSD) and

chronic fatigue syndrome (CFS).333 In other populations, PTSD is associated with reduced baseline levels

of serum cortisol, elevated levels of corticotrophin releasing factor (CRF), increased levels of

glucocorticoid receptors and an enhanced cortisol and ACTH suppression response to low-dose

dexamethasone (DEX) challenge.1822-1824 One small study assessed eight active duty Gulf War veterans

within 18 months of their return from theater. Findings indicated that, as expected, posttraumatic

symptoms were correlated with lower salivary cortisol levels. All Gulf War veterans who took the DEX,

however, had a dramatically enhanced cortisol suppression response, independent of the effects of combat

or posttraumatic symptoms.785,786
250  Biological and Clinical Characteristics of Gulf War Illness

In several recently-reported studies, investigators at the Bronx VA assessed HPA parameters in Gulf War

veterans in more detail. Gulf War veterans with and without PTSD were compared to nondeployed

controls. No differences in baseline levels of cortisol, ACTH, or glucocorticoid receptors were identified

between the three groups. However, Gulf War veterans responded to low dose DEX with significantly

greater suppression of both ACTH501 and cortisol502 than nondeployed veterans. Identified differences

were associated with Gulf War deployment, overall, but were unrelated to combat exposure or whether

veterans had PTSD. In Gulf War veterans, the degree of ACTH suppression was significantly related,

instead, to veterans’ symptoms, most prominently musculoskeletal symptoms. Cortisol suppression was

also significantly related to musculoskeletal symptoms in Gulf War veterans and significantly more

pronounced in veterans who reported using pyridostigmine bromide in theater.

502

Twenty-four hour ACTH levels were also found to be significantly reduced among Gulf War veterans

who did not have PTSD.503 Lowered ACTH values were associated with veterans’ reported use of

pesticides and pyridostigmine bromide during deployment, especially in veterans who had experienced

acute symptoms at the time of exposure. The ratio of cortisol to ACTH was also significantly elevated in

Gulf War veterans, and significantly associated with veterans’ cognitive and mood symptoms. None of

the 24-hour HPA measures were associated with combat stress, with other self-reported exposures during

deployment, or with PTSD.

This group of studies provides a first detailed look at HPA function in Gulf War veterans. Results

indicate that Gulf War service, and symptoms in Gulf War veterans, are associated with significant

alterations in HPA function, many years after the war. Identified changes are independent of combat

stress, but significantly correlated with veterans’ use of pesticides and/or pyridostigmine bromide during

deployment. It is important to note that identified HPA abnormalities in Gulf War veterans constitute a

unique profile, which is biologically distinct from the HPA profile associated with PTSD.500 Additional

research on HPA function in symptomatic Gulf War veterans is needed, however, and the Committee

looks forward to reviewing findings from ongoing research at the Bronx VAMC, as well as related

research at the St. Louis and East Orange, New Jersey VAMCs.

Vulnerability to Neurotoxicants: Variation in Genotype and Activity of Protective

Enzymes

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.

There is more than one possible reason for this. Genetic and other differences between individuals can

dictate different reactions to a given exposure. Additionally, different individuals encountered varying

doses and combinations of exposures in theater, over different durations. Identifying specific factors

responsible for these differences would provide important insights into the biological nature of Gulf War

illness, as well as its causes. It could also help prevent similar problems in future deployments.

A large body of research, from different sectors, has demonstrated that some individuals are more

vulnerable to adverse effects of certain chemicals than others.469,884,928,983,1533 Such differences relate to

variability in biological processes associated with binding, metabolizing, and clearing these chemicals

from the body. The enzyme paraoxonase (PON1), for example, circulates in the blood and hydrolyzes

organophosphate compounds, converting them to relatively harmless chemicals that are excreted from the

body. There is more than one form of this enzyme, and inherited variations determine what form and how

much the body produces. Individuals who produce different types and amounts of PON1 differ,

sometimes dramatically, in their ability to neutralize organophosphate compounds.281,317,877

Other enzyme systems are also involved in neutralizing neurotoxic chemicals, including some that are not

as well characterized as PON1.468,602,1130,1440 In several studies, both Gulf War illness and service in the
Vulnerability to Neurotoxicants  251

Gulf War theater have been linked to variation in PON1 measures. Preliminary information is also

available concerning a possible link between Gulf War illness and another enzyme, butyrylcholinesterase,

which also plays an important role in protecting the body from some types of chemical exposures

associated with the Gulf War.

Paraoxonase (PON1) variability and Gulf War illness. Differences in PON1 genotype,

concentration, and activity levels all contribute to individual variability in the degree to which

organophosphate chemicals are neutralized by the body. PON1 genetic variants produce different

isozyme forms that hydrolyze specific organophosphate chemicals at different rates. The isoform

containing the amino acid glutamine (Q) at gene locus 192 hydrolyzes diazinon, sarin, and soman at a

high rate, but paraoxon more slowly. The isoform with arginine (R) at position 192 hydrolyzes paraoxon

at a high rate, and hydrolyzes chlorpyrifos more efficiently than the Q form.262,317,468 Other PON1

polymorphisms, including the L/M (leucine/methionine) substitution at position 55, are also associated

with variations that affect organophosphate detoxification.176,281,1150 PON1 enzyme activity can also vary

substantially among people with the same genotype, and has been shown to be affected by factors such as

diet, medical conditions, smoking, medications, and some environmental chemicals.

282,325,1457

In laboratory studies, information on PON1 activity is only meaningful in the context of the specific

substrate in which enzyme activity is measured. Similarly, in chemically-exposed human populations,

whether a given PON1 genotype provides better protection or increased vulnerability depends on the

chemical exposure in question.

Recent studies have identified significant links between PON1 variability and conditions that are relevant

to Gulf War illness. As previously described, a chronic symptomatic illness similar to Gulf War illness

affects some British sheep farmers who regularly use a chemical sheep dip containing organophosphate

pesticides. A large study has reported that sheep farmers with this illness were significantly more likely

to have at least one R allele at PON1 site 192 than healthy farmers, who were more commonly QQ

homozygotes. Compared to healthy sheep farmers, symptomatic farmers exhibited poorer PON1

hydrolysis of diazinon, an organophosphate chemical used in sheep dip.242,1223

Studies of both Polish and North American populations have linked PON genetic polymorphisms to nonfamilial amyotrophic lateral sclerosis (ALS). In the Polish study, significantly more ALS patients than

controls had the R allele at PON1 position 192, and a second polymorphism in the PON2 gene, which

codes for a similar enzyme widely distributed in the body.1426 The North American study identified PON

gene cluster variants that significantly distinguished sporadic ALS cases from healthy controls and

identified both protective and detrimental ALS haplotypes.1338 Additional research, from multiple

studies, links Parkinson’s disease to increased frequency of the L allele at PON1 position 55.1840 Multiple

chemical sensitivity has also been associated with higher rates of PON1 heterozygosity at positions 55

and 192.1005 For all these conditions, investigators concluded that the disease-PON1 connection indicates

that interaction between an environmental exposure and genetic vulnerability leads to increased risk for

developing the disease.

Results from published studies that have evaluated PON1 measures in Gulf War veterans are summarized

in Table 8. These studies addressed different questions in different ways, in case and control populations

that differed markedly from one another. Additional information on the PON1-Gulf War illness

relationship is available from two federally-funded projects whose results have not been published.

Findings were presented to the Committee for discussion at public meetings and/or are available in

agency research reports. Results from these projects can only be considered preliminary pending peer

review and publication, but provide additional insights and context for the published research findings.
252  Biological and Clinical Characteristics of Gulf War Illness

Five of the six Gulf War projects identified significant PON1 differences related to Gulf War illness or,

more generally, with Gulf War service. Specific findings from these studies have varied, however,

reflecting different types of data obtained to address different questions. As a result, existing studies do

not provide a complete understanding of the Gulf War illness-PON1 relationship. The Committee

examined the study questions, measures, and outcomes evaluated by each study to identify commonalities

and differences, and to determine what issues remain.

The earliest study, from the University of Texas Southwestern (UTSW) evaluated PON1 measures in 25

ill veterans from a single Navy reserve unit, compared to 20 veteran controls. Investigators reported

differences between cases and controls associated both with PON1 genotype and enzyme activity.561

Overall, PON1 activity using phenyl acetate as a substrate (also referred to as arylesterase activity) was

lower in cases than controls—significantly lower for the type Q isozyme, which provides the most

efficient hydrolysis of sarin. A follow up study, in fact, indicated that serum hydrolysis of sarin was

highly correlated with PON1 type Q isozyme activity in the veterans studied, reflecting a reduced

capacity for neutralizing sarin in this group.853 In contrast, PON1 activity using paraoxon as a substrate

was nonsignificantly higher in cases than controls. Significantly more cases than controls had the R allele

at position 192, the polymorphism that provides less efficient hydrolysis of sarin. The study found no

genetic differences at locus 55 and did not evaluate differences between deployed and nondeployed

veterans.

In a second, larger study, investigators from the University of Manchester reported that 152 British Gulf

War veterans who self-identified as having Gulf War illness had significantly reduced PON1 enzyme

activity, compared to controls, using paraoxon as a substrate. PON1 activity appeared to be unrelated to

disease severity; it was reduced in veterans with both low- and high-level symptomatology. No genetic

differences between groups were identified, either at position 152 or position 55, and enzyme activity was

not measured using phenyl acetate as a substrate.947 Investigators suggested their results indicated that

veterans with reduced PON1 enzyme activity, due either to environmental or unidentified genetic factors,

had developed Gulf War illness at higher rates. The control group in this study had not served in the Gulf

War, however, so it was not possible to determine whether PON1 activity differences related to Gulf War

illness specifically or, more generally, to Gulf War deployment.

A second British study compared PON1 measures in a subgroup of the most disabled Gulf War veterans

from a large population sample (“ill” Gulf War veterans) to those in three other groups: (1) other Gulf

War veterans in the sample (“well” Gulf War veterans), (2) “ill” nondeployed Gulf War-era veterans, and

(3) “ill” Bosnia veterans.645 PON1 genotype at position 192 did not differ between ill and well Gulf War

veterans, but significantly fewer ill Gulf War veterans were LM heterozygotes at position 55. Ill and well

Gulf War veterans had similar mean PON1 activity using paraoxon as a substrate. As a group, however,

Gulf War veterans had significantly lower PON1 activity than ill nondeployed and Bosnia veterans.

Investigators commented that service in the Gulf War theater, or specific exposures during deployment,

appeared to produce reduced PON1 activity that persisted many years after veterans returned from

theater. As in the earlier British study, it is difficult to disentangle “illness” effects in this study, since

the “well” Gulf War control group reported symptom levels similar to those of the “ill” Bosnia and

nondeployed Gulf War-era groups, and no “well” Bosnia or era veterans were evaluated.

The only report that identified no PON1 differences in relation to Gulf War service was a collaborative

project from the University of Iowa, the West Haven VA, and Hebrew University of Jerusalem.266 The

study analyzed enzyme activity in blood samples retained from an earlier clinical study that addressed

other, unrelated questions. Results indicated that PON1 activity did not differ between veterans who met

case criteria for chronic multisymptom illness (CMI)464 and controls. Key information was not provided,
Vulnerability to Neurotoxicants  253

Table 8. Evaluation of PON1 Genotype and Enzyme Activity in Gulf War Veterans

Study Group Studied Parameter/Assay Key Findings

Haley561

1999

25 Navy Seabees with

Haley Syndromes, 10

well GWV controls, 10

nondeployed era controls

PON1 genotype (positions

192 and 55). Enzyme

activity in paraoxon, phenyl

acetate (arylesterase),

calculated Q,R–specific

arylesterase activity

GWV with Haley syndromes sign. more likely to have PON1 R

allele than controls. No sign. differences in L,M alleles. Mean

PON1 activity nonsign. higher in cases, mean arylesterase activity

nonsign lower in cases; type Q arylesterase activity sign. lower in

cases; low Q arylesterase activity also sign. associated with

having more severe side effects from PB during deployment.

Mackness947

2000

152 GWV with selfreported GWI, 152

nonveteran controls

PON1 genotype (positions

192 and 55), serum PON1

concentration, enzyme

activity in paraoxon and

diazoxon

GWV with GWI had sign. lower PON1 concentration and activity

in paraoxon than controls (activity < 50% of controls), overall and

within genotype. No differences in Q,R gene frequencies or L,M

frequencies in cases vs. controls. No differences in PON1 activity

in diazoxon.

Hotopf645

2003

115 “ill” GWV, 95 “well”

GWV controls, 137 ill

nondeployed GW era

and Bosnia veterans

PON1 genotype (positions

192 and 55), enzyme

activity in paraoxon

Sign. lower proportion of ill than well GWV had LM genotype

(position 55). Overall, Gulf–deployed had sign. lower PON1

activity than non-PGW veterans. No sign. PON1 activity

difference between ill and well GWV.

Concato266

2007

140 male GWV with CMI,

125 male GWV controls,

80 nondeployed era

veterans (29 with CMI)

PON1 activity (substrate not

specified)

No sign. difference in adjusted mean difference of PON1 activity

between cases and controls, or in deployed vs. nondeployed

veterans.

Abbreviations: PON1 = paraoxonase, GWV = Gulf War veteran, GWI = Gulf War illness, CMI = chronic multisymptom illness,464 PB =

pyridostigmine bromide, sign. = statistically significant

however, concerning substrate and assay methods, test results, and health characteristics of the sample. It

was therefore not possible to clearly interpret these results or compare them with other studies. It is not

known, for example, how many study subjects were healthy Gulf War controls or healthy nondeployed

veterans, since subjects identified as both CMI “cases” and “controls” also had conditions evaluated in the

original clinical study—depression, cognitive dysfunction, and fibromyalgia.

The two additional federal projects that have evaluated PON1 measures in Gulf War veterans provide

information relevant to results of published articles. Investigators from the East Orange, New Jersey VA,

reported to the Committee preliminary results of analyses of PON1 activity in blood samples collected for

the large VA Gulf War clinical study of over 1,000 deployed Gulf War and 1,000 nondeployed era

veterans. Results indicated that Gulf War veterans with chronic multisymptom illness (CMI)464 had

elevated PON1 activity using paraoxon as a substrate, with the increase most pronounced in veterans who

also had PTSD.

1160,1161

Preliminary results from the Midwest Research Institute project, described previously in relation to

autonomic testing, also indicated that PON1 activity using paraoxon as a substrate was significantly

higher in 40 Gulf War illness cases than in 18 healthy Gulf War controls.1353 The 18 Gulf War controls,

however, had lower PON1 activity (p=0.09) than the 15 healthy nondeployed controls evaluated for the

study. Both associations were masked when the two control groups were combined, giving the

appearance that PON1 activity did not differ between cases and controls. These preliminary findings

suggest the possibility that PON1 activity differences may be associated both with Gulf War illness and,

more generally, with Gulf War service, but in opposite directions. Such differences can be obscured

unless appropriate subgroups are evaluated.
254  Biological and Clinical Characteristics of Gulf War Illness

Overall, differences between studies related not only to which PON1 measures were assessed, but also to

how “symptomatic” and “healthy” veterans were identified, if comparisons were made to healthy

controls, and whether controls had also served in the Gulf War. Several commonalities exist between

study findings, but the importance of specific differences are difficult to interpret without more

comprehensive evaluation of larger samples of well characterized Gulf War illness cases, healthy Gulf

War controls, and healthy nondeployed controls.

Four of the six existing Gulf War PON1 projects identified altered PON1 enzyme activity in symptomatic

veterans compared to controls, three using paraoxon as the substrate.561,947,1161,1353 The remaining study,

from UTSW, identified reduced arylesterase activity of PON1 type Q isozyme, a measure not assessed by

other studies. It is not clear whether different results from individual studies relate to chance findings, or

to actual differences that reflect PON1 factors associated with subgroups of Gulf War veterans with

different illness or exposure histories, as suggested by the New Jersey and UTSW studies. It may also be

important that only projects that compared ill Gulf War veterans to healthy Gulf War veterans found ill

veterans to have elevated PON1 activity using paraoxon as the substrate.

561,1161,1353 All studies that

identified reduced PON1 hydrolysis of paraoxon in Gulf War veterans compared them to individuals who

had not served in the Gulf War.645,947,1353

A key issue not addressed by Gulf War PON1 studies relates to the important fact that the effects of

variability in PON1 hydrolyzing activity are substrate specific. While one PON1 genotype might render

an individual more vulnerable to specific types of pesticides, another would be more problematic if an

individual had been exposed to nerve agents. As a result, differences in health effects that might have

occurred in relation to different PON1 genotypes during the Gulf War would only be apparent among

subgroups of individuals with specific chemical exposures. No adverse effects or PON1-related

differences would be apparent in individuals who were not exposed to chemicals affected by their

genotype. Therefore, PON1 studies that do not assess Gulf War illness case status as a function of both

PON1 parameters and exposure history could easily mask differences related to PON1 subgroups of

importance. Unfortunately, Gulf War studies have not yet evaluated case/control outcomes in relation to

both exposures and PON1 measures.

If considered in the context of differences in methods, research questions, and study populations, results

from Gulf War PON1 studies are not so much contradictory as they are parallel findings that remain to be

reconciled. There is a general type of consistency from these studies indicating that variations in PON1

activity are linked to Gulf War service. But important questions have only been partially addressed.

More comprehensive research and analyses are needed to provide the answers needed to better

characterize the relationship of PON1 variability with Gulf War illness and/or Gulf War service.

Observed PON1 variability in relation to Gulf War service provides additional support for other types of

evidence that implicate neurotoxic exposures in the etiology of Gulf War illness. Major research issues

that remain to be addressed in relation to PON1 and the health of Gulf War veterans include: (1) whether

Gulf War service, in general, produced alterations in PON1 activity in Gulf War military personnel, and if

specific exposures in theater can account for those changes, (2) whether persistent alterations in PON1

activity put Gulf War veterans at increased risk for adverse effects of chemical exposures encountered

after their return from theater, and (3) further characterization of specific PON1 parameters and

PON1/exposure interactions associated with Gulf War illness. The Committee looks forward to

reviewing final results from the preliminary findings described, as well as results from recently-funded

Gulf War PON1 studies undertaken by UTSW and the Naval Health Research Center.1205

Butyrylcholinesterase (BChE) and Gulf War illness. As previously described, the best

understood mechanism through which organophosphate and carbamate compounds exert their toxic

effects involves inhibition of the enzyme acetylcholinesterase (AChE). Another enzyme,

butyrylcholinesterase (BChE), circulates in the blood and brain and binds irreversibly to AChE-inhibiting
Vulnerability to Neurotoxicants  255

chemicals, acting as a “scavenger” that protects AChE from inhibition by these compounds. Because of

its efficiency in binding AChE-inhibitors, BChE is now being evaluated as a protective pretreatment

against nerve agents on the battlefield.1357,1389 Recent animal studies have shown that circulating BChE

spares AChE inhibition both in peripheral blood and in the brain following sarin inhalation1389 and may

directly control excess levels of brain acetylcholine when AChE levels are reduced.380,590

A number of BChE genetic variants have been identified, with different affinities for AChE-inhibiting

chemicals. Individuals with certain BChE genotypes, for example, have long been known to be at risk for

adverse effects from the use of succinylcholine as a muscle relaxant in surgery.926 Individuals with

slower-acting BChE are thought to be at potentially greater risk for adverse effects from AChE-inhibiting

pesticides and nerve agents.928

Three published studies have evaluated BChE measures in Gulf War veterans. The UTSW enzyme study

assessed BChE phenotype and enzyme activity in 25 Gulf War veterans with the three Haley syndromes,

compared to 20 veteran controls.561 Mean BChE activity levels did not differ between cases and controls,

although Gulf War illness cases were almost three times as likely to have BChE activity levels in the

lowest activity quartile, and veterans with the AU phenotype had a nearly four-fold increased risk for

having Haley Syndrome 2. Neither association was statistically significant in this relatively small group,

however. The larger British study found that Gulf War veterans who self-identified as having Gulf War

illness had significantly higher BChE enzyme activity than nonveteran controls.947 And the Iowa/West

Haven/Hebrew University collaborative study reported that mean BChE activity did not differ between

Gulf War multisymptom illness cases and controls, although it is not clear what specific measures and

comparisons were made.266

Additional information on BChE-Gulf War illness associations is provided by reports from two additional

federally-funded projects that are publicly available, but not yet published in research journals. A DOD

report on a study of 221 Gulf War veterans conducted by the University of Nebraska indicated that mean

BChE activity levels were similar in veterans who indicated they had Gulf War illness and controls. A

significant association was found between BChE genotype and Gulf War illness, however. All but one

(91%) of the 11 Gulf War veterans with the rare atypical (A) or fluoride (F) BChE alleles had Gulf War

illness symptoms. 927 Given the small number of A and F variants in this study, however, investigators

cautioned that this finding required further testing.

A second DOD-funded project, conducted by Midwest Research Institute, further evaluated the

association of BChE with Gulf War illness in 304 Gulf War veterans. Results were presented at a public

Committee meeting, and are also provided in a DOD project report.1352,1353 Mean BChE activity, again,

did not differ between Gulf War illness cases and controls. Neither were individual BChE genotypes or

specific alleles associated with Gulf War illness. As a group, veterans with the most common BChE

genotypes (U/U and U/K) were identified as “nonvariants,” and veterans with other, rarer, genotypes were

identified as BChE “variants.” As expected, the BChE variant group had significantly lower BChE

activity than nonvariants. Subgroup analyses revealed that associations between Gulf War illness and

several wartime exposures differed dramatically in BChE variants compared to nonvariants. Most

prominently, nonvariants who reported using pyridostigmine bromide (PB) were 2.7 times as likely to

have Gulf War illness as those who did not use PB. However, BChE genetic variants who used PB had a

40-fold increased risk of Gulf War illness, compared to variants who did not use PB. Although these

results can only be considered preliminary pending peer review, they suggest the importance of assessing

enzyme-exposure interactions in relation to Gulf War illness, as was previously described for PON1

research.

Overall, studies of BChE measures in relation to Gulf War illness have produced varied results. Like

PON1 studies, BChE projects are generally not directly comparable, owing to important differences in

study questions, populations, and methods. The most consistent finding, from four of the five Gulf War
256  Biological and Clinical Characteristics of Gulf War Illness

BChE projects, was that mean BChE activity does not differ between Gulf War illness cases and controls.

More complex associations were suggested by three of the projects, however. The Nebraska study

suggested a possible link between BChE genotype and Gulf War illness, limited to the subgroup of

veterans with relatively rare genetic BChE alleles. The UTSW and Midwest Research Institute studies

suggest that Gulf War illness may be associated with BChE in subgroups of Gulf War veterans with

particularly low BChE activity. The Midwest Research Institute study also suggests that this association

is only apparent in the context of exposures in theater. That is, BChE genotype is a risk factor for Gulf

War illness only among veterans who experienced specific war-related exposures, most prominently PB.

A similar gene-exposure-illness interaction was previously suggested by the reported case of an Israeli

soldier who suffered severe symptoms after taking PB during the Gulf War.929 This soldier was

determined to be a rare AA homozygote for BChE, with dramatically reduced ability to bind carbamate

compounds. Although generally healthy before the use of PB, the soldier had previously experienced

succinylcholine-induced difficulties following surgery.

Acetylcholinesterase (AChE) and Gulf War illness. A number of chemical exposures in the Gulf

War theater acutely reduce serum and brain levels of acetylcholinesterase (AChE), but only one study has

assessed AChE measures in relation to Gulf War illness. Research in other populations has shown that

individuals chronically exposed to low-level pesticides or stress express increased levels of the AChE

read-through variant, AChE-R.1024,1418,1448 Based on these reports and early indications of possible

treatment implications424,1446,1447 the Committee suggested that VA assess levels of AChE-R in veterans

with Gulf War illness. VA Office of Research and Development subsequently authorized a study to

determine whether AChE enzyme activity, more generally, was associated with anxiety and mood

disorders in Gulf War veterans previously evaluated in the Iowa clinical study. Investigators later

attempted to accommodate the Committee’s original suggestion by adding an evaluation of AChE-R in

relation to Gulf War illness to the study, but this was not accomplished because of insufficient serum.

Instead the study focused on AChE enzyme activity in relation to Gulf War deployment, as well as

anxiety disorders and multisymptom illness in Gulf War veterans.266

Study results indicated that Gulf War deployment, overall, was not associated with significant differences

in AChE activity. Mean value of AChE activity for veterans with chronic multisymptom illness (CMI)

was nonsignificantly higher than in veterans who did not have CMI. For all veterans combined (sick and

healthy), AChE activity was not significantly associated with any self-reported exposures during

deployment. Veterans who reported exposure to chemical warfare agents, however, had an adjusted mean

activity level that was 126 points lower than those not exposed, a difference that approached significance

(p=0.09).266 As previously described, results of this study are difficult to interpret. Both Gulf War illness

cases and controls had originally been recruited for a study of depression, fibromyalgia and cognitive

dysfunction, and study subjects, overall, had elevated rates of anxiety disorders. Further, the study did

not evaluate associations between AChE and Gulf War illness in veterans with different exposure

histories, particularly AChE-inhibiting chemicals. The Committee therefore concludes that the question of

whether AChE variability is associated with Gulf War illness has not been adequately addressed, and so

remains open.

Summary. Vulnerability to neurotoxicants: variation in genotype and activity of

protective enzymes. Explanations for why some Gulf War veterans developed Gulf War illness while

others remained well may relate to different exposure profiles between individuals in theater, and to

biological differences in veterans’ vulnerability to those exposures. The enzyme paraoxonase (PON1) has

an important role in neutralizing effects of organophosphate exposures, and PON1 genetic differences

have been implicated in the risk for developing conditions relevant to Gulf War service, including ALS.

Six projects have evaluated diverse PON1 measures in Gulf War veterans; five identified significant

differences in PON1 enzyme activity related to Gulf War illness and/or Gulf War deployment. Available

results, however, have provided a somewhat piecemeal look at the potentially complex relationships
Immune Parameters  257

between PON1 measures and the health of Gulf War veterans. More precise understanding of PON1

variability in relation to Gulf War illness requires more comprehensive comparisons of PON1 measures in

suitable Gulf War illness cases and healthy Gulf War and nondeployed controls. It also requires a

detailed evaluation of PON1-exposure interactions in relation to Gulf War illness and, more broadly, to

Gulf War deployment.

Gulf War illness may also be linked to biological variability related to other enzymes that protect from,

and are affected by, neurotoxic exposures. The question of whether acetylcholinesterase (AChE)

variability is associated with Gulf War illness remains open, due to limited research in this area. Three

Gulf War studies have provided preliminary indications of a possible link between BChE variability and

Gulf War illness. Several studies have reported that mean BChE enzyme activity is not related to Gulf

War illness, but provided preliminary indications that an identifiable link involves the subgroup of Gulf

War veterans with very low BChE activity. Precise understanding of BChE variability in relation to Gulf

War illness requires more thorough evaluation of interactions between BChE genetic factors, enzyme

activity, and specific exposures.

Overall, identified differences in PON1 measures, and preliminary indications related to BChE, suggest

that variability in circulating enzymes that confer protection from AChE-inhibiting chemicals rendered

some Gulf War veterans more susceptible to prolonged, adverse effects of neurotoxic exposures.

Although details of gene-enzyme-exposure interactions remain to be fully elucidated, current findings

provide support for consistent evidence from other sectors that implicates neurotoxic exposures as causal

factors in Gulf War illness.

Immune Parameters in Gulf War Veterans

The immune system, the body’s multifaceted defense system, involves the production and coordination of

diverse cells and messenger chemicals in multiple tissues and organs. This system provides the body’s

response to potential threats, on a continuing basis, and restores equilibrium in the wake of the defensive

response. Healthy immune function depends on multiple regulatory mechanisms that involve actions and

counteractions not only of immune cells, but of diverse neurological and endocrine processes.23,1485

Abnormalities in the intricate workings of the immune system, or its complex interactions with other

biological systems, can result in diverse types of pathology.

In 2001, the Research Working Group of the federal Military and Veterans Health Coordinating Board

reported on immune function in Gulf War veterans by indicating that studies had not identified excess

rates of serious infectious or autoimmune diseases in Gulf War veterans,1273 based largely on

hospitalization rates identified in military hospitals. Studies of this type do not provide satisfactory

insights into the question of immune abnormalities, however, since infectious diseases and autoimmune

diseases are not adequately tracked by hospitalization rates, and most ill Gulf War veterans were no

longer in service at the time of this assessment. In addition, the report did not consider other types of

immune alterations potentially associated with Gulf War illness.

Multiple studies have now assessed immune parameters in Gulf War veterans, as summarized in Tables 7

and 8. As shown, different immune parameters have been evaluated using varied methods in different

groups of veterans. In a general sense, results have been mixed, with some studies showing immune

alterations in symptomatic veterans, and others finding no abnormalities. But as with other areas of Gulf

War research, a simple tabulation of whether Gulf War immune studies have yielded positive or negative

results is not sufficiently informative. It is important to assess which types of immune parameters have

been found to differ in relation to veterans’ symptoms, and which have not.
258  Biological and Clinical Characteristics of Gulf War Illness

Table 7. Immune Evaluation of Gulf War Veterans, Not Differentiated by Veterans’ Health Status

Study Groups Evaluated Immune Findings

Bregenholt167

2001

686 Danish GWV, 231

nonveteran controls

No sign. differences in NK activity or levels of most cytokines, with possible

exception of CD2+ production of IL-2. Results unclear, due to effects of

freezing/thawing on samples.

Eisen393

2005

1061 GWV, 1128

nondeployed era veterans

No sign. differences in mean levels of total leukocytes, leukocyte counts,

ESR.

Abbreviations: GWV = Gulf War veterans, NK = natural killer cells, ESR = erythrocyte sedimentation rate, sign. = statistically significant

Two studies, including the large national VA clinical study, have broadly compared immune measures in

veterans who deployed to the Gulf War with those of a nondeployed reference group,

167,393 as shown in

Table 7. Results reported in these studies combine data from symptomatic and healthy Gulf War

veterans, so are of limited use in understanding possible immune aspects of Gulf War illness. In both

studies, no immune findings were associated with Gulf War service, when deployed veterans were

evaluated as a single group.

The Rook hypothesis: Th1-Th2 immunity in Gulf War veterans. In 1997, Drs. Graham Rook

and Alimuddin Zumla, of University College in London, hypothesized that the symptoms of Gulf War

illness could be the result of a systemic shift towards a Th-2 immune profile.1306 The human immune

response includes two functionally distinct classes of CD4, or T-helper (Th) cells. Th-1 cells are

associated with cell-mediated immunity and phagocyte-dependent inflammation, and production of the

cytokines IL-2 and IFN-γ. Th-2 cells are associated with humoral immunity and allergy, and production

of IL-4,5,6,9,and 13. 329,1305 The suggested association of Gulf War illness with a Th1-Th2 shift

constituted a plausible and testable hypothesis, often referred to as the Rook hypothesis. According to the

original hypothesis, this shift could have been precipitated by the many vaccines received by service

members, perhaps in conjunction with deployment-related stressors and exposures.1306

The Rook hypothesis received early support from two large epidemiologic studies of British Gulf War

veterans, which found that veterans who had received a greater number of vaccines had modestly elevated

rates of multisymptom illness, compared to veterans who received fewer vaccines.241,1698 Several studies

subsequently assessed the Rook hypothesis more directly, by evaluating levels of different classes of T

lymphocytes and cytokines in veterans with Gulf War illness.

In 1999, Dr. Quanwu Zhang and colleagues from the East Orange, NJ, VA reported that compared to

healthy veteran controls, Gulf War veterans with chronic fatigue syndrome had significantly more total

lymphocytes, and significantly higher levels of mRNA for IFN-γ, TNF-α, IL-2 and IL-10.1835 IL-10 was

once thought to be produced by Th-2 cells, but is now known to come from multiple cell types, and to

have a role in limiting excess inflammation.1065,1556 Results of this study indicated that Gulf War illness

was associated with immune alterations, but did not support a shift towards Th-2 immune reactivity.

Findings instead suggested a possible increase in Th-1-type immunity.

A 2002 study from investigators at the Birmingham VA evaluated in vitro levels of cytokines produced

by blood cells both at rest, and after PHA stimulation.422 Supernatant levels of IL-4, associated with Th2-

type activation, did not differ between sick and healthy veterans. Nor did levels of IL-6, IL-10, or TNF-α.

The study did not assess levels of IL-2, but IFN-γ levels produced by cells at rest were significantly lower

in symptomatic veterans, while stimulated levels of IFN-γ were nonsignificantly higher. Results

therefore did not support the notion of Th-2 immune activation, while insights regarding Th-1 activation

were limited.
Immune Parameters  259

Table 8. Studies Comparing Immune Measures in Symptomatic Gulf War Veterans and Controls

Study Groups Evaluated Immune Findings

Haley563

1997

23 GWV with Haley Syndromes,

10 GWV, 10 nondeployed controls

ESR, ANA, and IG levels similar in symptomatic GWV and controls.

Zhang1835

1999

Brimacombe172

2002

43 GWV with CFS, 34 GWV

controls

Peripheral blood lymphocytes of symptomatic GWV included sign. more total T

cells and MHC II+ T cells, higher % CD3 cells, lower % NK cells, sign. higher

levels of mRNA for IFN-γ, TNF-α, IL-2 and IL-10. In modeling, apparent

association of factor grouping of Th-2 cytokines with CFS was related to slowed

cognitive reaction time in ill veterans.

Asa69

2000

38 symptomatic GWV, 12 GWV

controls

36/38 (95%) of symptomatic veterans had IgG antibodies to squalene, compared

to 0/12 GWV controls.

Everson422,423

2000, 2002

52 symptomatic GWV, 31 healthy

GWV controls

No differences on in vitro measures of acquired immunity, including mean levels

of mitogen-stimulated T cell proliferation, mixed leukocyte reactivity, IG

production. Antibody response to anthrax vaccine was sign. greater in healthy

GWV. NK cell activity nonsign. lower in symptomatic GWV. Unstimulated IFN-γ

sign. lower in symptomatic GWV; stimulated IFN-γ nonsign. higher.

Skowera1421

2002

130 symptomatic British GWV, 90

healthy GWV controls

No difference in levels of ANAs generally, no evidence of ANAs against nuclear

envelope antigens in either symptomatic or healthy GWV.

Skowera1420

2004

40 symptomatic British GWV, 80

healthy GWV

Symptomatic veterans had sign. elevated levels of unstimulated IL-2+ cells, IFN-γ

cells. Sign. elevated IL-10 producing cells following polyclonal stimulation.

Vojdani1734

2004

100 symptomatic GWV, 50

healthy GWV, 50 healthy

nonveteran controls

Higher proportion of symptomatic GWV had elevated T cells, elevated B cells,

elevated CD4:CD8 ratio, decreased NK activity, reduced response to PHA and

PWM, increased immune complexes, increased antibodies to myelin basic protein

and muscle.

Allen39

2006

17 symptomatic GWV, 11 healthy

GWV controls with vaccine records

12-15 years after being vaccinated in the Gulf War, GWV exhibit immune

responses to anthrax and plague vaccines. Cytokine responses to vaccines were

similar in symptomatic and well GWV.

Hokama617

2007

8 GWV, 328 nonveteran CFS

patients, 52 controls

All 8 GWV, 91% of CFS patients, and 8% of controls had elevated antibody titers

for CTX, a neurotoxic lipid associated with ciguaterra poisoning.

Abbreviations: GWV = Gulf War veterans, ESR = erythrocyte sedimentation rate, ANA = antinuclear autoantibody, IG = immune globulin , NK

= natural killer cells, PHA = phytohemagglutin, PWM = pokeweed mitogen, CFS = chronic fatigue syndrome, sign. = statistically significant

Dr. Anna Skowera and colleagues at King’s College in London took a different approach by directly

assessing levels of different classes of Th cells in relation to Gulf War illness. They identified evidence

of persistent cellular immune activation in symptomatic veterans, finding significantly elevated levels of

IL-2 and IFN-γ-producing cells, in the absence of stimulation.1420 Short term in vitro polyclonal

stimulation resulted in significantly greater memory cell production of IL-10 in ill veterans, compared to

healthy controls. This study provides the most direct assessment of the posited Th1-Th2 shift, since cell

counts were specifically measured, rather than inferred from cytokine levels. Cytokine levels in serum or

supernatant may not accurately reflect levels of different CD4 cytokine-producing cells, since cultured

macrophages and NK cells can also produce IFN-γ, IL-4, and IL-10.1065 Investigators concluded that,

nine years after the Gulf War, symptomatic veterans showed evidence of an ongoing, low-grade Th-1-

type immune activation.

The King’s College team has also suggested that assessing global T cell cytokine production may not

reflect Gulf War-related changes, given the complex mix of vaccines, infections, and other antigens that

veterans have likely encountered since deployment. Taking an alternate approach, they looked
260  Biological and Clinical Characteristics of Gulf War Illness

specifically at T cell responses to vaccines, including two that provided novel exposures at the time of the

war: anthrax and plague vaccine antigens. Results indicated that 12-15 years after the Gulf War,

vaccinated veterans continued to have T cell memory responses to anthrax and plague antigens. Cytokine

responses to anthrax and tetanus-diptheria vaccines were balanced, with neither TH1 nor TH2 response

dominating, while plague and pertussis vaccine responses were Th-1 dominant. Importantly, there were

no vaccine response differences between symptomatic and well veterans.39

Although these studies provide support for an association between Gulf War illness and immune

alterations, a shift towards a Th-2 immune profile has not been supported. The posited link between Gulf

War illness and receipt of multiple vaccines has not been ruled out, however, in light of modest

associations identified in several epidemiologic studies.241,789,1698 Animal experiments have identified

CNS-related changes, but not peripheral immune effects, following receipt of multiple vaccines, or

vaccines combined with other Gulf War exposures.535,632,1486,1752,1789

It is of interest that, using entirely different methods and study populations, researchers from the New

Jersey VA and King’s College both identified evidence of elevated production of IL-2 and IFN-γ (Th-1-

related cytokines) and increased levels of the regulatory cytokine, IL-10, in symptomatic Gulf War

veterans.1420,1835 These studies provide independent support for an ongoing, low level cellular immune

activation in veterans with Gulf War illness.

General evaluation of immune competence in symptomatic veterans. As summarized in

Table 8, individual studies have assessed a variety of immune parameters in relation to Gulf War illness.

The focus of the Birmingham VA immune study was to assess the functional integrity of the acquired

immune response in symptomatic veterans, using multiple in vitro measures.422 Immune challenges to

blood cells of symptomatic and healthy veterans revealed no differences in reactions of antigen presenting

cells, primary and secondary responses to a variety of antigens, or T cell-dependent B cell response to

pokeweed mitogen. Investigators concluded that their results provided no indication that symptomatic

veterans were immunodeficient, that is, that veterans with Gulf War illness had impaired ability to

respond to infection. This is compatible with results from population studies, which have provided little

indication that veterans with Gulf War illness have excess rates of commonly diagnosed infectious

diseases.393,464,1698

In contrast, a number of immune alterations were identified by a study that compared clinical blood

testing results in symptomatic Gulf War veterans, nondeployed veterans, and community controls. Dr.

Aristo Vojdani and colleagues at Immunosciences Lab1734 reported that Gulf War illness was significantly

associated with values either above or below the normal reference range for percentages of CD3 T cells

(30% of ill veterans above normal, 9% below) and CD19 B cells (49% above normal, 4% below), as well

as the CD4:CD8 ratio (33% above normal, 4% below). Significantly more ill veterans also had belownormal responses to mitogens, and exhibited depressed NK cell activity. For several tests, these

differences were not apparent when average values of the patient and control groups were compared.

Differences related, instead, to the distribution of results, with an excess number of symptomatic veterans

having abnormally high or abnormally low test results. Investigators concluded that significant subsets of

veterans with Gulf War illness exhibit immune alterations.

Although different studies have assessed different immune cell parameters in differently-defined groups

of ill veterans, several commonalities can be identified. Symptomatic veterans were reported to have

elevated percentages of CD3 cells in both the New Jersey VA study and the Immunosciences study.

Mitogen responses appeared similar in cases and controls in both the Birmingham and Immunosciences

studies, when group means were compared. However, the Immunosciences study identified a significant

subgroup of veterans with below-normal mitogen responsivity, a difference that was obscured when only

group means were considered.
Immune Parameters  261

NK cell function. As shown in Table 8, three studies have evaluated NK cell number or function in

relation to Gulf War illness. The New Jersey VA study reported a significantly lower mean percent of

NK cells in symptomatic veterans than controls,1835while the Immunosciences study reported

significantly reduced NK cell activity in symptomatic veterans.1734 The Birmingham study, in

preliminary results, reported that NK cell activity was lower in symptomatic than healthy veterans, but

this difference was not statistically significant.423 Dr. Nancy Klimas at the Miami VA also reported to the

Committee that preliminary results from her ongoing immune study indicated that veterans with Gulf War

illness have significantly reduced NK cell numbers and activity levels.813

Abnormal antibody production and autoimmunity in relation to Gulf War illness. Some

observers have suggested that the symptoms of Gulf War illness may result from persistent production of

antibodies or autoantibodies generated in response to wartime exposures.69,1077 There is limited research

information on the question of autoimmunity in Gulf War veterans, however. Hospitalization studies

have not identified excess rates of diagnosed autoimmune diseases in Gulf War veterans.1432 Reliable

prevalence information cannot be provided by hospitalization studies, however, but require more

comprehensive population-based research. Results provided by clinical assessments of symptomatic Gulf

War veterans have provided little support for an association between Gulf War illness and nonspecific

indicators of autoimmunity, such as erythrocyte sedimentation rates (ESR) and antinuclear autoantibodies

(ANA).160,464,563

As previously described, Dr. Pamela Asa and colleagues at Tulane University reported that 36 of 38

symptomatic Gulf War veterans tested positive for IgG antibodies to squalene, compared to none of 12

healthy Gulf War veterans tested.69 A minority of symptomatic veterans in this study also had test

abnormalities suggestive of autoimmunity, and several met criteria for Sjogren’s syndrome and systemic

lupus erythematosus. Although the use of a squalene-containing adjuvant in anthrax vaccine has not been

supported by analyses of vaccine lots used during the Gulf War, a possible link between Gulf War illness

and squalene antibodies has not been directly assessed by other investigators. No conclusions concerning

the prevalence of autoimmunity or other immune abnormalities in Gulf War veterans can be drawn from

the Asa/Tulane study, in light of the relatively small, nonrepresentative sample evaluated.

Three additional studies have evaluated indicators of autoimmunity in relation to Gulf War illness.

Symptomatic Gulf War veterans were reported to have ANA and ESR values similar to those of healthy

controls in the King’s College study of U.K. veterans,1421 in Navy Seabees,563 and in the Immunosciences

evaluation of clinical samples.1734 The Immunosciences study, however, reported that symptomatic

veterans were significantly more likely to have antibodies to striated and smooth muscle, and to myelin

basic protein (MBP).1734 Elevated levels of MBP antibodies may have relevance to concerns raised by

veterans’ groups about a possible excess of multiple sclerosis among Gulf War veterans,1694,1721 but no

studies have investigated this issue. Additional studies are required to determine whether these

abnormalities are detectable in other groups of symptomatic Gulf War veterans.

Assessment of allergy in Gulf War veterans. Although sinus congestion and dermatitis are

commonly reported in surveys of Gulf War veterans,464,751,789,1476,1698 little information is available

concerning the prevalence of diagnosed allergies in this group. Ten percent of Kansas Gulf veterans

reported being diagnosed by a physician with allergies, similar to the rate reported by nondeployed era

veterans.1476 Diagnosed hay fever has also been reported at similar rates by Gulf War and nondeployed

veterans.464,789,1698

In the first reported study of immune function among ill Gulf War veterans, investigators from an allergy

and immunology clinic tested a sequential series of 20 symptomatic veterans evaluated in a Gulf War

referral center at the West Los Angeles VA.810 As a group, these symptomatic Gulf War veterans had

higher-than-average levels of IgE, and nearly two-thirds had positive allergy tests. No evidence of

immune deficiencies were identified in any of the symptomatic veterans. Although a high proportion of
262  Biological and Clinical Characteristics of Gulf War Illness

symptomatic Gulf War veterans were classified as atopic in this clinical series, it is not possible to draw

conclusions about the prevalence of allergies in symptomatic veterans overall, and no additional studies

of this issue have been reported.

Summary. Immune parameters in Gulf War veterans. Although questions have been raised for

many years about immune function in ill Gulf War veterans, limited research has been conducted in this

area. No population studies have provided comprehensive information on rates of infectious or

autoimmune diseases in Gulf War veterans. The largest clinical study of U.S. Gulf War veterans

provided no information on immune characteristics of veterans with Gulf War illness. Other clinical

studies have provided only limited information regarding indicators of autoimmunity and allergy in

relation to Gulf War illness.

A well-known hypothesis, suggesting that veterans’ multisymptom illness is related to a systemic shift

favoring Th-2-type immunity, has not been supported by studies comparing Th-1 and Th-2 measures in

symptomatic and healthy veterans. Clinical findings from several studies have provided no indication

that veterans with Gulf War illness are immune deficient, that is, that they have an impaired ability to

respond to infection. However, a number of immune parameters have been associated with Gulf War

illness. These generally occur as research findings that differ between groups of sick and healthy

veterans, as opposed to clinical test results that are diagnostic of familiar disease conditions in individual

veterans. Although parameters evaluated by different studies have been highly variable, some areas of

consistency 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. In addition, several studies have 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. It is also important to determine the extent

to which identified immune perturbations may be associated with altered neurological and endocrine

processes that are associated with immune regulation.

Additional Clinical and Research Findings Associated with Gulf War Illness

As described throughout this section, a variety of studies have identified biological measures that

distinguish veterans with Gulf War illness from healthy controls. The areas of research already described

have included multiple studies focused on different biological characteristics of symptomatic veterans.

Most positive findings were obtained using research protocols that compared groups of symptomatic Gulf

War veterans to healthy controls. Few of the identified Gulf War illness-related differences or

abnormalities—whether related to the central nervous system, autonomic function, neurotoxicantneutralizing enzymes, endocrine parameters, or immune perturbations—were identified with diagnostic

tests routinely used in clinical practice.

There is comparatively little information on other types of biological processes or objective measures in

relation to Gulf War illness. The limited information available comes primarily from two sources: (1)

reports describing clinical findings from specialty evaluations such as rheumatologic or gastrointestinal

workups, and (2) results from single studies that have evaluated particular issues, such as pain sensitivity

or the burning seminal fluid problem reported by veterans and their spouses.
Additional Clinical and Research Findings  263

Table 9. Clinical Findings in Symptomatic Gulf War Veterans:

Rheumatologic and Pain Evaluations

Report/Study Key Findings

Rheumatologic evaluation of a subgroup of

20 GWV with muscle weakness or pain46

No autoimmune or connective tissue disorders identified.

Evaluation of 139 GWV referred for

rheumatology consult by CCEP517

Most diagnosed conditions similar to those of other veteran populations (e.g. 25%

patellofemoral syndrome, 18% mechanical low back pain). Higher than usual rate of

FM (17%). 21 veterans positive for RF, 2 diagnosed with RA; 14 had abnormal ANA,

1 diagnosed with SLE.

Musculoskeletal symptoms evaluated in

145 symptomatic GWV referred to a

rheumatology clinic412

Most patients had widespread pain. FM diagnosed in 34%, variety of other

diagnoses in fewer GWV. Overall, 4 were positive for RF, 3 had elevated ANA.

Veterans’ functional status substantially impaired, with all mean SF36 scores below

national 25th percentiles.

Evaluation of 60 male GWV referred to VA

rheumatology clinic for myalgia1362

15% had elevated muscle enzymes (CPK or aldolase) with weakness, arthralgia, and

rashes. Limited other test abnormalities.

Evaluation of 241 GWV with GWUI,

including 92 with unexplained

musculoskeletal symptoms160

21% of GWV with GWUI diagnosed with FM (16% male, 43% female). Higher rate of

patellofemoral syndrome in GWV than controls, but similar rates of other diagnoses.

No autoimmune or inflammatory conditions identified.

Pain tolerance assessment in 11 GWV, 25

FM patients, 24 controls1481

Pain ratings indicated sign. greater pain sensitivity in GWV than controls, and sign.

greater pain sensitivity in female GWV than male FM patients.

Tender point evaluation of 327 GWV with

CMI and 708 GWV without CMI142

GWV with CMI had sign. higher rate of FM (5.2%) than GWV without CMI (0.7%).

Synovial biopsy in 10 GWV with GWI and

arthralgia342,1199

Despite significant joint pain, GWV biopsies were normal on histology findings,

vascular density, and inflammatory cell populations.

Abbreviations: GWV = Gulf War veteran, CCEP = DOD Comprehensive Clinical Evaluation Program, FM = fibromyalgia, SF36 = Medical Short

Form Survey, GWUI = Gulf War unexplained illness, RF = rheumatoid factor, RA = rheumatoid arthritis, ANA = antinuclear antibodies, SLE =

systemic lupus erythematosus, CPK = creatine phosphokinase, sign. = statistically significant

Clinical findings related to pain and musculoskeletal symptoms. Widespread muscle and joint

pain are among the most prevalent complaints of symptomatic Gulf War veterans.1489 Objective findings

from studies and clinical evaluations of Gulf War veterans with prominent pain symptoms are

summarized in Table 9. As shown, the profile of clinical rheumatologic findings in Gulf War veterans

has been unremarkable in most respects. The one exception is the observation of a higher-than-expected

number of fibromyalgia cases in this primarily young, male population.46,142,160,517 This parallels results

from one study indicating that veterans with Gulf War illness have significantly greater sensitivity to

peripheral pain stimuli than controls, on objective measures of hyperalgesia.1481

Assessment of gastrointestinal symptoms and conditions. Gastrointestinal (GI) difficulties

are frequently reported by ill Gulf War veterans, with individual cases ranging from serious, ongoing

problems with diarrhea to less severe, but persistent, abdominal pain or indigestion. Despite the

prominence of these symptoms, few studies have investigated the biological underpinnings of veterans’

gastrointestinal difficulties. As previously described, one early report identified an excess of gallbladder

disease requiring surgery in Gulf War veterans compared to other veterans in the VA healthcare

system.1049 Clinical case series of symptomatic Gulf War veterans, summarized in Table 10, generally

identified GI diagnoses and laboratory findings similar to those of other patients referred to

gastroenterologists. Several reports indicated that veterans’ GI symptoms resembled irritable bowel
264  Biological and Clinical Characteristics of Gulf War Illness

Table 10. Clinical Findings in Symptomatic Gulf War Veterans:

Gastrointestinal Evaluations

Report/Study Key Findings

Upper and lower endoscopy and biopsies in

15 GWV from a group of 57 symptomatic

GWV and 44 nondeployed veterans from a

single Guard unit.1451

Most GWV had GI symptoms during deployment that continued to the time of the study.

No specific or consistent GI pathology identified. Six of 15 biopsies showed evidence

of mild chronic inflammation.

Visceral and cutaneous sensitivity in 12

GWV with chronic abdominal pain and

diarrhea that began during the Gulf War,

12 civilian and veteran controls370

All GWV met criteria for irritable bowel syndrome. Visceral pain sensitivity (rectal

distension) and cutaneous pain sensitivity (foot immersed in hot water) sign. greater in

GWV than controls

Different GI endoscopic, laboratory, and

histological evaluations in 24 male GWV on

VA Registry referred to GI clinic for chronic

GI symptoms824

8/17 GWV had hiatal hernia, 10/17 had antral erythema, 2/17 had ulcers, 5/18 had

diverticulosis, 9/17 had gastritis (6 with H. pylori), stool cultures normal, diverse other

findings in individual GWV

327 GWV with CMI, 708 GWV without

CMI142

16% of GWV with CMI diagnosed with dyspepsia, sign. more than GWV without

CMI (6%)

Abbreviations: GWV = Gulf War veterans, GI = gastrointestinal, CMI = chronic multisymptom illness,464 sign. = statistically significant

syndrome (IBS), a “multisymptom illness” found in the general population characterized by prominent GI

symptoms, often with no objective diagnostic abnormalities. The prevalence of IBS in Gulf War veterans

has not been assessed, but preliminary information from an ongoing VA study of IBS in Gulf War

veterans was presented to the Committee by Dr. Ashok Tuteja.1565 The project includes assessment and

treatment of Gulf War veterans with IBS, and the Committee looks forward to reviewing study results

when they become available.

Respiratory function in Gulf War veterans. Respiratory symptoms like wheezing, shortness of

breath, and persistent cough are also commonly reported by ill Gulf War veterans. As previously

described, studies have suggested that rates of asthma and chronic bronchitis may be elevated in U.S.

Gulf War veterans exposed to pollutants from the Kuwaiti oil fires.285,866 Several articles have reported

results of pulmonary function testing in symptomatic Gulf War veterans. Two indicated that a subset of

veterans referred for evaluation by respiratory specialists do exhibit evidence of reduced pulmonary

function.313,1012 The large VA clinical study later reported that Gulf War veterans with chronic

multisymptom illness (CMI) have the same rate of identifiable obstructive lung disease as veterans

without CMI.142

Several large population studies have compared respiratory function in Gulf War veterans overall—those

with and without multisymptom illness—to nondeployed veterans. A large study of Navy Seabees

conducted in 1994 and 1995 indicated that, overall, Gulf War and nondeployed era veterans had similar

values on pulmonary function tests.524 In the large VA clinical study, U.S. Gulf War and nondeployed era

veterans had similar rates of respiratory symptoms, pulmonary function abnormalities, and diagnosed

obstructive lung disease.393,755 However, active duty military personnel potentially exposed to nerve

agents after the 1991 Khamisiyah demolitions, based on DOD models, were reported to have a small, but

significant, increased rate of hospitalization for respiratory diseases.529 For Australian Gulf War veterans,

exposure to oily smoke was associated with reduced pulmonary forced vital capacity (FVC) and with an

increased risk of emphysema.790 Findings such as these underscore the importance of evaluating

respiratory and other health outcomes in Gulf War veterans in subgroups with specific exposure histories.
Additional Clinical and Research Findings  265

Table 11. Clinical Findings in Symptomatic Gulf War Veterans:

Evaluation of Respiratory/Lung Function

Report/Study Key Findings

Evaluation of 29 GWV referred to

pulmonary clinic for assessment of

dyspnea on exertion

1012

15 of 29 GWV had abnormal resting pulmonary function measures. No common

pattern of pulmonary abnormality identified on resting or exercise tests.

Pulmonary function tests in 37 GWV

volunteers (32 with respiratory

symptoms), 38 veteran and nonveteran

controls313

Midvital capacity ratio was sign. higher in GWV than controls, and greater than 1.0 in

86% of GWV, indicating variable extrathoracic airflow obstruction. All GWVs evaluated

by bronchoscopy and biopsy showed evidence of larynx and trachea inflammation;

findings not attributable to smoking.

Pulmonary function at baseline and

during low-level acetone inhalation in 8

symptomatic GWV and 8 well GWV193

Pulmonary function similar in symptomatic and healthy GWV at baseline and during

acetone exposure.

Pulmonary function tests in 327 GWV

with CMI and 708 GWV veteran

controls142

GWV with CMI had similar rate of diagnosed obstructive lung disease as GWV without

CMI.

Abbreviations: GWV = Gulf War veterans, CMI = chronic multisymptom illness,464 sign. = statistically significant

Women’s health issues in Gulf War veterans. As described in the first section of the report,

multiple studies have assessed pregnancy outcomes and fertility issues in Gulf War veterans. But little

information is available on other types of health problems of concern for women veterans, and no studies

have assessed female-specific complaints in women with Gulf War illness. A study of over 200 British

women Gulf War veterans found that overall, in contrast to other populations, women and men Gulf War

veterans report generally similar rates of symptoms.1699 Compared to nondeployed female veterans,

however, women who served in the Gulf War reported substantially higher rates of frequent yeast

infections (OR=5.0) and bladder infections (OR = 9.8). A longitudinal study of Air Force women

veterans of the Gulf War conducted by the University of Michigan found that, in addition to the Gulf War

illness-type symptoms reported by other studies, women Gulf War veterans were significantly more likely

to report lumps or cysts in their breasts and abnormal Pap smears than era veterans.1207,1208 This contrasts

with a report from DOD’s Armed Forces Institute of Pathology, which identified similar types and rates

of cervical findings in Gulf War and nondeployed era veterans from Pap smears conducted on 6,715

active duty Air Force women in 1994.463 It is important to emphasize, again, that these studies only

looked at Gulf War veteran women overall, and did not provide information specific to women with Gulf

War illness.

Skin abnormalities in Gulf War veterans. Skin problems that include anomalous rashes and

growths, and other abnormalities, are commonly reported by symptomatic Gulf War veterans but have

only minimally been evaluated in research studies. Skin conditions are among the most prevalent

physician diagnoses reported in surveys of Gulf War veterans,751,789,1476,1698 and an early case series report

indicated that rashes were clinically verified in 39 percent of 166 symptomatic Gulf war veterans.1050 In

the large King’s College study, 48 percent of disabled U.K. Gulf War veterans had diagnosed skin

conditions.607 A group of miscellaneous benign skin problems—including lipomas, seborrheic warts, and

vitiligo—were significantly more common in disabled Gulf War veterans than well veterans. Seborrheic

dermatitis occurred in more Gulf War veterans (8%), overall, than non-Gulf veterans (2%). In the large

U.S. clinical study, skin conditions were not evaluated in relation to multisymptom illness. Overall, 35

percent of deployed Gulf War veterans, were diagnosed with “Type 2” skin conditions, that is, various

dermatologic findings more serious than freckles, moles, and scars.393
266  Biological and Clinical Characteristics of Gulf War Illness

Genetic findings in symptomatic Gulf War veterans. In addition to research on genetic

variability related to toxin-neutralizing enzymes, two studies have evaluated other genetic parameters in

symptomatic Gulf War veterans. Investigators at the East Orange, New Jersey VA assessed allele

frequencies and genotypes associated with muscle metabolism and physical endurance in 49 Gulf War

veterans and 61 nonveterans with chronic fatigue syndrome (CFS).

1725 In Gulf War veterans, CFS was

highly associated with insertion/deletion (I/D) polymorphisms in the gene that encodes for angiotensinconverting enzyme (ACE), an enzyme associated with muscle metabolism, electrolyte balance, and blood

pressure. Frequency of the I allele was significantly reduced in ill veterans. Compared to II

homozygotes, the DD genotype was associated with an eight-fold greater risk for CFS in Gulf War

veterans, but was not related to CFS in nonveteran patients.

Researchers from Pennsylvania State University evaluated the frequencies of HLA A, B, DR, and DQ

antigens in 32 symptomatic Gulf War veterans compared to a local reference population.1139 One HLA

class I antigen, A28, was significantly elevated in Gulf War veterans (22%) compared to the general

population (7%). This antigen has been associated with a variety of clinical conditions, and possible

implications for Gulf War illness are unclear. Investigators suggested the association may have been a

chance finding and concluded that HLA variability is not strongly associated with Gulf War illness.

Additional findings in symptomatic Gulf War veterans. A number of additional studies have

provided single looks at specific medical problems or laboratory parameters in Gulf War veterans.

Findings from these studies are briefly summarized below.

Burning seminal fluid in Gulf War veterans. After the Gulf War, some returning male veterans and

their female sexual partners reported a painful burning reaction to veterans’ seminal fluid. The problem

was particularly unique to Gulf War service, with mild-to-severe “burning semen” reported by seven

percent of Gulf War veterans nationally, but mild problems only by one percent of nondeployed

veterans.751 Researchers from the University of Cincinnati collected questionnaire data from 211 Gulf

War veterans with this problem and conducted detailed clinical evaluations of 20 Gulf War couples (male

veterans and their female partners).131 For about half the veterans, the problem had initially occurred with

their first sexual contact after the war. Most had not sought medical attention for the problem and fewer

than half the couples obtained relief using a condom. About 40 percent of women met criteria for seminal

hypersensitivity syndrome, which is also found in the general population, but important differences were

identified in Gulf War couples. In the general population, male partners typically do not react to their

own seminal fluid and nearly all cases are relieved using condoms. For Gulf War couples in which

women did not have IgE-mediated reactivity to veterans’ semen, no explanation for the burning semen

problem was identified.

Coagulation abnormalities in symptomatic Gulf War veterans. Based on earlier indications of

coagulation abnormalities in chronic fatigue syndrome patients, a team of clinical investigators compared

results from a battery of five coagulation assays done on 33 symptomatic veterans (27 Gulf War veterans,

six era veterans) and 33 healthy nonveteran controls.577 Two-thirds of symptomatic veterans tested

positive on two or more of the assays, compared to none of the controls, a highly significant difference.

Investigators concluded that veterans’ symptoms were associated with reduced blood flow resulting from

a hypercoagulable state, likely induced by exposures in theater, particularly in veterans with inherited

thrombotic risk factors. The proposed association between hypercoagulation and Gulf War illness is

being further investigated by a research team at the Minneapolis VA. Dr. Ronald Bach presented

preliminary findings from the pilot project to the Committee, which identified significantly greater

platelet tissue factor procoagulant activity in veterans with Gulf War illness than in veteran controls.81

The Committee looks forward to reviewing final results from this project, which will evaluate additional

markers of coagulation in larger samples.
Additional Clinical and Research Findings  267

Identification of RNA sequences associated with Gulf War illness. Chromosomal abnormalities

have been reported in Gulf War veterans evaluated in relation to depleted uranium exposure, as

previously described. An additional study evaluated genetic alterations in 24 symptomatic veterans by

testing their sera for the presence of polyribonucleotides with enterovirus-related primers.1700 Using

reverse transcriptase PCR, researchers identified multiple nucleotide bands common to Gulf War

veterans, mostly in the 300-750 base pair range with some longer than 2,000 base pairs. Few bands were

identified in healthy nonveteran controls, and all were under 450 base pairs. DNA sequencing of two of

the amplicons unique to Gulf War veterans identified polynucleotides that had not previously been

characterized, but contained sequences with 100 percent homology to sequences in human chromosome

22q11. Alterations at 22q11 have been associated with other medical conditions, and investigators

suggested it contains “hot spots” for genetic deletions and rearrangements. They concluded that their

findings indicate that Gulf War illness may be associated with genetic alterations, induced by exposure to

multiple hazardous substances during the war.

Proteomic findings in Gulf War veterans and other multisymptom illness patients. Investigators

from Georgetown University evaluated proteins expressed in the cerebral spinal fluid (CSF) of study

subjects with Gulf War illness, fibromyalgia (FM), and chronic fatigue syndrome (CFS) that

differentiated them from healthy controls. Results from two study cohorts identified 10 proteins that were

differentially expressed in the multisymptom illness patients, whose CSFs were pooled for these

analyses.96 The identified proteome included central nervous system, innate immune, and amyloidogenic

proteins not expressed in the CSF of healthy controls. Investigators had earlier indicated, in a conference

presentation, that a substantial number of proteins differentiated veterans with Gulf War illness from

FM/CFS patients,215 but these differences were not identified or further explored in the research

publication.

Report of reduced bone formation in Gulf War veterans. A study of British veterans compared

results of ileac crest bone biopsies from 17 symptomatic Gulf War veterans and healthy nonveteran

controls.265 Histology and cell function measures indicated that symptomatic veterans had significantly

reduced bone formation at both the tissue and cellular levels, resulting in reduced areas of cancellous

bone. Investigators were not able to ascertain the cause of this reduction, but noted that the findings were

not associated with reduced physical activity in this group and that similar findings had been reported in

symptomatic farmers chronically exposed to organophosphate sheep dip.264 These results have since been

questioned by Ministry of Defence researchers, owing to several limitations in this small, preliminary

study.143

Future Directions in Identifying Physiological Mechanisms that Underlie Gulf War Illness

Information described throughout this report reflects the primary focus of the Committee’s work thus far,

reviewing all research studies, investigations, and reports that provide information pertaining to the health

of Gulf War veterans. To address the goal of improving the health of Gulf War veterans, the highest

priority research that remains will advance efforts to identify effective treatments and diagnostic tests for

Gulf War illness. To accomplish these objectives, it is essential that that the specific biological

mechanisms that underlie veterans’ symptoms be more specifically characterized.

The current phase of the Committee’s work, therefore, involves an expanded focus on reviewing research

related to pathophysiological processes that may underlie the symptoms of Gulf War illness. Research

will be considered that may not currently be directed to Gulf War health issues, but can potentially

contribute to improved understanding of the biology of Gulf War illness or identifiable subgroups. In

undertaking this work, the committee has conducted preliminary discussions in several areas, and has

considered one topic in more depth.
268  Biological and Clinical Characteristics of Gulf War Illness

In attempting to understand the biological mechanisms that contribute to Gulf War illness, it is useful to

consider physiological abnormalities that might explain some of the prominent “unknowns” related to this

condition. These include questions about what types of biological processes could manifest as multiple

diverse symptoms affecting different systems, what types of processes would elude detection by standard

medical evaluation and clinical testing, and what mechanisms might contribute to the long-term nature of

veterans’ symptoms. And, as the etiology of Gulf War illness has become better understood, it also

includes questions about what biological processes with these characteristics could be induced by toxic

exposures. The Committee has discussed diverse questions of this nature, and considered a variety of

possible answers.

The biological mechanism considered in most depth involves the potential for proinflammatory processes

in the central nervous system to precipitate and sustain the diverse symptoms associated with Gulf War

illness. In addition, preliminary discussions have focused on the possible role of neuroplasticity in

veterans’ chronic symptoms, neurological and neuroendocrine alterations associated with multisymptom

conditions in the general population, and the potential for mitochondrial deficiencies to contribute to Gulf

War illness. Information related to these topics is briefly summarized below. The Committee will

continue to consider research in these and other areas, and will provide additional information on research

that can potentially improve understanding, diagnosis, and treatment of Gulf War illness in future reports.

Neuroplasticity in relation to Gulf War illness. A fundamental question related to the biological

processes that underlie veterans’ chronic symptomatic illness relates to whether they are the direct result

of acute damage caused by a toxic insult in 1991, or the result of persistent alterations in brain processes

that are “downstream” from an initial insult. It was long believed that the adult brain is relatively static,

and that central nervous system tissues have little capacity for adaptive change in response to damage. In

recent years, processes involved in brain regeneration have begun to be better understood. The adult

human brain has substantial capacity for structural plasticity, that is, adaptation of brain cells and

reorganization of neural pathways in response to damage.248 These processes have an important role in

recovery from brain injury, but can also lead to problems that result from cellular changes and circuitry

alterations that are maladaptive. It has been suggested, for example, that some neurodegenerative diseases

may be the long-term effect of aberrant brain cell responses to injury.59

Dr. Floyd Bloom, a member of the Committee and a prominent neuroscientist, provided a preliminary

overview of processes involved in neuroplasticity for Committee discussion, and described how structural

reorganization of brain cells can be visually mapped.151,1820 Long-term damage from an acute central

nervous system insult could potentially result from induction of neuroplastic processes, leading to

sustained alterations in brain cells and pathways that are inefficient or pathological. For example,

repeated inhibition of acetylcholine receptors in the locus ceruleus might result in alterations, locally and

in other brain structure, that affect responses to subsequent exposures or other novel events. Knowing the

primary areas of cholinergic neurons in the brain, it might be possible to determine which specific areas

are dysregulated through animal research or human post mortem studies. Understanding the contribution

of these processes to persistent symptoms in Gulf War veterans would potentially have diagnostic and

treatment implications.

A variety of related concepts were considered in a 2000 conference on the role of neuroplasticity in

chemical sensitivity.1450 The conference, sponsored jointly by federal agencies and private organizations,

included information on Gulf War illness and other multisymptom conditions. Scientists from diverse

fields were convened to review relevant research and develop testable hypotheses, based on the premise

that chemical injury involves a change in central nervous system function that results in persistent

symptoms. Discussions included a chemical “kindling” model whereby chemical exposures precipitate

permanent hypersensitive responses to electrical stimulation in brain cells,490 and research indicating that

persistent pain states can result from central sensitization that involves neuroplastic processes in the spinal

cord that lead to hyperalgesia.1021,1790
Future Directions in Identifying Physiological Mechanisms  269

Central nervous system abnormalities associated with disordered sensory processing

and autonomic/neuroendocrine dysregulation. As will be described in the next section of the

report, Gulf War illness has similarities to multisymptom conditions found in the general population,

conditions like fibromyalgia (FM) and chronic fatigue syndrome (CFS). In addition to similarities in the

symptom profiles of these conditions, a number of biological systems affected by FM and CFS also

appear to be involved in Gulf War illness. This suggests some overlap in the pathophysiological

processes that underlie these conditions.

Dr. Daniel Clauw is a member of the Committee and a leading expert on FM and related pain and

multisymptom disorders. His research, and that of other FM researchers, indicates that FM is primarily a

central nervous system (CNS) disorder that involves abnormal CNS processing of pain stimuli.253,254 This

has been demonstrated in different ways, including FM-associated elevations in cerebrospinal fluid levels

of pronociceptive factors, and enhanced response to nonpainful stimuli in brain regions associated with

pain processing, demonstrated on functional MRI.515 Studies have also demonstrated autonomic

dysregulation and neuroendocrine alterations in FM patients, including abnormalities in HPA axis

parameters, and reduced circulating levels of norepinephrine and serotonin.975,1330 Many of the biological

abnormalities associated with FM have not been evaluated in Gulf War veterans, however. Research in

these areas can potentially provide important insights into biological mechanisms that underlie veterans’

symptoms. This is especially important in relation to biological processes amenable to treatment. Two

medical FM treatments that address neuroendocrine irregularities have recently been approved by the

U.S. Food and Drug Administration (FDA).398,1666 Additional information comparing FM, CFS, and Gulf

War illness is provided in the following section of the report, with related recommendations.

Mitochondrial paradigm in relation to Gulf War illness. Mitochondria are the “power plants” of

the cell that produce adenosine triphosphate (ATP), the cell’s primary energy source. Mitochondrial

function is essential for cell viability, and cells that utilize large amounts of energy, like brain and muscle

cells, are particularly sensitive to effects of mitochondrial damage. Dr. Beatrice Golomb, a Committee

member, and Dr. Douglas Wallace, a prominent expert in mitochondrial disease, presented information

suggesting a link between Gulf War illness and multisystem effects arising from mitochondrial

injury.505,1744

Drs. Golomb and Wallace described a general model in which toxic environmental exposures can cause

damage by inducing increased cellular levels of reactive oxygen species (ROS). The ROS damage

mitochondrial DNA, leading to mitochondrial dysfunction, cell damage and cell death. This generates

additional release of ROS, triggering a self perpetuating cycle. Clinical effects become apparent over

time, as cell and tissue damage accrue. Prominent symptoms associated with mitochondrial disease can

include fatigue, headache, muscle weakness, and cognitive problems, symptoms that parallel those

affecting Gulf War veterans. In addition, recent research has indicated that acetylcholinesterase

inhibitors, and other toxic chemicals, can exert adverse effects on brain and muscle tissues through

pathways that involve oxidative stress and mitochondrial damage.775,1030,1400

Studies have linked mitochondrial DNA damage with age-related diseases that include cancer, diabetes,

and neurodegenerative diseases.1742,1743 But there is little information from studies of veterans with Gulf

War illness to indicate whether mitochondrial abnormalities may play a role in veterans’ symptoms. As

previously described, muscle tests and biopsies have generally found little indication of muscle pathology

in veterans with Gulf War illness, although one study identified an exercise-induced excess of circulating

lactate suggestive of low-level mitochondrial insufficiency.1311 Muscle symptoms in other multisymptom

conditions are generally considered central in origin, although limited muscle abnormalities have been

identified.1470,1832 Identification of frank mitochondrial damage in symptomatic veterans could have

important implications for diagnostic testing and treatment.
270  Biological and Clinical Characteristics of Gulf War Illness

Multisymptom illness associated with central nervous system inflammatory processes.

The Committee reviewed extensive materials and heard multiple interrelated presentations concerning the

potential for chronic central nervous system inflammatory processes to contribute to Gulf War illness.

Attention to this area stemmed from the Committee’s interest in identifying pathophysiological processes

that could explain the complex of concurrent symptoms affecting Gulf War veterans but would go

undetected with routine clinical testing.

The Gulf War illness symptom complex prominently includes chronic widespread pain, cognitive

difficulties, and unexplained fatigue, along with diverse other symptoms. Similar, usually time-limited

symptom complexes, occur in relation to a number of other health conditions that include infection, sleep

deprivation, and the therapeutic use of cytokines.310,378,549,784,876 All these time-limited “multisymptom

illness” conditions have one thing in common: they occur in conjunction with increased levels of

proinflammatory cytokines. Cytokines are chemical messengers generated as part of the body’s

nonspecific, innate immune response to diverse threats that include infection, tissue injury, and toxic

exposures. Proinflammatory cytokines have a variety of effects. In infectious disease, they precipitate a

specific immune response that neutralizes the infection, but they also precipitate the pain/fatigue/impaired

cognition complex of somatic symptoms. These symptoms are commonly believed to be adaptive,

promoting recovery from sickness by imposing reduced physical and mental activity.784

This symptom complex parallels a group of “symptoms” studied in animal models that are referred to as

“sickness behaviors”—reduced activity, impaired memory and learning, and heightened pain sensitivity—

which are precipitated by infection and proinflammatory cytokines.309,330,784 The association between

proinflammatory cytokines and “sickness response” symptoms in animals and humans has been known

for some time,311 but in recent years has been the subject of a fast-growing body of research in diverse

fields. 37,82,309,694,715,1041,1524,1736,1784 Studies have demonstrated that these symptoms are the result of

cytokines acting in the brain, not the periphery, and can be precipitated by increases in brain cytokine

levels that are either stimulated from the periphery, or generated by resident brain cells.95,784,794

Immune processes in the brain differ in important ways from those in the periphery and involve different

cell populations.84 Microglial cells are widely distributed in the brain and have a primary role in immune

surveillance and the central immune response, including production of proinflammatory cytokines in

response to injury—chemical, physical, or biological.1153,1502

The Committee reviewed diverse types of information related to central proinflammatory processes and

discussed them with scientists whose research related these processes more specifically to Gulf War

illness. Dr. James O’Callaghan, a Committee member and the director of the Molecular Neurotoxicology

Laboratory at the U.S. Centers for Disease Control and Prevention, provided an introductory overview of

toxin-induced inflammation and cytokine activation in the brain.1140 He described the multiple

overlapping feedback mechanisms whereby the brain, autonomic, immune, and endocrine systems

interact with and regulate one another. Acute microglial activation is a protective response to toxins, brain

injury, and infection. Persistent microglial activation, however, has been linked to a number of chronic

disease states, including Parkinson’s disease. Dr. O’Callaghan’s own research has demonstrated the role

of the proinflammatory cytokine TNF-α in the generation of cell damage and gliosis by the dopaminergic

neurotoxicant MPTP.1473

Beyond the parallels between Gulf War illness and symptoms that develop with increased brain levels of

proinflammatory cytokines, the potential relevance of these processes to Gulf War illness is suggested by

several indicators. First, studies indicate that exposures encountered in the Gulf War can stimulate

production of cytokines and related proinflammatory processes in the brain, and inhibit processes that

down regulate inflammation. Inflammation is controlled by both autonomic and hypothalamic-pituitaryadrenal (HPA) axis function in the periphery, both of which appear to be dysregulated in Gulf War

veterans. There are also indications that Gulf War illness is associated with a low-level immune
Future Directions in Identifying Physiological Mechanisms  271

activation, evident in the peripheral circulation, although this has not yet been assessed in the central

nervous system.1420,1835

Enhanced glial activation and central nervous system cytokine production have been demonstrated in

animal models following exposure to high306 and low-level 601 sarin, in response to combined exposure to

PB, DEET, permethrin and stress, at levels comparable to those of Gulf War veterans,3and in response to

inhalation of DU896 and particulates.147,1719 In addition, animal studies have demonstrated that low level

sarin exposure results in a delayed reduction of M1 cholinergic receptors in the brain,601 delayed effects

on autonomic function,1070,1071 and persistent reduction of corticosteroid.740,868,1445

Dr. Kevin Tracey presented research from his laboratory, which has characterized the mechanism by

which the autonomic nervous system regulates cytokine production and inflammation in the periphery,

termed the “cholinergic anti-inflammatory pathway.” 1552 It involves autonomic detection of

inflammation, afferent vagal signaling to the brain, and efferent signaling that inhibits cytokine

production.301 This pathway is regulated by the brain, and depends on the activation of central muscarinic

receptors, specifically M1 receptors.1178 It is not known if similar processes are involved in regulating

inflammatory processes in the brain.

Additional information was presented by Dr. Mariana Morris, who described her research demonstrating

delayed autonomic and neuroendocrine effects of low-level sarin exposure1070,1071 and Dr. Mohan Sopori,

describing M1 receptor alterations, increased central cytokine production,601 and persistent reductions in

corticosteroid levels following low-level sarin exposure.740,868,1445 Dr. Nancy Klimas summarized the

broad spectrum of findings related to increased cytokine production in patients with CFS.812,814

Dr. Jau-Shyong Hong described his research demonstrating the potential for an acute proinflammatory

stimulus to generate a persistent, self-perpetuating process of microglial activation and inflammation in

the brain following toxic insult.146,625 Dr. Hong also provided preliminary information related to several

compounds that are being studied for their potential to inhibit aberrant microglial activation and

inflammation in the brain, including drugs currently approved for use in other conditions. In addition, Dr.

Tomas Guilarte provided an overview of the use of PET scans and other methods to detect PK11195

binding on peripheral benzodiazepine receptors in the brain, a sensitive marker for glial cell activation.540

These methods are used in research studies to identify and localize evidence of central nervous system

inflammation resulting from neurotoxicant exposures in animal models. They are also used to

characterize central inflammatory processes associated with neurological diseases in humans, including

ALS, multiple sclerosis, and Parkinson’s disease.94,204,481,843,1564

The research considered suggests the potential for Gulf War exposures to precipitate an inflammatory

response in the brain, a response that may have become dysregulated due to effects of multiple repeat

exposures and/or disruption of processes that down regulate the central inflammatory response. It also

suggests the potential for persistent neuroinflammatory processes to develop, promoted by alterations in

autonomic and neuroendocrine mechanisms that normally keep inflammatory processes in check, or by

self perpetuating mechanisms.146,494 Lastly, it suggests that these processes can precipitate a

multisymptom complex similar to that affecting Gulf War veterans.

The Committee considers the potential involvement of central proinflammatory processes in precipitating

and sustaining veterans’ multisymptom illness to be a promising area for further research. The

mechanisms of central nervous system injury and chronic illness suggested by this model also appear to

be compatible with other mechanisms considered more briefly by the Committee. Central nervous system

inflammatory processes may contribute to or result from neuroplastic changes following an initial insult

to the brain or additional alterations that develop over time.204,309,510 The mechanisms described imply an

epiphenomenon involving interactive dysregulation of neuroendocrine parameters, autonomic function,

and neuroinflammatory processes that, in combination, result in persistent symptoms that include
272  Biological and Clinical Characteristics of Gulf War Illness

widespread pain, cognitive difficulties, fatigue, and additional problems. Central inflammatory processes

also generate, and can be triggered by, increased levels of ROS and mitochondrial alterations in brain

tissues.93 Whether or not these processes are detectable in the peripheral circulation and tissues, their

occurrence in the brain and spinal cord may plausibly explain veterans’ symptoms.

Research in this area is especially warranted because of its possible clinical implications. If veterans with

Gulf War illness are affected by dysregulated central inflammatory processes, imaging methods are

available that can potentially identify these abnormalities in ill veterans, providing possible diagnostic

applications. Most importantly, a number of therapeutic agents have been studied and are being further

developed for their effectiveness in treating dysregulated central inflammatory processes.289,1047,1417
Recommendations  273

Recommendations

The Committee places a high priority on identification of biological markers for Gulf War illness and

measurable differences between groups of symptomatic and healthy Gulf War veterans. In light of

findings from current and ongoing studies describing significant associations between Gulf War illness

and neurological, immune, endocrine, and enzyme parameters, the Committee recommends the following

research:

 Studies that utilize state-of-the-art neuroimaging technologies to characterize aspects of brain

structure and function that may distinguish veterans with Gulf War illness, including illness or

exposure subgroups, from healthy Gulf War veterans

 Comprehensive evaluation of autonomic nervous system function in veterans with Gulf War

illness, including illness and exposure subgroups

 Research that investigates biological and genetic variability potentially linked to differences in

vulnerability to Gulf War exposures, including studies that evaluate associations between Gulf War

illness and genetic polymorphisms and activity levels of enzymes associated with uptake and

metabolism of neurotoxic exposures

 Comprehensive evaluation of immune parameters associated with Gulf War illness, including

parameters that may differ among illness and/or exposure subgroups

 Comprehensive evaluation of hypothalamic-pituitary-adrenal axis parameters associated with Gulf

War illness, including parameters that may differ among illness and/or exposure subgroups

 Studies that evaluate alterations in central proinflammatory and inflammatory processes in Gulf

War veterans affected by Gulf War illness

 Animal studies that characterize persistent effects of Gulf War-related exposures, alone and in

combination, on central proinflammatory processes and their biological mediators in the central

nervous system and target organs

 Studies that utilize new technologies (proteomic, genomic, and metabolomic methods) capable of

identifying unique molecular characteristics of Gulf War illness, as well as illness and exposure

subgroups
274  The Nature of Gulf War Illness

Gulf War Illness in Relation to Multisymptom Conditions

in the General Population

Research reports often point to general similarities between Gulf War illness and multisymptom

conditions found in the general population—conditions such as chronic fatigue syndrome and

fibromyalgia—that are defined primarily on the basis of patients’ symptoms. Such conditions share many

features with Gulf War illness. They are characterized by multiple symptoms affecting multiple systems,

are not well understood biologically, and are not typically distinguished by objective diagnostic tests.

The symptoms of these conditions are also rather general, that is, they include problems such as fatigue,

pain, and cognitive/mood difficulties that are commonly seen in healthcare settings, and are associated

with a wide range of medical conditions. These general similarities were recognized by Congress when,

in 1998, it directed that special regulations permitting Gulf War veterans to receive disability

compensation for “undiagnosed illnesses” also apply to veterans diagnosed with chronic fatigue

syndrome, fibromyalgia, and similar conditions defined primarily on the basis of symptoms.259

There are also strong parallels in the historical and social contexts surrounding Gulf War illness and other

multisymptom conditions. All are chronic and debilitating to varying degrees, often persisting for many

years, and present difficult challenges for patients seeking healthcare support and for clinicians seeking to

provide useful treatments.369,919,1535,1783 All of these conditions have been considered controversial,

particularly so in the early years they were recognized, with much of the controversy focused on the

degree to which the conditions represent distinct syndromes and are essentially organic or psychiatric in

nature.

For its initial consideration of similarities between Gulf War illness and multisymptom conditions in the

general population, the Committee focused on three defined syndromes—chronic fatigue syndrome

(CFS), fibromyalgia (FM), and multiple chemical sensitivity syndrome (MCS). A number of other

conditions also reasonably fall under the “multisymptom illness” rubric, conditions such as irritable

bowel syndrome, myofascial pain syndrome, and temporomandibular joint dysfunction syndrome. Such

syndromes may have similarities to some of the symptom domains affecting veterans, but are less

obviously associated with the diversity of systems involved in Gulf War illness and have seldom been

evaluated in Gulf War veterans.

In contrast, multiple studies have reported the prevalence of CFS, FM, and MCS in Gulf War veterans.1534

Identification and diagnosis of CFS, FM, and MCS cases depends on definitions that have varied between

investigators and over time.299,465,621,1262,1398,1408,1437,1801 While each syndrome is associated with multiple

symptom types, CFS, FM, and MCS case definitions differ markedly from one another, with each

distinguished by a sentinel symptom or core characteristic. The sentinel symptom for CFS is persistent

and debilitating fatigue, for FM it is chronic widespread pain, and for MCS it is the exacerbation of

symptoms by low-level chemical exposures. However, the syndromes CFS, FM, and MCS are not

synonymous with these sentinel symptoms and are much less prevalent. The symptom of fatigue, for

example, is extremely common, affecting up to one fourth of the general population.1179,1234 Chronic

fatigue syndrome, on the other hand, is far less common. As currently defined, CFS affects less than one

half of one percent of the general population.709,1277

Research studies consistently find significant overlap between defined multisymptom conditions in the

general population. That is, patients who meet diagnostic criteria for one of these conditions frequently

also meet criteria for others.2,187,710,1425,1775 The extent to which some or all of these conditions represent

different aspects of a unified “multisymptom” disease entity or are associated with common underlying

physiological abnormalities has been the subject of considerable discussion by researchers. 255,807,1766

There is also ongoing discussion of the extent to which each syndrome, individually, should be

considered a single condition or a heterogeneous mix of illnesses that manifest in similar symptoms but
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  275

are actually the result of various etiologic pathways and underlying pathologies.72,1257,1330,1735

Investigators have observed that the most widely used case definition for CFS,465 for example, is

problematic in that it includes a heterogeneous group of symptomatic patients.707,708,793,1791 Therefore,

determining the extent to which Gulf War illness is essentially the “same type of thing” as CFS, FM,

MCS, or perhaps all of them, is complicated by the lack of agreement about whether these conditions

individually can rightly be considered single or unique disease entities.

Fatigue and Chronic Fatigue Syndrome in Gulf War Veterans

Poorly understood fatiguing conditions accompanied by multiple symptoms such as chronic pain and

cognitive impairment have been described in the medical literature for centuries.113,600,1498 The clinical

condition now identified as chronic fatigue syndrome (CFS) was first described in relation to an outbreak

of unexplained fatiguing illness in Nevada in 1984.622 CFS is now most often defined using criteria

established by an expert panel convened by the U.S. Centers for Disease Control and Prevention in

1994.465 According to these criteria, CFS is defined as the presence of debilitating fatigue for a minimum

of six months in the absence of exclusionary medical and psychiatric conditions, and the persistence of at

least four of eight chronic symptoms that include headache, muscle aches and pains, joint pain, problems

with memory or concentration, unrefreshing sleep, and atypical fatigue following exertion.

Prevalence estimates for CFS, as currently defined, range from 2351277 to 422709 cases per 100,000, or 0.2

- 0.4 percent of the general population. A recently-proposed broader CFS case definition yields higher

prevalence rates.1261 CFS affects about three times as many women as men, with individuals age 40-60

most often affected.

1277 The severity of CFS symptoms typically waxes and wanes over time.

Longitudinal studies report that between 10 and 60 percent of CFS patients may show symptom

improvement on follow-up but fewer than 10 percent achieve full recovery or sustained

remission.

205,733,1126,1792

Although there has been considerable research on patients with CFS—over 3,000 studies are listed in the

National Library of Medicine database—the nature and causes of this condition have remained elusive.

Studies have pointed to possible viral etiologies7,186,493 as well as abnormalities related to immune

function,814,815,1098,1175,1419 neurological function158,270,858,862,1375 and endocrine parameters.256,334,712,1170

However, results reported in each of these areas have been mixed, with questions about discrepancies

between findings still largely unresolved.26

As shown in Table 1, the symptom of persistent fatigue is commonly reported by Gulf War veterans. A

much smaller proportion meet CFS case definition criteria or report being diagnosed with CFS. By

almost any definition, however, the rate of CFS in Gulf War veterans is substantially higher than CFS

rates in nondeployed era veterans and the general population. In the subset of studies utilizing clinical

evaluations, CFS prevalence estimates have ranged from 1.6 - 5.1 percent in Gulf War veterans,

393,464,987

much higher than the 0.2 - 0.4 percent CFS prevalence in the general population. Most significantly,

recent findings from VA’s Phase III clinical study indicated that the rate of CFS in Gulf War veterans was

over 40 times the rate in their nondeployed veterans peers.393

Taken together, these results demonstrate a dramatically elevated rate of CFS in Gulf War veterans,

perhaps the highest rate of CFS yet documented in a large defined population. The VA study also

reported, however, that veterans who met diagnostic criteria for CFS represented only a small subset—

less than six percent—of Gulf War veterans affected by multisymptom illnesses.142
276  The Nature of Gulf War Illness

Table 1. Prevalence of Fatigue and Chronic Fatigue Syndrome

Among Gulf War Veterans and Nondeployed Era Veterans

Fatigue Chronic Fatigue Syndrome

Study

Fatigue

Measure

Non

deployed

vets

Gulf

War

vets OR

Chronic Fatigue

Syndrome Measure

Non

deployed

vets

Gulf

War

vets OR

Kelsall 2004789 fatigue 56 % 66 % 1.6* self-reported diagnosis 1.0 % 1.0 % 0.8

Eisen 2005393 clinically diagnosed 0.1 % 1.6 % 40.6*

Fukuda 1998464 fatigue

> 6 months

13 % 41 % 4.7*†clinically diagnosed 5.1 %

Goss Gilroy 1998511 presumed CFS based on

symptoms

1.9 % 8.5 % 5.3*

Gray 1999524 fatigue

> 1 month

5 % 20 % 4.4*

Gray 2002527 fatigue > 1 year 1 % 39 % 3.7* self-reported diagnosis 0.7 % 5.2 % 7.6*

Iowa 1997350,692 feeling tired 19 % 38 % 2.6*†presumed CFS based on

symptoms

0.6 % 1.9 % 3.1*

Ishoy 1999696 abnormal

fatigue

11 % 26 % 3.0*†

Kang 2000751,753 fatigue 15 % 38 % 3.5*†presumed CFS based on

symptoms

1.2 % 5.6 % 4.8*

McCauley 2002987 clinically diagnosed 2.2 %

Proctor 20011238 chronic fatigue 9 % 29 % 4.4*†presumed CFS based on

symptoms

0 2.0 % ns

Reid 20011264 presumed CFS based

on fatigue score, SF36

1.8 % 2.1 % 1.2

Simmons 20041411 fatigue 1 % 11 % 9.1* self-reported diagnosis 0.1 % 0.4 % 3.5*

Steele 20001476 fatigue > 1 year 12 % 36 % 4.1* presumed CFS based on

symptoms

0.7 % 7.1 % 8.2*

Unwin 19991698 fatigue 28 % 51 % 2.7* self-reported diagnosis 0.8 % 3.3 % 4.2*

Abbreviations: CFS = chronic fatigue syndrome, OR = odds ratio, SF36 = Medical Outcome Study Short Form Survey

Notes: * Odds ratio is significantly elevated in Gulf War veterans;

†Value calculated from data provided in referenced article

Chronic Pain and Fibromyalgia in Gulf War Veterans

Fibromyalgia, or fibromyalgia syndrome (FM) is a condition associated with chronic widespread pain that

is typically accompanied by a variety of persistent symptoms such as fatigue, cognitive and mood

disturbances, sleep abnormalities, headache, and gastrointestinal difficulties. Chronic widespread pain is

a common problem, affecting between seven and 11 percent of the general population.296,1774,1799

Fibromyalgia, as defined by the American College of Rheumatology, is much less common. Defining
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  277

Table 2. Prevalence of Pain and Fibromyalgia

Among Gulf War Veterans and Nondeployed Era Veterans

Pain Fibromyalgia

Study

Pain

Measure

Non

deployed

vets

Gulf

War

vets OR

Fibromyalgia

Measure

Non

deployed

vets

Gulf

War

vets OR

Bourdette 2001160 clinically diagnosed 2.5 %

Eisen 2005393 clinically diagnosed 1.2 % 2.0 % 2.3*

Fukuda 1998464 muscle pain > 6

months

6 % 18 % 3.4*†

Goss Gilroy 1998511 presumed FM based

on symptoms 9.6 % 16.2 % 1.8*

Gray 1999524 unusual muscle

pain > 1 month

2 % 7 % 3.8*

Gray 2002527 unusual muscle

pain > 1 year

6 % 23 % 4.4*

Iowa 1997350,692

muscle aches,

soreness or

stiffness

17 % 31 % 2.2*†

presumed FM based

on symptoms 11.1 % 20.9 % 2.1*

Kang 2000751 muscle pain 17 % 33 % 2.4*†

Kelsall 2004789 general muscle

aches or pains

56 % 66 % 1.3* self-reported

diagnosis

0 < 1 % -

Simmons 20041411 skeletal/muscular

symptoms

13 % 15 % 1.1*

Smith 20001432 hospitalization for FM 0.04 % 0.04 % 1.2*

Steele 20001476 muscle pain

> 1 year

6 % 21 % 4.6* self-reported

diagnosis

< 0.5% 2.0 % 3.7

Unwin 19991698 pain without

swelling

14 % 32 % 2.2*

Abbreviations: FM = fibromyalgia, OR = odds ratio

Notes: *Odds ratio is significantly elevated in Gulf War veterans; †Value calculated from data provided in referenced article

criteria require that a patient have a history of chronic widespread pain persisting for at least three

months, and experience pain in response to digital pressure applied to at least 11 of 18 specified locations

on the body, or tender points.1801 Fibromyalgia has been reported to affect two-to-three percent of the

adult population,

1340,1549,1774,1799 with rates substantially higher in women than men. Studies have also

consistently demonstrated a high degree of overlap between FM and CFS, with patients diagnosed with

one condition frequently also meeting criteria for the other.2,187,710,1775

An extensive amount of research has been conducted in relation to fibromyalgia—about 4,000 studies are

listed in the National Library of Medicine database. Although the precise pathophysiological mechanisms

underlying FM are not entirely understood, research conducted since the 1990s has provided a number of

important insights. Studies have suggested a genetic predisposition for FM, as indicated by the elevated
278  The Nature of Gulf War Illness

rate of FM among family members of FM patients.64,199,1191 Fibromyalgia has been reported to develop in

conjunction with a variety of conditions and apparent triggers, including physical trauma, infectious

diseases, and emotional stress.1,200,201,348,531 Affected patients have been shown to exhibit abnormalities of

the hypothalamic-pituitary-adrenal axis24,294,534,544,1106 as well as autonomic irregularities.974-976,1204 The

hallmark clinical finding associated with fibromyalgia is a significantly reduced threshold for pain, a

phenomenon associated with abnormalities in pain processing mechanisms in the central nervous

system.164,269,516,871,1210,1474

Epidemiologic studies have consistently found that chronic pain is one of the most frequently-reported

symptoms affecting Gulf War veterans, as summarized in Table 2. Clinical studies have also found that a

relatively high proportion of Gulf War veterans referred for rheumatology consults are diagnosed with

fibromyalgia.412,517 In two population-based studies involving clinical evaluation of Gulf War veterans,

the prevalence of FM was estimated to be about two percent.160,393 Although similar to the overall FM

prevalence in the general population, this rate is higher than would be expected in a predominantly male

population of comparable age, and about twice as high as the rate diagnosed in nondeployed Gulf War era

veterans. 393 Additional results from VA’s large clinical study of Gulf War veterans indicate that among

Gulf War veterans with multisymptom illnesses, only a small fraction—about five percent—meet

diagnostic criteria for fibromyalgia.142

Sensitivity to Chemicals and Multiple Chemical Sensitivity in Gulf War Veterans

The condition referred to as multiple chemical sensitivity (MCS), like CFS and FM, is characterized by

diverse types of symptoms in the absence of other explanatory conditions. The unique hallmark of MCS

is that these symptoms are exacerbated by exposure to common chemicals (e.g. household cleaners, motor

vehicle exhaust, perfumes, paint, pesticides, tobacco smoke) at levels that do not cause symptoms in

healthy individuals. Several case definitions for MCS have been proposed and used in different studies,

71,140,299,1006,1408 although none has been widely adopted as a standard. About half of MCS patients report

that their condition first developed after identifiable exposures to chemicals of various types, such as

remodeling their home, occupational exposure to solvents, or exposure to agricultural pesticides.212,1044

Regardless of the presence of an initiating event or specific type of exposure, MCS patients typically

report symptoms in response to a variety of odors and classes of chemicals, often including sensitivity to

specific foods.

Epidemiologic studies indicate that the symptom of being sensitive to common odors or chemicals is

fairly common, affecting between 13 and 33 percent of the general population, with rates higher in

women than men.

211,837,1018 Investigators have suggested that self-reported rates of chemical sensitivity

may underestimate the actual extent of the problem, since some individuals may not be aware that

symptoms they experience are triggered or perpetuated by chemical exposures.1042

No studies have yet determined the proportion of the general population who meet criteria for the more

debilitating manifestation of chemical sensitivity, MCS or MCS syndrome, as defined by any of the

proposed case definitions. These criteria generally require that cases be affected by symptoms in multiple

organ systems that are made worse by low-level chemical exposures, and sometimes require that patients

report some type of lifestyle accommodation to minimize such exposures. In general population surveys,

three-to-six percent of respondents have reported being medically diagnosed with MCS or environmental

illness.211,837

There has been considerably less scientific research on MCS than on FM and CFS, and little consensus

with respect to its nature and underlying physiological mechanisms. Historically, persistent reactivity to
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  279

Table 3. Prevalence of Sensitivity to Chemicals and Multiple Chemical Sensitivity Syndrome

Among Gulf War Veterans and Nondeployed Era Veterans

Sensitivity to Chemicals or Odors Multiple Chemical Sensitivity

Study

Symptom

Measure

Non

deployed

vets

Gulf

War

vets OR

Multiple Chemical

Sensitivity Measure

Non

deployed

vets

Gulf

War

vets OR

Australian DVA

200375

self-reported MCS

diagnosis < 1 % < 1 % 1.3

Black 2000141 sensitive to chemicals 6 % 13 % 1.9* presumed MCS

based on symptoms 2.6 % 5.4 % 1.9*

Fukuda 1998464 sensitive to chemicals

> 6 months 2 % 5 % 2.6*†

Goss Gilroy 1998511 presumed MCS

based on symptoms 0.5 % 2.7 % 4.0*

Gray 2002527 chemical sensitivity

> 1 year 0.7 % 4 % 5.9* self-reported MCSdiagnosis 0.4 % 1.6 % 4.5*

Kang 2000751 sensitive to chemicals 8 % 15 % 2.0*†

McCauley 2002989 self-reported MCS

diagnosis 1.2 % 1.2 % 1.0

Proctor 20011238 symptoms triggered

by odors 2 % 14 % 7.6*† presumed MCSbased on symptoms 0 2.9 % -

Reid 20011264,1265 symptom response to

any of 11 chemicals 14 % 28 % 2.3* presumed MCSbased on symptoms 0.2 % 1.3 % 7.2*

Steele 20001476 symptom response to

chemicals > 1 year 4 % 17 % 4.6*

Unwin 19991698 self-reported MCS

diagnosis 0.3 % 0.8 % 2.2

Abbreviations: MCS = multiple chemical sensitivity, DVA = Department of Veterans Affairs, OR = odds ratio

Notes: *Odds ratio is significantly elevated in Gulf War veterans; †Value calculated from data provided in referenced article

low-level chemical exposures following an acute initiating exposure was described by Hans Selye in the

1930s.1385 In the 1960s, Theron Randolph diagnosed a chemical maladaptation syndrome in patients

whose diverse symptoms improved after living up to a week in a specially designed chemical-free

environment.1253 Inhaled exposure to the types of chemicals that trigger MCS symptoms have also been

reported to induce or exacerbate diagnosable medical conditions. These include, most prominently,

asthma, rhinosinusitis, and inflammation of the upper airway.175,1019 Physicians who treat chemical injury

have also reported that headache, depression, arthritis, and a persistent intestinal dysfunction syndrome

can be precipitated by common chemical exposures.902,1252,1254

A limited number of studies have investigated possible biological mechanisms underlying MCS. These

have included enhanced neural sensitivity resulting from a time-dependent kindling process elicited by

chemical exposure,50,121,431,1449 a generalized loss of tolerance to chemicals induced by toxic exposures,1043

chronic neurogenic inflammation106,1015 possibly in conjunction with chronic airway

inflammation,358,1016,1017 and behaviorally-conditioned responses to odors.152 Japanese investigators have
280  The Nature of Gulf War Illness

reported that MCS patients have significantly elevated plasma levels of substance P and other

neuroinflammatory mediators, levels that are further increased with exposure to volatile organic

compounds.804 Researchers have also suggested that MCS is associated with other immune and

neuroendocrine abnormalities,

604,808,891,1014 although none of the proposed biological mechanisms for MCS

have been extensively studied.

Several studies have evaluated chemical sensitivity and MCS in Gulf War veterans, as shown in Table 3.

Among generally representative groups of Gulf War veterans, 13-17 percent endorse the symptom of

being sensitive to chemicals or odors, with lower rates (4-5%) among Air Force and Navy veterans.

Although the proportion of Gulf War veterans with this symptom appears, overall, to be similar to that in

the general population, it may be higher than rates expected among males of similar age in the general

population, and is significantly higher than rates found in nondeployed Gulf War era veterans. As is the

case for the symptoms of fatigue and widespread pain, the symptom of chemical sensitivity is more

commonly reported by veterans who are ill, or have enrolled in VA’s Gulf War Registry.

123,809,1044

As summarized in Table 3, studies have indicated that a much smaller proportion of Gulf War veterans

meet criteria for a MCS syndrome, variously defined, with rates ranging from 1.3 to 5.6 percent. Because

there are no population-based prevalence estimates for defined MCS, it is not clear whether Gulf War

veterans experience higher rates of MCS than the general population. However, studies using MCS–

defining criteria have consistently found MCS to be significantly more common in Gulf War veterans

than in nondeployed era veterans.

Clinical studies have evaluated additional characteristics of Gulf War veterans who report being

chemically sensitive.122,140,1044 For example, research from the University of Arizona and the Tucson

VAMC found that veterans with Gulf War illness were more likely to report being chemically sensitive

before the war than veterans who did not have Gulf War illness.

123 In addition, the subset of ill veterans

with increased chemical sensitivity also reported the highest degree of chemical exposures during the war,

particularly exposures to pesticides and insect repellants. Similarly, a U.K. study found a dramatically

elevated MCS risk (ORs = 10.9 – 12.3) among U.K. veterans who reported using personal pesticides

during the war, an association substantially higher than with other reported exposures.1264 A team of

investigators from the University of Medicine and Dentistry of New Jersey reported that Gulf War

veterans who met criteria for both CFS and MCS had a significantly greater symptomatic response to

experimental diesel vapor exposure than healthy controls.433 This response was accompanied by

increased autonomic arousal, as indicated by changes in blood pressure and respiratory measures, but not

with measurable declines in cognitive performance.

Is Gulf War Illness the Same as Multisymptom Conditions Found in the General

Population?

Direct comparisons between Gulf War veterans and nonveterans with multisymptom

conditions. Researchers have commonly alluded to similarities between ill Gulf War veterans and

patients diagnosed with CFS, FM, and MCS. But few studies have directly compared illness

characteristics of Gulf War veterans with those of civilian patients with other multisymptom diagnoses.

The general impression that these conditions are similar is largely the result of their “multisymptom”

nature. Only one published study has directly compared symptom frequencies and patterns reported by

Gulf War veterans with those of civilians with the same defined multisymptom diagnosis. Investigators

at Ninewells Hospital and Medical School in Scotland compared the symptoms of three groups who met

CFS case-defining criteria: CFS cases in the general population, individuals with CFS who had served in

the Gulf War, and individuals who developed CFS following occupational exposure to high levels of
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  281

Table 4. Projects Evaluating Biological Measures in Both Ill Gulf War Veterans

and Nonveteran Patients with Defined Multisymptom Conditions

Study Groups Studied

Results similar in

veterans and

nonveterans? Findings

Khan800

2004

24 symptomatic Gulf veterans, 52

nonveterans with CFS, 40 healthy

controls

no

Enhanced vascular sensitivity to acetylcholine in

peripheral circulation among civilians with CFS,

but not symptomatic Gulf War veterans

Peckerman1186

1999

29 Gulf veterans with CFS, 31

healthy Gulf veterans, 11

nonveterans with CFS, 29 healthy

nonveterans

no

Gulf veterans with CFS had sign. higher tactile

threshold than healthy veterans. CFS not

associated with differences in tactile thresholds in

nonveterans.

Skowera1419,1420

2004

40 ill Gulf veterans, 80 healthy

Gulf veterans, 35 nonveterans

with CFS, 28 healthy controls

no

Ill Gulf veterans, but not civilians with CFS, exhibit

TH1-type immune activation, increased levels of

IFN-γ, IL-2, and IL-10 producing cells

Stein1481

2004

11 Gulf veterans with FM,

26 nonveterans with FM,

36 healthy controls

yes

Reduced 24-hour heart rate variability in

symptomatic women Gulf War veterans and

women with FM

Vojdani1732

1999

40 ill Gulf veterans, 100

nonveterans with CFS, 40

nonveterans with FM,160 controls

yes

55% of ill Gulf veterans, 52% of CFS patients,

54% of FM patients, and 15% of controls tested

positive for mycoplasma infection

Vladitiu1725

2004

49 Gulf veterans with CFS,

61 nonveterans with CFS,

75 healthy controls

no

Angiotensin-converting enzyme genotype was

associated with CFS among Gulf War veterans but

not with CFS in nonveterans

Zhang1835

1999

43 Gulf veterans with CFS,

68 nonveterans with CFS,

87 healthy controls

no

Gulf War veterans with CFS, but not civilians, had

sign. elevated levels of IFN-γ, TNF-α, IL-2, and

IL-10

Abbreviations: CFS = chronic fatigue syndrome, FM = fibromyalgia, sign. = statistically significant

organophosphate insecticides. Severity of physical symptoms, overall, was significantly greater in Gulf

War veterans with CFS than in the other two groups. Severity measures for fatigue, muscle and joint

pain, and headaches were particularly prominent in Gulf veterans. Gulf War veterans with CFS were also

more impaired on measures of general health and bodily pain than nonveteran CFS patients.793 In

contrast, investigators from the East Orange, New Jersey, VA, have reported that Gulf veterans diagnosed

with CFS were considerably less disabled by their condition than nonveteran CFS patients.250,1219

A number of research teams have evaluated identical physiological parameters in both symptomatic Gulf

War veterans and multisymptom illness patients from the general population. Results of these studies are

summarized in Table 4. Of the seven studies, five found differences between Gulf War veterans and

nonveteran patients with similarly-defined multisymptom conditions and two found similarities. These

results suggest that there may be some parallels between physiological mechanisms underlying Gulf War

illness and conditions such as CFS and FM, but there also appear to be differences. No definitive

conclusions can be drawn from this small group of studies, however, since they address a limited number

of research questions and have not been replicated in larger, more representative samples. It is interesting

to note, however, that two groups have identified indicators of immune activation that distinguish ill Gulf

War veterans, but not civilian CFS patients, from healthy controls.
282  The Nature of Gulf War Illness

Research findings in multisymptom conditions compared to those in Gulf War illness.

The relationship of Gulf War illness to other multisymptom conditions can also be evaluated by a general

comparison between research findings in Gulf War veterans and those associated with CFS, FM, and

MCS. A large number of studies have investigated a variety of biological mechanisms potentially

underlying CFS and FM, some of which have also been studied in Gulf War veterans. These include

studies evaluating neurological, endocrine, immune, and infectious processes in multisymptom

conditions. In addition, epidemiologic studies have provided a fairly consistent picture of multisymptom

illnesses in the general population, one that differs from epidemiologic patterns associated with Gulf War

illness.

Neuroimaging findings. Neuroimaging studies have identified a variety of differences between

multisymptom illness patients and healthy controls.164,274,1315 Imaging studies have provided useful

insights concerning altered central pain processing in FM patients. Both SPECT and fMRI studies have

identified consistent differences between FM patients and controls in cerebral blood flow responses to

low-level pain stimuli.164,515,1079 A recently-reported positron emission tomography (PET) study indicated

that FM patients exhibit reduced binding of endogenous opioids in brain regions associated with pain

processing, compared to healthy conrtols.587

Studies utilizing structural MRI have reported significantly reduced total volume of gray matter in CFS

patients, compared to controls.

322,1143 Regional differences in grey matter volume have also been

described in FM patients.1363 An early report from an ongoing MRI study indicates that symptomatic

Gulf War veterans may have significantly reduced white matter volume, compared to veteran controls.1780

MRI studies have also found evidence of increased ventricular volume and the appearance of scattered

punctuate lesions in the white matter of brains of CFS patients.186,270,863,1375 Foci of increased signal

intensity in white matter have also been described in Gulf War veterans, but these did not differ between

Gulf War illness cases and controls.

563

Proton magnetic resonance spectroscopy (1H MRS) studies have reported a significantly elevated ratio of

choline to creatinine in the occipital cortex and basal ganglia of CFS patients compared to controls.235,1245

This contrasts with the reduced choline to creatinine ratios identified by one study in the basal ganglia of

subgroups of ill Gulf War veterans, relative to healthy controls.568 In short, brain imaging studies have

provided diverse types of information regarding multisymptom conditions. Studies conducted to date,

however, have not permitted clear comparisons between brain abnormalities in patients with FM and CFS

and those in veterans with Gulf War illness.

Neurocognitive studies. Patients with CFS, FM, MCS, and Gulf War illness commonly report

difficulties with memory and concentration, sometimes referred to as “brain fog” or “fibrofog” by

patients. Research studies evaluating neurocognitive function in CFS and FM patients have identified

objective indicators of impaired information processing, memory, and attention in some patients, although

measured deficits are often not as severe as patients’ subjective impressions of their cognitive

difficulties.434,743,874 Neurocognitive studies of veterans with Gulf War illness have reported similar,

limited types of measurable cognitive impairment, as previously described.864,1497,1512

Autonomic dysregulation. Abnormalities in autonomic nervous system function have been described in

studies of CFS and FM patients, with somewhat inconsistent findings,

155,277,323,456,482,974-976,1204 and in

several studies of Gulf War veterans. For example, some studies have reported that FM and CFS patients

have elevated rates of neurally mediated hypotension (NMH), an autonomic abnormality characterized by

a drop in blood pressure after moving to an upright position.157,158,261,467,722,858,1367 A significantly elevated

rate of NMH has also been reported from one study of Gulf War veterans with CFS321 but not in a study

of Gulf War veterans with multisymptom illness.937 Additional studies have demonstrated other ANS

abnormalities in Gulf War illness patients, as previously described.569,1185,1353,1481 The specific nature and
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  283

role of autonomic dysfunction has not been clearly elucidated in Gulf War veterans nor in nonveterans

with multisymptom conditions.

Endocrine measures. Endocrine abnormalities associated with the hypothalamic-pituitary-adrenal

(HPA) axis have been associated with both CFS and FM.24,294,333,1170,1210 Reported alterations in HPA

parameters have varied somewhat between studies, and differed between CFS and FM patients. Most

consistently, CFS patients have been shown to have reduced baseline cortisol levels and accompanying

indicators of central adrenal insufficiency, possibly involving modulation of central CRH and 5-HT

feedback loops.

256,334,712,1170 There is less information on HPA parameters in FM patients, with conflicting

findings on whether baseline cortisol is normal or low24,294 and two studies indicating enhanced ACTH

response to CRH.294,534 HPA perturbations in both CFS and FM differ from those seen in primary

depression,

256,534 which is associated with hyperactive HPA function and elevated cortisol levels.1171 As

previously described, investigators at the Bronx VA Medical Center reported that Gulf War veterans do

not differ from nondeployed veterans on baseline measures of cortisol and ACTH, but that both are

significantly reduced in response to dexamethasone challenge, responses that correlate with veterans’

symptom levels and exposures in theater.501,502

Sleep abnormalities. Unrefreshing sleep and difficulties getting to sleep or staying sleep are among the

most commonly-reported problems associated with multisymptom conditions, including Gulf War illness.

Disturbed sleep and lack of sleep, even in healthy individuals, can result in increased levels of pain and

fatigue and reduced levels of cognitive function.885,1059,1300,1319 Identifiable sleep abnormalities have been

described in multiple studies of FM and CFS patients.189,443,580,834,872,1058,1073,1437,1695 Although sleep

difficulties are commonly reported by ill Gulf War veterans, only two reports have described results of

sleep studies in this population. Researchers from Brooke Army Medical Center reported that, of 192

Gulf War veterans evaluated in their CCEP program, 46 (24 %) were referred for formal sleep evaluation

and 16 (8 %) were diagnosed with sleep apnea.1181 Investigators considered this rate to be lower than that

in CFS patients, and comparable to the rate in the general population. University of Texas Southwestern

investigators reported that symptomatic Gulf War veterans did not differ from healthy control veterans in

any measures evaluated in sleep studies.569

Immune parameters. Research studies have assessed diverse immune parameters in CFS patients, and,

to a lesser degree in FM and MCS patients and in Gulf War veterans. As previously indicated, results of

immunological studies in CFS and FM patients have been mixed.

419,603,861,941,1707,1737 Positive findings

most consistently relate to indicators of low-level immune activation or limited deficits in immune

response (reduced activity of NK cells and cytotoxic T cells) in CFS patients.186,208,814,958,1174,1200,1328,1329,1745

Elevated levels of some cytokines have been associated with symptoms of fatigue, cognitive impairment,

muscle pain, respiratory distress, and altered sleep patterns and mood in other medical

conditions224,572,901,1424,1736 and may also be associated with these symptoms in patients with multisymptom

illnesses. A recent study identified elevated levels of white blood cells and cytokines in the cerebrospinal

fluid of a subgroup of CFS patients, pointing to possible immune dysregulation within the central nervous

systems of this group.1099 Alterations in an antiviral pathway (2-5A synthetase/RNAse L) have been

reported in some CFS patients.1122,1511,1543 Subgroups said to be affected include CFS patients with

evidence of viral activation, and those who developed multisymptom illness following chemical

exposures.1510,1733

Many of the immune parameters reported in CFS and FM patients have not been evaluated in Gulf War

veterans. As previously described, however, several research teams have identified evidence of reduced

NK cell function812,1734,1835 and low level immune activation in symptomatic Gulf War veterans.1420,1835

Taken together, these studies indicate that Gulf War illness, as well as CFS and perhaps FM, are

associated with variable immune perturbations, although a signature immune abnormality has not been

clearly established for any multisymptom condition. Studies suggest that reduced NK cell activity may
284  The Nature of Gulf War Illness

be common to both CFS and Gulf War illness. But two studies have reported that measures of cellular

immunity differ between symptomatic Gulf War veterans and CFS patients.1420,1835

Infectious agents in multisymptom illnesses. Infectious agents have long been thought to play a role

in either triggering or perpetuating the symptoms of some patients with CFS and FM. Elevated rates of

fibromyalgia have been reported among patients infected with human immunodeficiency virus, hepatitis

C, and Lyme borreliosis.198,201,348 Prospective studies have also demonstrated that a subset of patients

develop CFS following different types of acute viral infection.209,796,875,1718,1776,1777,1787 Although findings

have been mixed, some studies have identified elevated viral titers in CFS and FM patients who have

been ill for prolonged periods—most prominently human herpes viruses and enteroviruses—suggesting a

possible role for reactivation of latent viruses in multisymptom conditions.

7,186,243,360,471,493,822,1100,1499,1797

An association between mycoplasma infection and chronic multisymptom illness has been suggested for

both veteran and nonveteran populations.402,1118 Standard serological evaluations have not detected

evidence of mycoplasma infection in either Gulf War illness patients525,923 or civilians with CFS.

829

However, studies using specialized polymerase chain reaction (PCR) methods have detected excess rates

of mycoplasma infection in both symptomatic Gulf War veterans355,1732 and in civilians with CFS and

FM.1095,1114,1123,1731,1732

Genetic parameters. A number of studies have indicated that multisymptom illnesses—both in the

general population and in Gulf War veterans—occur at higher rates among individuals with specific

genetic vulnerabilities or predispositions. Fibromyalgia and CFS have been reported to aggregate in

families64,199,1750 with CFS occurring at particularly elevated rates in identical twins of CFS cases.188,1513

Findings related to CFS and HLA genotype have been mixed,783,1429,1693 but several specific genetic

differences have been found to distinguish multisymptom illness patients from healthy controls. These

include associations between CFS and polymorphisms of the corticosteroid-binding globulin gene1550 and

between FM and polymorphisms in both serotonin receptor genes154,452 and a gene that encodes an

enzyme that inactivates catecholamines.546 Chronic fatigue syndrome, but not FM, has been associated

with serotonin transporter gene variants.

545,1094,1141

As previously described, one study has reported that Gulf War illness is associated with a variant in

position 192 of the PON1 gene, which encodes for paraoxonase, an enzyme involved in neutralizing sarin

and organophosphate pesticides.

561 Other studies have reported associations between PON1 enzyme

activity and Gulf War illness or Gulf War service.

645,947,1353 Canadian researchers have reported that

women with MCS are significantly more likely than controls to be heterozygous for the PON1 gene at

positions 192 and 55. 1005 These results are consistent with views that both MCS and Gulf War illness are

related, in some individuals, to biological vulnerability to particular types of environmental exposures.

Multisymptom illness parameters not evaluated in Gulf War veterans. A variety of biological

parameters have been studied in civilian patients with FM and CFS, but have not yet been evaluated in ill

Gulf War veterans. As previously described, recent progress in understanding FM has resulted from

studies demonstrating that the chronic pain of FM likely results from abnormal pain processing in the

central nervous system. Studies have reported that FM patients have abnormally high cerebrospinal fluid

levels of substance P, a neuropeptide involved in pain signal transmission.1333,1702 Additional findings

indicate that FM patients have reduced levels of an enzyme, prolyl endopeptidase, that can break down

substance P as well as other neuropeptides associated with central pain processing.952,1330 Fibromyalgia

patients have also been shown to have reduced levels of norepinephrine metabolites and, in some patients,

reduced serotonin levels.1106,1332,1800,1831 Two studies have reported that CFS patients have reduced levels

of serotonergic receptors and transporters in the brain.258,1815 Increased levels of substance P have been

reported in MCS patients,

804 but not CFS patients.420 None of the neuropeptides studied in relation to

these conditions have yet been evaluated in ill Gulf War veterans.
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  285

In recent years, research teams in the U.S. and U.K. have used microarray technologies to compare gene

expression in the blood cells of CFS patients and healthy controls. Such studies can potentially provide

insights into the pathophysiology of CFS and lay the groundwork for developing biomarkers and

treatments. Genes differentially expressed in CFS patients have included those associated with basic

metabolic processes as well as immune and neuronal function.776,1482,1717,1769 A massive project

undertaken by the U.S. Centers for Disease Control and Prevention (CDC) integrated genomic

information with epidemiologic and clinical data obtained from a large population-based study of CFS

patients and controls.1716 These data, analyzed by multiple groups from different disciplines, supported

previous observations that patients meeting CFS criteria are heterogeneous. Specific differences in gene

expression that distinguished CFS cases from healthy controls included genes related to function of the

HPA axis, immune function, and a number of neurotransmitter systems. More recently, British

investigators have identified seven CFS patient subgroups, based on different patterns of gene expression,

groups that also differed in their clinical characteristics.795 No information of this type is yet available in

relation to Gulf War illness, although a genomic profile study is currently underway at the Miami VA and

another is planned at UTSW.

Epidemiologic comparisons between Gulf War illness and multisymptom conditions in

the general population. From an epidemiologic perspective, Gulf War illness is very different from

multisymptom conditions like CFS and FM. Chronic fatigue syndrome and FM are generally not

identified at high rates in large defined populations, but develop sporadically in different individuals and

under different circumstances. In contrast, Gulf War illness developed within a relatively short time

period in a well-defined group of individuals who were, in 1990, much healthier on average than people

in the general population. After a shared experience, deployment to the Kuwaiti Theater of Operations,

this group developed a much-higher-than-normal rate of unexplained symptoms and multisymptom

illness. Gulf War illness, from this perspective, more closely resembles an illness associated with an

epidemic or a common hazardous exposure than it does CFS or FM.

One of the most striking differences between Gulf War illness and other multisymptom conditions relates

to the population groups who are most affected. In the general population, CFS, FM, and MCS affect

women at much higher rates than men. CFS and MCS also disproportionately affect those age 40-60,

compared to younger and older age groups. Gulf War illness occurs in a distinctly different pattern.

About seven percent of U.S. troops who served in the Gulf War were women.1594 On a proportional basis,

however, women are affected by Gulf War illness at the same464,753,1699 or only slightly higher

rates142,160,1476,1804 than men. Studies have also not found that veterans over age 40 have higher Gulf War

illness rates. In fact, several studies have reported that younger veterans are more affected by Gulf War

illness than older veterans.160,753,1476

As previously described, there has been considerable discussion about the extent to which symptomdefined conditions such as FM, CFS, and MCS themselves represent distinct disease entities. Studies

have indicated a high degree of overlap between patients meeting criteria for these conditions, with 58 –

70 percent of FM patients meeting CFS criteria187,1775 and 40 percent of CFS patients meeting criteria for

MCS.710 In general, Gulf War illness appears not to overlap with these conditions to the same extent,250

although the degree of overlap depends on how Gulf War illness is defined. The largest clinical study of

Gulf War veterans found that only 5-6 percent of Gulf War veterans with multisymptom illness met

criteria for CFS or FM.142 A smaller study from the Pacific Northwest found that, after clinical

evaluation, 25 percent of veterans who met Oregon criteria for Gulf War illness also met criteria for FM,

18 percent met CFS criteria, and 19 percent reported symptoms of chemical sensitivity.160

Treatments for multisymptom illnesses. Identifying effective treatments for conditions whose

pathophysiological mechanisms are not clearly understood has been an ongoing challenge both for Gulf

War illness and for multisymptom conditions in the general population. Over the years, numerous studies

have evaluated the effectiveness of many different types of therapeutic interventions for CFS and FM.
286  The Nature of Gulf War Illness

Most notably, a burgeoning number of clinical trials have evaluated new pharmacologic treatments for

FM in recent years.

8 The majority of tested drugs act on one or more neurotransmitter systems. Drugs

that inhibit uptake of both serotonin and norepinephrine have been shown to provide significant

improvement in pain and other symptoms for FM patients, and global improvements in function. These

include pregabalin,295,1011 milnacipran,479,886,1724 and duloxetine.65,66 Symptomatic and functional

improvements have also been reported from early studies of the serotonin reuptake inhibitor

paroxetine,1176 the selective serotonin-3 antagonist tropisetron,594,1382 the dopamine agonist

pramipexole,

619 and the synthetic cannabinoid nabilone.1422 Pregabalin, marketed as Lyrica, became the

first drug to receive FDA approval for the treatment of FM in 2007.1666 In 2008 a second drug,

duloxetine (trade name Cymbalta), was approved for FM treatment.398

Studies of graded exercise and cognitive behavioral therapy (CBT) have consistently demonstrated

benefit for FM patients, yielding improvements in both functional status and symptoms.196,962,1318,1410

Antidepressant medications have also been shown to benefit some FM patients, providing significant

improvements in somatic symptoms, as well as mood and functional status. 1154,1318,1545 Researchers report

that the most optimal FM treatment strategies combine pharmacologic with nonpharmacologic

interventions.292,1256,1318 A variety of complementary therapies have been suggested for their potential in

benefiting FM patients, but relatively few have been studied.293 Acupuncture treatment has been

evaluated in multiple trials for its effectiveness in relieving FM symptoms, with mixed results.73,128,588,1413

Suggestive evidence of benefit has also been reported from small studies of massage therapy166 and

several nutritional supplements.701,1023,1331,1526

A 2001 systematic review identified 350 CFS treatment studies, including 44 controlled treatment trials,

in the published literature.1783 This and similar projects have identified a number of treatment approaches

that appear to benefit CFS patients, providing improvements both in symptoms and level of function.

However, evidence related to many treatments is often too scant to provide firm conclusions.

1084,1286,1783

The most consistent treatment benefits for CFS have been demonstrated from studies of graded exercise

and CBT.389,1233 Studies of immune-related therapies have provided mixed findings1084,1783 with the most

promising results obtained from infusions of the drug Ampligen.1501,1510 Studies indicate that

antidepressant medications provide limited benefits for some CFS patients, with improvements in energy

that are not related to the antidepressant effects of the drugs.606,1097

Studies have reported that glucocorticoids may provide some symptomatic benefit for CFS patients,

257,1004

but one concluded that adverse effects of these medications outweigh their benefits.1004 Smaller studies

have also suggested therapeutic benefit from antiviral drugs in CFS patients with evidence of herpes virus

infection,825,888 from the antibiotic azithromycin,1714 and from a multimodal treatment that addresses

endocrine and nutritional parameters identified in individual patients.1529 Preliminary indications of

benefit have also come from studies evaluating complementary therapies such as osteopathic

treatment,1197 massage therapy,437 magnesium,286 NADH,451 and essential fatty acids.120 The quality and

size of these studies, however, were not sufficient to support firm conclusions concerning treatment

effectiveness.

Graded exercise therapy and CBT have also been studied for their effectiveness in treating Gulf War

illness in a large multicenter trial conducted by VA and DOD.354 Cognitive behavioral therapy provided

substantial improvement for just 18 percent of ill Gulf War veterans, compared to the 11 percent who

improved with usual treatment, while graded exercise provided no benefit over usual treatment. Results

indicated these treatments may be less helpful for veterans with Gulf War illness than for civilian patients

with CFS and FM.639

Very little scientific information is available regarding treatments that are effective for MCS. Although

not evaluated in formal trials, patients have reported that avoidance of chemicals and odors that

exacerbate MCS-related symptoms has been most useful for them in reducing symptoms of this
Gulf War Illness in Relation to Multisymptom Conditions in the General Population  287

condition.488 Chemical avoidance has not been studied in ill Gulf War veterans, although one VA

clinician has testified that her use of this approach, in conjunction with dietary modifications, provided

improvement for her Gulf War veteran patients with chemical sensitivity.

1399

Summary. Gulf War illness in relation to multisymptom conditions in the general

population. 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. Research studies, however, have identified both similarities and

differences between Gulf War illness and these conditions. The prevalence of CFS in Gulf War veterans

is unique, and dramatically higher than CFS rates in nondeployed veterans and 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 used to define CFS, FM, and MCS do not adequately

describe the chronic symptom pattern that affects Gulf War veterans at excess rates. Only a fraction of

veterans with Gulf War illness can be diagnosed with CFS, FM, or MCS. The epidemiologic profile of

Gulf War illness is also unique. Unlike CFS and FM, Gulf War illness occurs in a pattern consistent with

a common exposure, and affects female and male veterans at about the same rate.

Studies have also provided indicators of physiological similarities and differences between Gulf War

illness and other multisymptom conditions. Many objective measures associated with CFS and FM in the

general population, however, have not yet been evaluated in veterans with Gulf War illness. General

similarities may be 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 genetic

variants of the PON1 enzyme. In contrast, studies have identified immune parameters that differ between

veterans with Gulf War illness and civilians with CFS, and neuroimaging studies have not thus far

identified specific abnormalities that are common to Gulf War illness and CFS or FM. Cognitive

behavioral therapy and exercise were found to be less beneficial for Gulf War illness than for CFS and

FM. But the extent to which other treatments useful in treating CM and CFS could improve symptoms

and function in ill Gulf War veterans is not known.

Much remains to be learned about the pathophysiology of Gulf War illness, as well as the biological

mechanisms that underlie conditions such as CFS, FM, and MCS that occur in the general population.

Because of possible similarities in some physiological processes underlying these conditions, it is

important that findings related both to biological abnormalities and treatments for these conditions be

evaluated in veterans with Gulf War illness. But until Gulf War illness is better characterized

physiologically, the degree to which it overlaps with other multisymptom conditions remains largely a

matter of conjecture.
288  The Nature of Gulf War Illness

Recommendations

Research studies have demonstrated both differences and similarities between Gulf War illness and

multisymptom conditions found in the general population. Symptom complexes consistent with defined

chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivity (MCS) are found

in Gulf War veterans at elevated rates, but account for only a fraction of the excess morbidity affecting

Gulf War veterans. Research related to these conditions may provide useful insights regarding biological

processes that underlie veterans’ symptoms, treatment interventions that may benefit ill veterans, and

research methodologies useful in studying syndromes defined primarily by symptoms. The Committee

therefore recommends the following research:

 Studies that determine the extent to which objective measures that distinguish CFS, FM, and MCS

patients from healthy controls are also associated with Gulf War illness. Such studies should include

comprehensive evaluation of autonomic function and hypothalamic-pituitary-adrenal parameters in ill

veterans, studies of immune and inflammatory parameters associated with multisymptom illnesses,

evidence of infection by herpes viruses and enteropathogens, identification of cerebrospinal fluid

levels of neuropeptides associated with central pain processing, and genomic and proteomic

evaluation of blood and cerebrospinal fluid of veterans with Gulf War illness.

 Pilot studies and, where indicated by preliminary evidence, clinical trials to determine whether

veterans with Gulf War illness benefit from therapies shown to improve the health of patients with

FM and CFS.

The Committee also recommends that federal Gulf War illness research programs coordinate efforts

with federal research programs that focus on other multisymptom conditions like CFS and FM.
Federal Research on Gulf War Illness and the Health of Gulf War Veterans  289

4| Federal Research on Gulf War Illness and

the Health of Gulf War Veterans

In addition to reviewing scientific studies and government reports, the Committee is charged with

reviewing federal research programs established to address health consequences of the 1991 Gulf War.

As with other aspects of its work, the Committee’s assessment of these programs is guided by the premise

that the purpose of this research is, ultimately, to improve the health of ill Gulf War veterans. In its

ongoing review of Gulf War research, the Committee has emphasized the importance of high quality

studies that provide insights into biological processes underlying veterans’ symptoms or contribute

directly to identifying diagnostic tests and treatments. Although the government has sponsored some

studies of this nature, these central objectives have not historically been the focus of federal Gulf War

research programs.

Developing research programs capable of determining the nature and causes of Gulf War illness, and

identifying effective treatments, has proven to be a difficult challenge for the agencies tasked with this

responsibility. In the seventeen years since the war, hundreds of millions of federal dollars have been

spent on Gulf War research. Many federally-funded studies have provided valuable insights regarding the

health of Gulf War veterans. But much of the federal research has not usefully advanced understanding

of Gulf War illness or other Gulf War-related health problems. Consequently, important questions have

remained unanswered. The unsatisfactory pace of progress can be attributed to a variety of factors,

including federal agencies’ long-time emphasis on research that was peripheral to priority Gulf War

health issues.

Some observers have suggested that the Departments of Defense and Veterans Affairs should not have

been given primary responsibility for conducting and managing research on Gulf War–related health

problems.137,1562,1684 One reason relates to the scientifically complex nature of the required research and

the need for a multifaceted, highly coordinated effort involving top investigators—the type of scientific

program for which these agencies are not ideally suited. There is also a common perception that federal

policy makers have not vigorously pursued key research in this area and that federal agencies have

disincentives—whether political or fiscal—for providing definitive answers to Gulf War health questions.

Historically, the situation parallels delayed federal responses to health problems stemming from

hazardous exposures in earlier wars, such as consequences of radiation exposure in World War II and

effects of herbicides in Vietnam. Although cynical, such views are reinforced by the slow progress made

by federal agencies in addressing fundamental questions about the nature, causes, and treatments for Gulf

War illness.

In its 2004 report, the Committee described systemic problems in the federal Gulf War research effort.

Federal programs were not designed or managed to achieve identified research objectives related to Gulf

War illness or other Gulf War health issues.1268 The Committee has had continuing concerns about Gulf

War research programs since 2004. Regrettably, seventeen years after the war, this research still has not

provided tangible results in improving the health of ill Gulf War veterans. In 2006 and 2007 however,

new developments in the management and federal funding of Gulf War research have provided positive

indications that priority Gulf War research issues can now be more effectively addressed.
290  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

Historical Funding and Management of Federal Gulf War Research

Since 1992, the U.S. federal government has reported expenditures of hundreds of millions of dollars for

hundreds of individual research projects related to the health of Gulf War veterans.340 This research has

been funded by three agencies: the Department of Defense (DOD), the Department of Veterans Affairs

(VA) and the Centers for Disease Control and Prevention (CDC) within the Department of Health and

Human Services. The Persian Gulf Veterans Coordinating Board, an interagency committee of

representatives from the three agencies, was formed in 1994 to plan and coordinate the federal response to

health problems affecting veterans of the 1991 Gulf War1274 Since 1997, this board and its successor, the

Deployment Health Working Group, have provided annual reports to Congress describing federally

sponsored research on Gulf War veterans’ illnesses. Although the reports identify substantial federal

expenditures for Gulf War research, administration and use of these funds have historically been

problematic.

As demonstrated throughout the present report, many individual federally-sponsored studies have been

highly productive and provided extremely valuable insights into the nature and causes of Gulf War

illness. Overall, however, there have been persistent shortcomings in federal Gulf War research

programs. Foremost have been problems related to the specific types of studies selected for funding and

the overall lack of cohesion and results-focused management of the federal Gulf War research effort.

Many of the funded projects identified as “Gulf War research” in the federal portfolio have had little if

anything to do with the health of Gulf War veterans. And a substantial proportion of funded studies have,

historically, focused on stress and psychiatric disease as the central explanation for Gulf War illness,

despite accumulated evidence to the contrary.

Federal expenditures for Gulf War research. The Deployment Health Working Group, each year

in an annual report to Congress, identifies the amount of federal funding allocated for studies identified as

research on Gulf War veterans’ illnesses. As shown in Figure 1, total funding levels have varied from

year to year, reaching their peak between 1999 and 2001, when total expenditures ranged from 43 to 50

Figure 1. Total Funding For Studies Identified as Gulf War Research by Federal Agencies:

1994 – 2007

0

10

20

30

40

50

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Annual Funding ($ millions)

Direct Costs Indirect Costs

Sources: Deployment Health Working Group Annual Reports to Congress, 2003-2007336-340

Note: References indicate that indirect costs were calculated as 30% of direct costs.336
Historical Funding and Management of Federal Gulf War Research  291

million dollars annually. In all, 345 distinct projects categorized as Gulf War research were sponsored by

the federal government between 1992 and 2007.340

The exact amount spent by the U.S. government on Gulf War research has been obscured to some degree

by differences in how federal funding has been calculated and presented to Congress from year to year.

For example, early interagency reports identified annual funding totals, by year, from 1994 onward.

Since 2004, funding details for projects funded more than 10 years earlier have been dropped from the

reports, and expenditures for those projects no longer included in cumulative totals. In addition, reports

in some years identified funding for both direct and indirect costs, but in other years included only direct

costs. In some cases, total expenditures reported for a given year have varied. For example, federal Gulf

War FY2005 research expenditures were reported as $16.2 million in the 2005 Annual Report to

Congress, but later reported as $21.6 million in the 2006 Annual Report to Congress, and as $20.1 million

in the 2007 report.338-340 Such year-to-year inconsistencies have introduced substantial uncertainty in

identifying the precise amount spent by the federal government on Gulf War research.

Taking into account these uncertainties, estimated federal expenditures between 1994 and 2007 for

projects identified as Gulf War Research have totaled $340 million in direct costs, and $442 million if

indirect costs are considered at the historical rate of 30 percent, as indicated in some interagency annual

reports to Congress. These summary estimates are based on figures provided in the Deployment Health

Working Group’s most recent Annual Report to Congress for fiscal years (FY) 1997 through 2007340 and

pre-1997 figures provided in the 2003 Annual Report to Congress.336

The Committee reported in 2004 that the majority of federal funding for Gulf War research had

historically been provided by the Department of Defense. But as shown in Figure 2, DOD support for

Gulf War illness research declined substantially after 2001. Few new Gulf War projects were funded by

DOD between 2003 and 2006, although support continued for previously approved multiyear projects.

Research funded by the U.S. Department of Health and Human Services has consistently represented only

a small fraction of total Gulf War expenditures. Total expenditures have ranged from $1.6 million

annually between 1998 and 2000 to less than $0.5 million annually between 2004 and 2007.

Figure 2. Direct Funding for Studies Identified as Gulf War Research

by the U.S. Department of Defense and U.S. Department of Veterans Affairs: 1994 - 2007

0

10

20

30

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Annual Funding ($ millions)

Department of Defense Funding Department of Veterans Affairs Funding

Sources: Deployment Health Working Group, Annual Reports to Congress, 2003-2007336-340
292  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

Since 2002, VA has sponsored a steadily increasing proportion of federal Gulf War research, although

this increase has not matched the dramatic decline in funding at DOD. The large majority of new Gulf

War research projects initiated after 2003 have been funded by VA.

As pointed out in the Committee’s 2004 report, if progress in the Gulf War research effort were to be

measured by the number of dollars spent, or the number of projects funded, it might be argued that the

federal government has mounted an impressive research effort on behalf of ill Gulf War veterans. But the

Committee is committed to assessing federal Gulf War research in terms of its scientific merit and

progress made in improving the health of ill veterans. Although substantial funding has been allocated

for studies identified as “Gulf War research” by federal agencies since 1994, the Committee has identified

significant problems related to the effective use and management of these funds.

Many “Gulf War” studies in the federal Gulf War research portfolio have not addressed

Gulf War-related issues. A prominent concern over the years has been that many of the studies

identified as “Gulf War Research” in the federal research portfolio have been unrelated, or only

marginally related to the health of veterans who served in the 1991 Gulf War. Representative examples

are provided in Table 1.

Table 1. Examples of Federally-Funded Studies Identified as “Gulf War Research”

that have Little Relevance to Health Problems Resulting from Gulf War Service

Project

Number

Year Initially

Funded

Amount

Funded Study Title

DOD-143 2000 $18,224,000 Millennium Cohort Study

DOD-108 1999 $ 1,107,996 Health Status of Current National Guard Members

VA-047 1997 $ 1,089,060 Retrospective Verification of Mustard Gas Exposure

DOD-145 2001 $ 800,000 Early Intervention Research Program to Enhance Soldier Resilience

DOD-140 2001 $ 764,879 U.S. Department of Defense Surveillance for Neoplasms in Infancy

DOD-097 1999 $ 626,244 Surveillance of B. Pertussis Among Military Trainees with Respiratory

Disease: Development and Validation of a Highly Sensitive PCR and Beacon

Probe based Methods for Diagnosis of Pertussis

DOD-083 1997 $ 299,700 Risk for Stress-Related Substance Abuse: Effects of Family History of

Alcoholism

Sources: Deployment Health Working Group Annual Report to Congress, 2006-2007339,340

The Millenium Cohort study, for example, received over $18 million in DOD funding between 2000 and

2007. This ambitious project involves long-term assessment of an initial sample of nearly 80,000

personnel serving in the military in and after October, 2000.522,1336 The study includes relatively few

personnel who served in the 1991 Gulf War—all presumably in good enough health to remain in the

military 10 years after the war.1427 Some other projects identified as “Gulf War Research” in interagency

reports to Congress have even less connection to the health consequences of Gulf War service. These

include studies of infectious diseases, such as pertussis, never identified in Gulf War veterans. It also

includes studies to develop tests for mustard gas, although DOD has identified only one Gulf War veteran

with a possible, but “indeterminate” exposure to mustard.1614

The Committee is not questioning the scientific merit or the need for the types of projects listed in Table

1. But labeling these studies as “Gulf War Research” in Congressional reports is misleading and has
Historical Funding and Management of Federal Gulf War Research  293

given the impression to Congress and the general public that more federal funding has been provided for

research on the health of Gulf War veterans than has actually been the case. Use of Gulf War research

funds for studies with minimal connection to the health of Gulf War veterans has also meant less support

for studies that do specifically address health consequences of the 1991 Gulf War.

Excess emphasis on studies of stress and psychiatric illness in federally-funded Gulf

War research. A second major concern relates to the use of substantial amounts of Gulf War research

funding for studies focused exclusively on psychiatric disorders and psychological stress. Putative

relationships between Gulf War illness, wartime stress, and psychiatric disorders were reasonable areas to

investigate in the early years after the war, when little was understood about Gulf War-related conditions.

The emphasis on studies focused on stress and psychiatric disorders in the federal Gulf War research

portfolio has continued into recent years, however, long after multiple studies demonstrated that Gulf War

illness is not explained by psychological stress and that relatively few Gulf War veterans have psychiatric

disorders.

The Committee considers research on the effects of combat and war-related trauma to be extremely

important for military populations in general. But such issues are notably less prominent among Gulf

War-related health concerns, compared to other warzone deployments.689,969 Among the many unique

aspects of the 1991 Gulf War were the short duration of hostilities, the limited number of troops affected

by combat and other traumatic experiences, and the relatively low number of Gulf War veterans who

developed psychiatric disorders. The use of significant amounts of Gulf War research funding for studies

focused on stress has been inappropriate, based on what is known about the Gulf War and the health of

Gulf War veterans.

The Committee also noted that the prominence of psychological research in the federal Gulf War research

portfolio has not been readily apparent in interagency reports to Congress. These reports categorize

federal Gulf War research projects into five topic areas: (1) Brain and Nervous System Function, (2)

Environmental Toxicology, (3) Immune Function and Infectious Diseases, (4) Reproductive Health, and

(5) Symptoms and General Health.339,340 There is no category for psychological or psychiatric research.

Instead, studies of this type are identified as “Brain and Nervous System Function” research, the category

that has historically included the largest number of Gulf War projects. It includes all research—both

clinical and basic laboratory studies—related to stress and psychiatric illness, along with research that is

more commonly considered brain and nervous system research, such as neuroimaging and ALS studies.

As shown in Table 2, examples include a nearly $5 million study of cognitive behavioral therapy for

posttraumatic stress disorder, primarily due to sexual trauma, that did not focus on Gulf War veterans,1364

a $1 million trial of two medical treatments for PTSD in OIF/OEF veterans, and a trial of a provider

education program to improve treatment for major depression in primary care.

The types of studies listed in Table 2 may have importance for military populations in general, but would

more accurately be identified as psychological or psychiatric research than as research on the brain and

nervous system. Further, these projects are not focused on Gulf War veterans or health issues that

prominently affect Gulf War veterans. In identifying stress-related studies as brain research in

interagency reports to Congress, the Deployment Health Working Group has obscured the historical

emphasis on stress and psychiatric research in federal Gulf War research programs, and provided an

inflated impression of the number of studies focused on central nervous system abnormalities in Gulf War

veterans.

In its 2004 report, the Committee pointed out that 57 percent of VA’s projected 2003 Gulf War research

expenditures would support studies of psychological factors and stress.335,1268 In response, then-Secretary

of Veterans Affairs Anthony Principi pledged that VA Gulf War research funding would no longer be

used for studies focused on stress as the central cause of Gulf War illness.473,1644,1648 Although previously
294  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

Table 2. Examples of Psychiatric and Stress-Related Studies Identified as

Gulf War Research on Brain and Nervous System Function in Reports to Congress

Project

Number

Year First

Funded

Amount

Funded Study Title

DOD-125

VA-74

2001 $4,892,743 A Randomized Clinical Trial of Cognitive-Behavioral Treatment for PTSD in

Women

DOD-166 2005 $1,000,000 A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat StressInduced PTSD Nightmares and Sleep Disturbance

DOD-144 1999 $ 954,000 Psychological Health Screening: Methods and Metrics for Deployed Forces

VA-087 2002 $ 572,271 Improving Outcomes of Depression in Primary Care

VA-086 2002 $ 410,494 A Clinical Trial of Magnetic Stimulation in Depression

DOD-092 1997 $ 249,700 Traumatic Experiences Persistently Enhance Cue-dependent Learning:

toward an Animal Model of Chronic Stress and Posttraumatic Stress Disorder

DOD-082 1997 $ 172,000 Feasibility of Developing a Registry of PTSD Affected Veteran Sib Pairs

Source: Deployment Health Working Group Annual Report to Congress, 2006339

approved studies continued to be funded after the Secretary’s announcement, VA has now sharply

reduced the number of newly-funded Gulf War studies focused on stress and psychiatric disorders.

Lack of a cohesive federal Gulf War research program managed to achieve identified

scientific objectives. A pervasive problem, described over the years in reports from the U.S. General

Accounting Office,1672,1677,1682 and more recently in the Research Advisory Committee’s 2004 report,1268

relates to the lack of management of the overall federal Gulf War research program to achieve identified

research goals. Specifically, the federal Gulf War research effort has not been organized or managed to

meet priority objectives such as identifying diagnostic markers and treatments for Gulf War illness, or

determining its cause.

In 1993, the “Persian Gulf Interagency Research Coordinating Council” was established to plan and

coordinate research on the health of Gulf War veterans. This task is now assigned to a successor group,

the Research Subcommittee of the Deployment Health Working Group.1274 The interagency group

developed a working research plan in 1995 that was subsequently revised.1198 The group’s plan initially

targeted three priority research areas related to the health of Gulf War veterans, and later identified 21

priority research questions. These questions were reformulated into a corresponding list of 21 research

topics in 2004.337 Interagency annual reports to Congress point out that “the comprehensive Gulf War

research portfolio has addressed each of these 21 questions, and relevant results have been published on

each one.”339 No assessment is provided, however, of the degree to which long-established priority

questions have been answered or research objectives have been met by the federal Gulf War research

effort.

The Committee recognizes that over the years, research studies have been funded that relate, in some

way, to each of the 21 identified research categories. But this falls considerably short of a wellcoordinated federal program with a management structure capable of achieving identified research

objectives. Such a program requires that strategies be in place to identify and fund specific studies most

capable of providing long-needed answers to priority questions. It also requires ongoing assessment of

the degree to which identified objectives have been met or require revision.

Identifying funded projects according to which of 21 research categories they fall into is not the same as

establishing and managing a research program to provide answers to priority scientific questions. The
Gulf War Research at the Department of Veterans Affairs  295

interagency group tasked with coordinating the Gulf War research effort appears to have served primarily

in the role of cataloguing and reporting federally-sponsored studies identified as “Gulf War research,” not

as managers of an effective, well-coordinated federal research program.

In its 2004 report, the Committee’s initial programmatic recommendation was that VA, in conjunction

with other federal agencies, develop a comprehensive federal research plan to address priority Gulf War

research questions. Since the Committee’s 2004 report, a number of funding and management changes

have taken place in the federal Gulf War research effort. For example, most newly-funded Gulf War

research projects have been sponsored by VA, following commitments made by the Secretary of Veterans

Affairs to support an expanded Gulf War research effort.1640,1644 In contrast, the Department of Defense

has greatly reduced funding for Gulf War-specific research. But over this period, regrettably, the federal

Gulf War research portfolio has generally continued to reflect a haphazard mix of studies not indicative of

a clear scientific plan or coordinated effort.

The overall focus and management of federal Gulf War research in recent years is described below for

each of the three contributing agencies. A number of programmatic changes and improvements have

been evident during this time, particularly at VA. The most significant changes in the direction and

management of Gulf War research, however, have occurred as a result of Congressional actions in 2006,

which provided funding for dramatic new directions in Gulf War research at both VA and DOD.

Gulf War Research at the Department of Veterans Affairs

In 2004, the Committee described shortfalls in the types of studies that constituted VA’s Gulf War

research portfolio, and problems in methods used by VA for soliciting and funding Gulf War research

proposals. At that time, VA funding projections for 2003 indicated that the majority of VA’s Gulf War

research spending would support studies related to stress and psychiatric illness.335,1268 Since then, the

Committee has continued to assess the focus of VA-funded Gulf War research studies and the processes

used for funding research proposals.

VA Gulf War programmatic changes and initiatives. In its 2004 report, the Committee described

administrative issues that had contributed, over the years, to an unacceptable profile of research projects

in VA’s Gulf War research portfolio. One major problem related to the content of VA’s research funding

announcements. Another was VA’s use of standing merit review panels for scientific review of Gulf

War-related proposals. This meant that Gulf War research studies proposed by VA investigators were

often judged for their scientific merit by scientists unfamiliar with research issues and findings on the

health of Gulf War veterans. Since the 2004 report, both of these issues have been directly addressed by

VA’s Office of Research and Development (ORD).

When it became apparent midway through FY2004 that VA had funded less than $500,000 of Secretary

Principi’s pledge of up to $20 million in new Gulf War research that year,1640 VA ORD issued a special

request for applications (RFA) for Gulf War research in April, 2004. This was the first VA Gulf Warrelated solicitation to specifically prioritize research on physiological consequences of service in the 1991

Gulf War. The RFA indicated that VA was most interested in funding studies on immune and

neurological processes associated with Gulf War illness, and neurological disorders in Gulf War

veterans.1658 The announcement attracted 49 proposals, which were reviewed by a special ad-hoc

scientific panel that included scientists with expertise in Gulf War illness, epidemiology,

neuropsychology, and neurotoxicology.497 Fourteen new Gulf War projects were funded in response to

the 2004 Gulf War RFA.

The Department of Veterans Affairs also issued a special Gulf War request for proposals (RFP) in June,

2005. This solicitation emphasized VA’s interest in funding projects focused on understanding and
296  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

treating Gulf War illness, on long-term health effects of Gulf War exposures, and on identification of

biomarkers for Gulf War illness.1659 Also for the first time, the announcement specified that proposals

whose principle focus was psychological stress or psychiatric disorders would not be funded. Forty-four

proposals were submitted in response to the RFP and again reviewed by a special panel of scientists with

expertise relevant to Gulf War illness, resulting in the selection of 12 new projects for funding.846

The Committee commends VA ORD for improvements in the 2004 and 2005 Gulf War funding

announcements. The Committee also applauds ORD’s efforts to include scientists with expertise

specifically relevant to Gulf War illness and effects of Gulf War exposures in the scientific review

process. VA’s expanded research effort dedicated to Gulf War illness and effects of Gulf War exposures,

evident in 2005 and 2006, consisted largely of projects funded under the 2004 and 2005 funding

announcements.

The Department of Veterans Affairs Office of Research and Development also informed the Committee

in December, 2005, that VA would develop and fund a Gulf War brain tissue bank and DNA

biorepository. The Gulf War Biorepository Trust would be managed by VA’s Massachusetts Veterans

Epidemiology Research and Information Center (MAVERIC) in Boston, which received nearly $1

million in funding for the project in early FY2006. The Committee had recommended, in 2004, that VA

develop a Gulf War brain tissue bank.1268 It considered this an important initiative to allow study of brain

tissues in deceased veterans whose health may have been affected by exposures and events of the Gulf

War.

Preliminary plans for establishing the Gulf War Biorepository Trust were presented to the Committee in

November, 2006.441,1225 The Committee was impressed by the level of commitment and professionalism

brought to the effort by the tissue bank management team. Committee members were concerned,

however, to learn that all tissue and DNA samples to be collected for the planned “Gulf War”

biorepository would come from the general population of veterans enrolled in VA’s ALS Registry. In

2006, this included approximately 1,500 veterans with ALS in the VA system—deployed and

nondeployed veterans of all ages and eras, about 50 of whom had served in the 1991 Gulf War. As a

result, VA’s “Gulf War” biorepository, as currently designed, will actually be an ALS biorepository.

Although program administrators indicated their interest in expanding the effort to include tissues from

Gulf War veterans with other conditions, including Gulf War illness, no such project has yet been

developed or funded. As the Committee has previously pointed out, brain tissues of symptomatic Gulf

War veterans could be a particularly valuable resource for determining the specific areas and types of

neuropathology affecting veterans with Gulf War illness.

The Department of Veterans Affairs has not issued additional funding announcements focused on the

health of Gulf War veterans since 2005. However, a significantly revised approach to sponsoring Gulf

War research at VA occurred in 2006. The changes have the potential to address ongoing concerns

regarding integration and management of a coordinated, multidisciplinary Gulf War research effort.

Focus of VA Gulf War research: 2003 – 2006. Table 3 identifies funding totals for projects

identified as VA-sponsored Gulf War research in interagency reports to Congress from 2003 through

2006. Yearly amounts are further categorized according to the focus of the funded studies, as identified

by the Committee. Overall, total funding for VA’s Gulf War research portfolio increased from $4.6

million in 2003 to $12.9 million in 2006.

A number of VA research projects of note were funded during this period. These include the previouslydescribed Gulf War Biorepository Trust, neuroimaging projects at the Boston and San Francisco VAMCs,

studies of immune function in ill Gulf War veterans at the Miami VAMC and hypothalamic-pituitaryadrenal function in Gulf War veterans at the Bronx VAMC. Three studies were funded to evaluate

treatments for ill Gulf War veterans. These included a trial of continuous positive airway pressure
Gulf War Research at the Department of Veterans Affairs  297

Table 3. Department of Veterans Affairs Gulf War Research: 2003-2006

Funding Levels and Focus of Studies

Focus of VA Gulf War Research Studies†

2003

Funding*

(% of 2003 funds)

2004

Funding*

(% of 2004 funds)

2005

Funding*

(% of 2005 funds)

2006

Funding*

(% of 2006 funds)

Gulf War illness, effects of Gulf War exposures $ 1,101,310

(24%)

$ 1,107,405

(14%)

$2,726,875

(29%)

$3,729,011

(29%)

Other health problems related to Gulf War service $ 72,700

(2%)

-

(0%)

$ 84,468

(1%)

$ 336,582

(3%)

ALS research $ 458,829

(10%)

$ 754,537

(10%)

$3,309,588

(35%)

$5,039,163

(39%)

Psychological stress, psychiatric illness $ 2,379,814

(51%)

$ 3,239,545

(42%)

$1,063,884

(11%)

$1,235,409

(10%)

Peripheral or no clear relevance to Gulf War service $ 633,587

(14%)

$ 2,570.284

(34%)

$ 2,299,864

(24%)

$ 2,601,898

(20%)

Total VA Gulf War Research Funding, by Year* $ 4,646,510

(100%)

$ 7,671,771

(100%)

$ 9,484,679

(100%)

$12,942,066

(100%)

*Direct costs, as reported in Deployment Health Working Group Annual Report to Congress for each year336-339

†Research focus of individual projects categorized by Research Advisory Committee on Gulf War Veterans’ Illnesses

(CPAP) treatment for dysregulated sleep in ill Gulf War veterans, antibiotic therapy for irritable bowel

syndrome in Gulf War veterans, and a telemedicine trial of cognitive behavioral therapy for veterans with

Gulf War illness. Despite VA pledges in 2004 and 2005 to fund a research center devoted to evaluation

of treatments for Gulf War illness, no such treatment research center was funded during this

period.473,846,1648

Overall, the profile of studies included in VA’s Gulf War research portfolio differed markedly between

2003 and 2006, as detailed in Table 3. This was due, in part, to completion of previously-funded projects

and addition of new studies funded in connection with VA’s 2004 and 2005 Gulf War research

solicitations. But the most significant changes during this period were the result of administrative

decisions made by VA ORD that determined which studies were identified as “Gulf War research” in a

given year. Among the most prominent changes in VA’s Gulf War research portfolio was the reduced

level of funding for studies focused on stress and psychiatric disorders—from 51 percent of total funds in

2003 to just 10 percent in 2006. In 2003-2004, the single project that received the most funding in VA’s

Gulf War research portfolio was the clinical trial of behavioral therapy for PTSD in women. That project

received $3.3 million in 2003-2004, but no additional VA Gulf War research funding in 2005 and 2006.339

During the same period, both previously funded and recently approved ALS studies were newly identified

as “Gulf War Research” by VA ORD. As a result, the amount allocated for ALS research in VA’s Gulf

War portfolio increased more then 10-fold, from less than $500,000 in 2003 to over $5 million in 2006.

This had a dramatic impact on the total level of funding and overall profile of VA’s Gulf War research

portfolio. The largest single recipient of VA Gulf War research funding in 2005 and 2006 was VA’s

National ALS Research consortium, funded at nearly $2 million over the two years. The second largest

allocation was for VA’s National Registry of Veterans with ALS, which received $1.7 million in 2005-

2006. Overall, 35-39 percent of total funding identified as “Gulf War research” in 2005 and 2006 was for

ALS research. This supported 14 projects, only four of which included any Gulf War veterans or any

element related to Gulf War service. And those four projects did not focus specifically on ALS in
298  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

connection with the Gulf War. They include, for example, VA’s National ALS Registry program, which

now includes over 2,000 veterans with ALS, only 60 of whom served in the Gulf War.

Research to better understand the causes of ALS and identify effective treatments is extremely important.

This fatal condition has been found to affect Gulf War veterans at twice the rate of nondeployed era

veterans.636 But relatively few Gulf War veterans have ALS, and they represent only a small fraction of

veterans in the VA system with ALS. The causes of ALS in Gulf War veterans cannot be presumed to be

the same as those for inherited forms of ALS or age-associated ALS seen in the larger veteran population.

In general, identifying the millions of dollars spent for all types of ALS research at VA as “Gulf War”

research is misleading, and has provided an inflated impression of the amount of funding provided for

research on the health of Gulf War veterans.

In recent years, VA also continued to identify other types of studies as “Gulf War research” that were not

related to the health of Gulf War veterans, or only peripherally so. Examples include animal research

evaluating effects of vaccines not used in the Gulf War, research on developmental factors in sensitivity

to alcohol withdrawal, basic science research on proteins that may regulate progression of astrocytomas,

genetic differences related to normal circadian sleep variation in mice strains, and preclinical studies that

may provide insights concerning vaccine prevention of leishmaniasis.339 Research questions addressed by

such studies, while perhaps worthwhile, had no direct bearing on understanding the nature, causes, or

treatments of health problems affecting veterans of the 1991 Gulf War. Studies of this type have

constituted up to 34 percent of VA’s Gulf War portfolio in recent years, and accounted for 20 percent of

VA’s Gulf War research expenditures in 2006.

The Committee was pleased to note the increase in total funding allocated in 2005 and 2006 for studies

focused on Gulf War illness and effects of Gulf War exposures. Improving the health of Gulf War

veterans requires that these Gulf War-specific areas be given high priority, since they are most relevant to

the largest number of ill veterans. It was troubling, however, that the overall percentage of VA Gulf War

research funding allocated to these areas remained relatively unchanged during this period. That is, from

2003 through 2006, just 24-29 percent of VA’s Gulf War funding supported studies related to Gulf War

illness and effects of Gulf War exposures. An additional three percent or less each year was for studies

related to other Gulf War-specific health concerns, such as studies to identify cancer and mortality rates in

Gulf War veterans. So as recently as 2006, a total of just 32 percent of VA’s “Gulf War Research”

funding was used for studies specifically focused on the health of Gulf War veterans. As the proportion

of projects related to stress and psychiatric conditions in the portfolio decreased after 2003, those studies

were largely replaced by ALS projects.

Recent VA Gulf War research program developments. The Committee’s 2004 report

recommended that Congress add an additional $15 million to VA’s research budget specifically for Gulf

War research. The Committee also recommended that VA work with other federal agencies to develop a

comprehensive plan to address Gulf War illness. This would include a strategic VA research program

managed to address priority research questions related to the health of Gulf War veterans.

In 2006, Congress added $19 million to VA’s requested research budget, and specifically directed that at

least $15 million be used annually to support a center of excellence for Gulf War illness research.1685 The

new center was to be a joint collaboration between VA and the University of Texas Southwestern

(UTSW) Medical School in Dallas. Since 1995, UTSW investigators have conducted an extensive Gulf

War research program, under the direction of Dr. Robert Haley. This program produced a number of the

neuroimaging results described in Section 3 of the present report, as well as other important findings

related to the health of Gulf War veterans.

In response to the 2006 Congressional directive, VA has worked with UTSW to develop the “Gulf War

Illness and Chemical Exposure Research Program” at UTSW. A memorandum of understanding between
Gulf War Research at the Department of Veterans Affairs  299

VA and UTSW to establish the center was signed in 2006.1645 In 2007, VA’s Gulf War research funding

included $15 million for the UTSW research program, and multiple research proposals have been

approved for funding. The Committee has reviewed information on the overall scope of the program and

its major elements, studies underway in the program’s initial year, and plans for additional research.559,560

In April of 2008, it provided its initial findings and recommendations on the UTSW program to the

Secretary.1272

The UTSW program will utilize a multidisciplinary approach focused on understanding the biological

underpinnings of Gulf War illness and its association with hazardous exposures during the Gulf War. It is

organized around four major, interrelated initiatives: (1) a national epidemiologic survey of Gulf War-era

veterans, (2) a serum and DNA repository, (3) clinical studies to compare sick and healthy Gulf War

veterans on a variety of objective measures, and (4) animal research to investigate biological effects of

Gulf War-related exposures. The initial project is an epidemiologic study of a national, random sample of

Gulf War-era veterans. Blood and DNA samples will be collected from survey participants and used to

study specific hypotheses concerning biological differences between sick and healthy veterans. A smaller

number of veterans will be brought to the UTSW Medical Center for clinical evaluation, using an

extensive battery of neuroimaging, laboratory, and physiological tests. Parallel to the human studies,

animal experiments are planned to evaluate molecular, cellular, and behavioral effects of exposures

associated with Gulf War deployment.

The UTSW program is the first comprehensive Gulf War research center of its type funded by the federal

government and is focused on issues long-identified by the Committee as having high priority. The

Committee is enthusiastic about the potential for a multidisciplinary, coordinated research effort to

achieve results not obtainable from federal Gulf War research programs of the past. It has offered

recommendations concerning the overall scope of research addressed by the program, as well as more

specific recommendations related to the design and conduct of program elements and individual

studies.1272 As the present report is being prepared, only the epidemiologic survey is underway, with

clinical studies and toxicological research to follow. As the program moves forward, the Committee will

continue to review the objectives, progress, and results of the UTSW research in detail, as it has reviewed

previous VA-sponsored Gulf War research programs.

With the development and funding of the UTSW Gulf War research program in 2007, VA’s Office of

Research and Development substantially reorganized the remainder of the VA Gulf War research

portfolio. Many of the ALS research projects included in the portfolio in 2005 and 2006, as well as other

projects, were reassigned and no longer identified as “Gulf War research.” In the Deployment Health

Working Group’s 2007 report to Congress on Gulf War research, VA reported total 2007 expenditures of

nearly $22 million dollars for Gulf War research: $15 million for the UTSW program, and nearly $7

million for additional research projects administered directly by VA ORD.340 Most of the additional

funding was for VA projects that had been funded in previous years, including the Gulf War/ALS tissue

bank at the Boston VAMC (funded at $1 million in 2007), and the large neuroimaging project at the San

Francisco VAMC (funded at $744,000 in 2007). Of the $7 million funding for projects administered

directly by VA in FY2007, 21 percent was for ALS research, seven percent for stress-related research,

and eight percent for projects that were of peripheral or no relevance to Gulf War veterans. The

remaining 64 percent of funding supported projects that addressed research questions related to Gulf War

illness, effects of Gulf War exposures, or other health issues specific to the health of Gulf War veterans.

The Committee commends recent changes in the composition of VA’s Gulf War research portfolio, and in

how Gulf War research funding is reported to Congress. Overall, VA-reported funding for Gulf War

research in 2007 more accurately reflected expenditures for research that was related to the health of Gulf

War veterans than had previously been the case. This shift was the result of two changes: (1) allocation

of $15 million in 2007 for the Congressionally-mandated UTSW Gulf War research program, and (2)

VA’s withdrawal of many ALS studies and other projects unrelated to the health of Gulf War veterans
300  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

from the portfolio of studies identified as “Gulf War research” in agency reports to Congress. The

Committee encourages VA to continue support for the multidisciplinary Gulf War research program at

UTSW. It is also important that additional VA Gulf War research projects be supported in a strategic way

that addresses priority issues identified in this report, as part of a coordinated federal Gulf War research

effort.

Gulf War Research at the Department of Defense

The U.S. Department of Defense historically provided the largest share of funding for federal Gulf War

research.335,1268 This has changed markedly in recent years, with DOD Gulf War research funding

declining from about $30 million in direct costs in 1997, to less than $4 million in 2007. Interagency

annual reports from 2003 through 2006 indicated that just three new Gulf War projects were funded by

DOD in 2003, and no new studies funded between 2004 and 2006.336-339

Focus of DOD Gulf War research: 2003 – 2006. As shown in Table 4, most research funded by

DOD in 2003 and 2004 related to Gulf War illness and biological effects of Gulf War exposures. Several

studies also focused on other Gulf War-related health issues, including rates of hospitalization and motor

vehicle accidents in Gulf War veterans. Between 2004 and 2006, however, the proportion of DOD “Gulf

War research” projects that had little or no direct relevance to the health of Gulf War veterans increased

dramatically.

The largest single allocation of DOD funding between 2003 and 2006 was $9.7 million provided to the

Naval Health Research Center for the Millenium Cohort Study. As previously described, this is an

ongoing longitudinal study of a large cohort of military personnel serving during and after the year 2000.

Other major DOD allocations during this period included $7.6 million to the University of Michigan for

studies of multisymptom illness, $4.9 million to Intracellular Therapies, Inc., for research on molecular

signaling pathways activated by nerve agents, and $3.9 million provided to the University of Texas

Southwestern for neuroimaging research.336-339

By 2006, the DOD Gulf War research portfolio included only three studies. Nearly all funding allocated

for “Gulf War” research—93 percent—was for research that had little direct relevance to the health of

Gulf War veterans. Department of Defense studies funded between 2004 and 2006, in large part, focused

on military personnel who served after Desert Storm. Although identified as “Gulf War Research” in

interagency reports to Congress, these projects would more accurately be considered research related to

“Deployment Health,” a term used by federal agencies to refer to health issues stemming from military

deployment in general, as opposed to issues associated with any specific war or deployment.

The funding levels and studies summarized in Table 4 reflect information provided by DOD in annual

reports to Congress from 2003 through 2006. In 2006, however, DOD retroactively added additional

studies that were funded in 2001, 2003, and 2005 to Gulf War research portfolios for those years. 339

These included two ALS studies, funded at over $2 million, and two PTSD treatment studies, also totaling

about $2 million. Had these additional studies been included in annual reports to Congress for 2003 and

2005, total funding levels for those years would appear greater than those indicated in Table 4, and the

profile of the DOD Gulf War research portfolio would have reflected substantial funding for studies

focused on ALS and psychiatric disorders.

Recent program developments in DOD Gulf War research. Recognizing the decline in DOD’s

support for Gulf War research after 2002, Congress appropriated $5 million for new DOD Gulf War

research in FY2006. Congressional language specifically directed that the funds be used for research that

provided insights into biological mechanisms that underlie Gulf War illness and for studies to evaluate

promising treatments for Gulf War illness.586,842
Gulf War Research at the Department of Defense  301

Table 4. Department of Defense Gulf War Research: 2003—2006

Funding Levels and Focus of Studies

Focus of DOD Gulf War Research Studies†

2003

Funding*

(% of 2003 funds)

2004

Funding*

(% of 2004 funds)

2005

Funding*

(% of 2005 funds)

2006

Funding*

(% of 2006 funds)

Gulf War illness, effects of Gulf War exposures $ 7,230,104

(58%)

$ 11,272,424

(73%)

$2,694,894

(44%)

$ 326,570

(7%)

Other health problems related to Gulf War service $ 2,031,950

(16%)

$ 1,750,000

(11%)

-

(0%)

-

(0%)

Peripheral or no clear relevance to Gulf War service $ 3,134,072

(26%)

$ 2,318,687

(15%)

$ 3,484,372

(56%)

$ 4,393,452

(93%)

Total DOD Gulf War Research Funding, by Year* $ 12,396,126

(100%)

$ 15,341,111

(100%)

$ 6,179.266

(100%)

$4,720,022

(100%)

*Direct costs, as reported in Deployment Health Working Group Annual Report to Congress for each year 336-339

†Research focus of individual projects categorized by Research Advisory Committee on Gulf War Veterans’ Illnesses

In previous years, Gulf War research at DOD was managed by the Military Operational Medicine

Research Program in the U.S. Army Medical Research and Materiel Command (USAMRMC). Funding

allocated in FY2006, however, was directed to USAMRMC’s Office of Congressionally Directed

Medical Research Programs (CDMRP). This multifaceted program was established in 1993 to manage

research conducted in areas of special Congressional and public interest.(CDMRP) CDMRP programs

emphasize innovative research studies of high scientific merit that have the potential for providing

breakthroughs in understanding and treating diseases and protecting the health of military personnel.

The CDMRP issued a funding announcement for its newly-established Gulf War Veterans’ Illnesses

Research Program in October, 2006.1634 The solicitation identified two funding priorities: (1) studies to

identify and evaluate treatments for Gulf War illness, and (2) studies to identify objective measures that

distinguish ill from healthy veterans. A total of 80 letters of intent and preproposals were submitted to

CDMRP in response to the announcement. Full proposals were invited for 34 of the projects, nine of

which were ultimately funded in 2007.586 The selection process involved scientific merit review of

proposals and an additional review to evaluate the projects’ relevance to identified research priorities.

Both stages of the review process included Gulf War veterans with Gulf War illness.

With the initial $5 million funding provided to CDMRP in the first year of the new Gulf War research

program, three of the nine funded studies focused on treatments for Gulf War illness, two focused on

objective biological measures that distinguish ill from healthy veterans, and three projects included both

treatment and biomarker components.737 This represents a clear departure from previous federal Gulf

War research programs. The Committee commends the results-oriented direction and management of the

program, now referred to as the Gulf War Illness Research Program (GWIRP). The GWIRP’s success,

with its initial $5 million allocation, in attracting and funding research studies focused on treatments and

objective biological measures for Gulf War illness is impressive, especially in comparison to the very

small number of studies funded in these areas during the entire previous history of federal Gulf War

research.

The CDMRP GWIRP program has clearly addressed Congressional directives and has also funded Gulf

War studies in areas given highest priority by the Committee, that is, identification of treatments and

objective biological markers for Gulf War illness. The program’s support of smaller treatment studies to

identify suitable candidates for larger clinical trials is also compatible with Committee recommendations.

In its 2004 report, the Committee called for lower-cost studies to provide preliminary data on currently
302  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

available, potentially promising treatments before allocating millions of dollars for large multi-center

clinical trials, as had previously been done by VA and DOD.1268

The Committee also applauds CDMRP’s inclusion of veterans with Gulf War illness, and scientists with

expertise in Gulf War illness, in reviewing research proposals. It is also of great importance that CDMRP

funding for Gulf War research is available to all investigators from academic and government institutions,

and can enlist the best ideas from the most qualified scientists, wherever they are found. In contrast, VA

research funding can only be provided to VA researchers, imposing significant restrictions on the

expertise brought to bear on Gulf War research issues and the types of studies done. The Committee was

favorably impressed, overall, with the general approach used by CDMRP, including its emphasis on

innovative studies that have the potential to yield clinically useful results in the near term.

Based on CDMRP’s initial success in attracting substantial scientific interest and its support of Gulf War

research projects in areas of highest priority, Congress allocated $10 million for the CDMRP Gulf War

research program in FY2008. The GWIRP research solicitation, issued in May, 2008, attracted 113

preproposals. The announcement again emphasized the program’s support of research focused on

treatment, diagnosis, and understanding of Gulf War illness, with highest priority given to identification

of treatments. 737 Submitted proposals will be reviewed in late 2008, and approved studies will receive

funding in 2009.737 The Committee commends the early successes of the CDMRP program, and will

continue to monitor the progress and productivity of the program, as it has reviewed previous federal Gulf

War research programs.

A limited number of additional projects, outside the CDMRP Gulf War research program, continued to be

identified by DOD as “Gulf War research” in the 2007 interagency report to Congress. Funding

continued to reflect trends of recent years. Ninety-five percent of the $3.4 million funding identified by

DOD as “Gulf War Research” in FY2007 was allocated for the Millenium Cohort Study which, as

previously described, represents “Deployment Health” research that has little relevance to the health of

veterans of the 1990-1991 Gulf War.340

Table 5. Centers for Disease Control and Prevention Gulf War Research: 2003—2006

Funding Levels and Focus of Studies

Focus of CDC Gulf War Research Studies†

2003

Funding*

(% of 2003 funds)

2004

Funding*

(% of 2004 funds)

2005

Funding*

(% of 2005 funds)

2006

Funding*

(% of 2006 funds)

Gulf War illness, effects of Gulf War exposures

-

(0%)

-

(0%)

-

(0%)

-

(0%)

Other health problems related to Gulf War service $ 164,291

(17%)

-

(0%)

-

(0%)

-

(0%)

ALS research -

(0%)

$ 461,951

(100%)

$ 462,071

(100%)

$ 466,000

(100%)

Peripheral or no clear relevance to Gulf War service $ 799,814

(83%)

-

(0%)

-

(0%)

-

(0%)

Total CDC Gulf War Research Funding, by Year* $ 964,105

(100%)

$ 461,951

(100%)

$ 462,071

(100%)

$ 466,000

(100%)

*Direct costs, as reported in Deployment Health Working Group Annual Report to Congress for each year336-339

†Research focus of individual projects categorized by Research Advisory Committee on Gulf War Veterans’ Illnesse
Additional VA Programs Relevant to Gulf War Research 303

Gulf War Research at the Centers for Disease Control and Prevention

The U.S. Centers for Disease Control and Prevention (CDC) has, for many years, participated as a

cooperating agency in the ongoing federal effort to address health consequences of the 1991 Gulf War.

But CDC has consistently funded only a small percentage of federal Gulf War research. In recent years,

Gulf War research funding at CDC has declined from nearly $1 million in 2003 to about half that amount

in 2006, as shown in Table 5.336-339

None of the CDC studies funded since 2003 have specifically addressed questions related to Gulf War

illness or the effects of Gulf War exposures. One study funded in 2003 addressed another important Gulf

War health issue, however, evaluating cancer rates in Gulf War veterans. Two additional studies funded

in 2003 had little relevance to the health of 1991 Gulf War veterans. Both involved identification of

strategies to improve health risk communications related to military deployments. In addition, CDC has

funded one ALS research project between 2004 and 2007, which is evaluating genetic and environmental

risk factors among veterans enrolled in VA’s ALS Registry. Although the $1.8 million funding provided

for the project over this period has been identified as “Gulf War Research” in the Deployment Health

Working Group’s reports to Congress, the study includes relatively few Gulf War veterans and does not

address scientific questions specific to Gulf War service.339

Additional VA Programs Relevant to Gulf War Research

Years ago, I left the VA healthcare system, after being prescribed a powerful medication by

VA ‘Obecalp’—a medication to be used with extreme caution. However, it did not work very

well. Spelled backward, it is simply ‘Placebo.’ To answer your questions [before you ask], I

have never participated in a study, much less one at the VA. After leaving the VA and

seeking private medical care, I found a good doctor and neurologist who managed to control

my declining health.

... Recently, we sold our home in Florida and moved back to our home state of Kentucky, at

which time I returned to the VA for my health care. My wife and I felt, after everything that had

been done over the years, that surely the VA healthcare system has improved for Gulf War

veterans. But to my surprise, returning to VA was like going back in time. I was once again

told there is nothing wrong with Gulf War veterans. Even worse, the doctor I saw on my last

visit even stated that she cannot believe veterans receive compensation for Gulf War

illnesses, because there is nothing really wrong with them that is related to their service.

... I cannot believe, after all the work that has been done on this issue, that this is still the

normal response from VA doctors.

--Gulf War veteran, 2005 Congressional Testimony1809

The Committee is charged with reviewing research studies and programs related to the health of Gulf War

veterans. There are additional programs and services provided by VA that, although not specifically

research programs, are connected to and affected by scientific research on the health of Gulf War

veterans. These include VA programs that provide information to healthcare providers caring for Gulf

War veterans, programs that provide clinical evaluations of Gulf War veterans, and programs that provide

disability benefits to ill veterans.

Veterans with Gulf War illness commonly inform the Committee in public testimony and in private that

their VA healthcare providers have little to offer for their conditions, do not take their illness seriously, or

believe their symptoms to be psychological. Veterans also question why their providers seem not to

know about the types of scientific research discussed in Committee meetings and reports. There are no
304  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

recent data that characterize VA healthcare providers’ attitudes about Gulf War illness or their familiarity

with Gulf War research. However, the Committee has reviewed sources of research information provided

to VA healthcare providers, and found them to be both selective and out-of-date. These include

continuing education materials provided to VA physicians through the Veterans Health Initiative (VHI),

clinical practice guidelines provided for chronic multisymptom illness, as well as other VA documents

and public statements made by VA officials. Information from these sources commonly ignores or

minimizes Gulf War illness and the wide-ranging scientific evidence that it is not a psychiatric condition

and that it affects a substantial number of veterans. This pattern of denying or minimizing the problem of

Gulf War illness is exemplified by the following paragraphs from physician education materials currently

in use at VA:

Most Gulf War veterans who come to VA for health care or to participate in the VA health

registry receive conventional diagnoses and treatments. Most have health problems similar to

those experienced by veterans of other eras. However, some veterans report chronic

multisymptom illnesses that often are difficult to diagnose. Thus, most of the symptoms

reported by veterans in VA registry examinations were found to be caused by conventional

illnesses.

... Considerable progress has been made in evaluating and treating illnesses among Gulf War

veterans and in determining the prevalence of symptoms. Most Gulf War veterans are healthy

today and have successfully readjusted to post-war life, or they have diagnosable health

problems. VA has been able to respond to the complexity of veterans’ health problems; most

are readily diagnosed and effective treatments are available.

--VA Continuing Medical Education Program1649

Information on Gulf War research provided to VA clinicians. The Veterans Health Initiative,

VA’s continuing medical education program, provides information on the health of Gulf War veterans to

VA clinicians. The independent study course, A Guide to Gulf War Veterans’ Health, was first prepared

in 1997 by VA’s Employee Education System in cooperation with VA’s Office of Public Health and

Environmental Hazards.1649 The currently-used guide was revised in 2001 and released in March 2002. It

provides general information from VA’s Gulf War Registry and from selected types of Gulf War

epidemiologic research available at that time, most prominently information on symptoms,

hospitalizations, and mortality rates. It also provides guidelines for clinical risk communications, to assist

clinicians in explaining causality information to veterans with Gulf War illness, as demonstrated by the

following excerpts:

Frequently, the veteran seems to overestimate or overvalue the apparently low chance that a

rare, improbable cause (e.g., in theater vaccinations or biological weapons exposures) is

responsible for symptoms than more ordinary and likely causes (e.g. early degenerative joint

disease in an airborne infantry soldier).

... discussing chronic illness with a Gulf War veteran or a woman with silicone breast

implants is a different matter from discussing it with the average patient. Of course, this is

because the Gulf War and silicone implants have been the focus of intense scientific,

governmental and media scrutiny as possible sources of illness.

--VA Continuing Medical Education Program1649

The course provides no information on many of the most significant research findings related to the health

of Gulf War veterans. That is, VA physicians trained using the Veterans’ Health Initiative course are not

informed about: (1) epidemiologic research showing high rates of multisymptom illness in Gulf War

veterans, significant associations between Gulf War illness and hazardous exposures during the Gulf War,

and elevated rates of ALS in Gulf War veterans, (2) clinical findings of objective indicators of
Additional VA Programs Relevant to Gulf War Research 305

neurological alterations and other biological abnormalities in ill veterans, or (3) toxicological studies

showing persistent neurological effects of low-level Gulf War-related exposures, and synergistic effects

of combined exposures. In short, Gulf War research information provided to VA clinicians through the

Veterans Health Initiative is unacceptably limited and out-of-date.

Information provided to VA clinicians on clinical management of Gulf War illness. As

previously described, VA and DOD commissioned expert panels to develop two sets of clinical practice

guidelines related to the health of Gulf War veterans. These guidelines, finalized in 2001, were informed

by available scientific research and by the clinical experience of panel members. One set of guidelines

provides information to assist clinicians in evaluating patients with “post-deployment health concerns”

but does not provide specific treatment recommendations.1656

The second set of practice guidelines provides information on evaluation and management of veterans

with chronic unexplained illness, specifically symptoms of chronic pain and fatigue.1656 Information

provided on recommended treatments is based on the limited number of clinical trials published by 2001

that evaluated therapies for fibromyalgia and chronic fatigue syndrome. Information on other potentially

useful treatments is also provided, based on more preliminary research findings and the clinical

experience of panel members. The guidelines emphasize the use of cognitive behavioral therapy (CBT),

graded exercise, and antidepressant medications. Although exercise and CBT have been shown to

provide improvements for fibromyalgia and chronic fatigue syndrome patients, studies have found them

to be less helpful for ill Gulf War veterans.226,354,406 The clinical practice guidelines are also seriously

outdated in terms of the many studies of treatments for multisymptom conditions published since 2001,

particularly treatments for fibromyalgia.

VA clinical programs relevant to Gulf War health research. VA has long maintained a national

Gulf War Registry that provides clinical evaluations to Gulf War veterans at no cost and serves, for some

veterans, as a gateway to other VA healthcare and benefits programs. Participating veterans complete

detailed questionnaires and are given standardized medical examinations.1654 Although not designed to

provide scientific research information, the registry relates to the federal Gulf War research effort in a

number of ways. Summary data from the registry are reported in medical journals and frequently cited in

government reports and testimony. In addition, VA’s Gulf War Registry is sometimes used as a resource

to identify veterans for Gulf War research projects. The Committee was informed by VA’s Office of

Environmental Hazards that, as of November 1, 2007, a total of 102,215 veterans of the 1990-1991 Gulf

War had enrolled in VA’s Gulf War Registry. Figures from recent years indicate that additional Gulf War

veterans have continued to come forward with health concerns, even 17 years after Desert Storm.

According to VA’s Office of Environmental Hazards, 3400-4400 Gulf War veterans have received VA

Gulf War Registry exams in each of the last three years.

The Department of Veterans Affairs also maintains a national referral program that provides more indepth clinical evaluations at specialty clinics for veterans with difficult-to-diagnose conditions.1653 The

War-Related Illness and Injury Study Centers (WRIISCs) were established in 2001 and initially located at

VA Medical Centers in Washington, D.C., and East Orange, New Jersey.1642 A third WRIISC was

recently established in Palo Alto, California.1657 Multidisciplinary clinical evaluations at the WRIISCs

require between two and five days and include detailed medical and psychological evaluations, as well as

other types of specialty testing, as indicated for individual patients. This might include environmental

exposure assessments, neurological testing, balance testing, neuropsychological assessments, or other

evaluations. The program is provided for veterans who served in a theater of combat operations and are

affected by undiagnosed or difficult-to-diagnose conditions. Veterans are referred by their local VA

clinicians, and all medical services, travel, and local accommodations are provided at no cost to the

veteran.1657
306  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

The WRIISCs were established both to provide multidisciplinary clinical evaluations for ill veterans, and

as research centers.1653 Investigators based at the Washington and New Jersey WRIISCs have conducted

dozens of studies on diverse topics related to Gulf War illness and other Gulf War health issues.

Relatively few veterans, however, have participated in the WRIISC clinical evaluation programs. A

published report indicated that, in their first two years of operation, the New Jersey and Washington

WRIISCs combined had evaluated a total of 53 combat veterans with difficult-to-diagnose conditions,

only 42 of whom had served in the Persian Gulf War.907 Figures provided to the Committee by VA’s

Office of Environmental Hazards indicate that a total of 168 Gulf War veterans were evaluated at the two

WRIISCS between 2001 and 2007.

VA disability benefits in relation to Gulf War research. The Department of Veterans Affairs

provides financial compensation to veterans of all eras who have disabling health problems in connection

with their military service. Disability compensation programs are administered by the Veterans Benefits

Administration (VBA) within VA. Department of Veterans Affairs regulations identify specific

requirements that must be met in order for veterans of a particular era or veterans with certain health

problems to receive disability benefits. There are special provisions, for example, that allow Gulf War

veterans disabled by chronic symptoms that are not explained by a specific diagnosis to receive disability

compensation for “undiagnosed illnesses.”1643 Although VBA does not sponsor scientific research

studies, decisions and regulations concerning disability benefits rely on scientific research.

As of February, 2008, VBA’s Gulf War Veterans Information System (GWVIS) reported that 33 percent

of the 631,477 service members who separated from military service after serving in the 1991 Gulf War

had filed disability claims and were found by VBA to have a service-connected disability. Among

personnel potentially exposed to low-level nerve agents in relation to the Khamisiyah demolitions in

March of 1991, 39 percent have a service-connected disability.1650 By comparison, 29 percent of military

personnel who deployed to Southwest Asia after 1991, and are now separated from service, have a

service-connected disability. Although crude figures provided for different groups in the GWVIS reports

cannot be directly compared without proper adjustments, available figures do suggest that veterans of the

1990-1991 Gulf War have a high rate of service-connected disabilities, especially considering the brevity

of the 1991 Gulf War and the low rate of injuries during the war.1607,1633

It is also important to note that very few Gulf War veterans have applied for disability compensation for

“undiagnosed illness.” As of February, 2008, just two percent of Gulf War veterans had filed disability

claims for undiagnosed illness and only 0.5 percent had been service-connected for undiagnosed

illness.1650 The very low number of claims for Gulf War-related undiagnosed illness is somewhat

unexpected, given the much larger number of veterans identified with multisymptom illness in research

studies. The explanation for this is not known, but may relate to several factors. VBA statistics suggest

that undiagnosed illness claims have been difficult for veterans, veterans service officers, and VA to

successfully execute. Eighty-seven percent of all disability claims filed by veterans who served since

1990 have been granted service-connection by VBA. In sharp contrast, only 26 percent of claims filed for

undiagnosed illness have been granted service-connection.1650 This may explain, in part, why few

veterans, or veterans’ service officers, have filed this type of claim. In any case, the very small number of

veterans who have applied for disability benefits for undiagnosed illness belies inferences made that Gulf

War veterans might be inclined to report difficult-to-diagnose symptoms for purposes of financial

gain.379,466

As described in an earlier section of this report, Congress directed VA, in 1998, to commission the

Institute of Medicine (IOM) to conduct comprehensive scientific reviews to assist the Secretary in making

decisions about service-connected disability compensation for Gulf War veterans in relation to Gulf War

service and Gulf War exposures. Congress specified that VA direct IOM to: (1) identify diagnosed and

undiagnosed conditions that affect Gulf War veterans at excess rates, and (2) evaluate scientific evidence

from human and animal studies concerning associations between those conditions and a detailed list of
Additional VA Programs Relevant to Gulf War Research 307

Gulf War exposures.1242,1243 As previously detailed, the resulting Gulf War and Health series of reports

have not fulfilled the purpose directed by Congress. As commissioned by VA, these reviews have either

excluded, or only superficially considered, key areas of research essential for understanding associations

between Gulf War illness and hazardous exposures in the Gulf War. Although intended by Congress to

provide support to the VA Secretary in making decisions about Gulf War-related disability benefits, the

Gulf War and Health reports have provided little information relevant to the most prominent Gulf War

health and disability issues. This includes Gulf War illness and ALS, for which no conclusions related to

Gulf War-related exposures have been provided.685,686 In the present report, the Committee has

recommended that the IOM Gulf War reviews be redone to reflect the purpose and content directed by

Congress.

In 2001, former VA Secretary Principi announced that VA would provide service-connected disability

compensation to all Gulf War veterans who had been identified at that time with a diagnosis of ALS.1639

The decision was based on emerging findings from epidemiologic research indicating that Gulf War

veterans had a significantly higher rate of ALS than their nondeployed counterparts. However, VBA did

not establish a regulation at that time that provided presumptive service-connection for all Gulf War

veterans with ALS. New claims related to ALS in Gulf War veterans continued to be adjudicated on a

case-by-case basis.1028,1639 This changed in September, 2008, when VA Secretary James Peake announced

that all U.S. veterans, of all eras, would be given presumptive service connection for ALS.1647 The

decision was based, primarily, on an IOM 2006 report on ALS, which concluded that there was limited,

suggestive evidence supporting an association between military service, overall, and development of

ALS.685

In summary, multiple issues have been raised concerning VA programs that are not specifically focused

on research, but are closely linked to scientific research on the health of Gulf War veterans. These

include programs that provide research information to VA clinicians, programs that provide clinical

assessments of ill Gulf War veterans, and programs that provide benefits to disabled Gulf War veterans.

In 2007, the Committee formally recommended that VA update and improve information on Gulf War

research provided to VA clinicians.1271 This included both the Veterans’ Health Initiative continuing

education program on the health of Gulf War veterans, and the VA/DOD Clinical Practice Guidelines for

Unexplained Symptoms.

The Committee also recommended that the Secretary establish a separate advisory committee to consider

issues related to clinical care and benefits for Gulf War veterans.1271 In April 2008, Secretary Peake

appointed a new public advisory panel, the Advisory Committee on Gulf War Veterans, and charged it

with an assessment of the full spectrum of VA healthcare and benefits issues that affect veterans who

served in the 1990-1991 Gulf War.1646 The Committee welcomes this development and looks forward to

working cooperatively with the new panel.

Summary. Federal research on Gulf War illness and the health of Gulf War veterans.

Since 1994, the federal government has reported spending hundreds of millions of dollars for projects

identified as Gulf War research, but prominent shortcomings have slowed federal progress in addressing

Gulf War-related health issues. Studies identified as federally-sponsored “Gulf War research” have often

been unrelated, or only marginally related, to the health of Gulf War veterans. In addition, a substantial

portion of Gulf War research funding has been used for studies focused on psychological stress and

psychiatric disorders. The federal Gulf War research effort has not, historically, been designed or

managed to achieve high-priority scientific objectives. Specifically, federal programs have not been

managed to resolve fundamental questions concerning the nature, causes, and treatments for Gulf War

illness. Consequently, federal Gulf War research programs have not, as yet, succeeded in improving the

health of ill Gulf War veterans.
308  Federal Research on Gulf War Illness and the Health of Gulf War Veterans

Congressional actions have brought about major changes in Gulf War research programs at both VA and

DOD in recent years. In 2006, Congress allocated an additional $15 million annually for Gulf War

research at VA 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 and effects of hazardous exposures during the Gulf War.

In addition, Congress appropriated $5 million in 2006 and $10 million in 2008 for 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 effective treatments and

objective biological markers for Gulf War illness, and funded multiple studies in these areas in 2007.

Early indications suggest that changes at both VA and DOD represent promising new directions in the

federal Gulf War research effort that have the potential to make a significant difference in the health of

Gulf War veterans. Despite these positive developments, overall funding for federal Gulf War research

has declined dramatically since 2001. A renewed federal research commitment is urgently needed to

restore Gulf War research funding to pre-2001 levels in support of research focused on identifying

beneficial treatments for Gulf War illness and other priority Gulf War research issues identified in this

report.
Recommendations 309

Recommendations

The Committee welcomes recent programmatic developments related to federal Gulf War research, and

urges the federal government to allocate no less than $60 million annually in the federal budget for Gulf

War research programs. This is consistent with annual funding levels committed for federal Gulf War

research between 1999 and 2001, adjusted for inflation. Specifically, the Committee recommends:

 That the Administration request and Congress appropriate a minimum of $40 million annually to

the Department of Defense for the Gulf War Illness Research Program managed by DOD’s Office

of Congressionally Directed Medical Research Programs. This funding should support openlycompeted, peer-reviewed studies focused on identifying: (1) effective treatments for Gulf War

illness, (2) objective measures that distinguish ill from healthy veterans, and (3) underlying

biological mechanisms potentially amenable to treatment, in accordance with the priorities

identified by the Committee.

 That the Administration request and Congress appropriate a minimum of $20 million annually to

the Department of Veterans Affairs for Gulf War illness research. This should include $15

million annually to support the Gulf War illness research center at the University of Texas

Southwestern through FY2010, with the balance to fund additional Gulf War research studies,

through Gulf War-specific and general solicitations for peer-reviewed proposals consistent with

research recommendations in this report.

 That VA continue to fund the ALS Registry and the Gulf War Biorepository, focused more

specifically on projects related to Gulf War era veterans. The biorepository should be expanded

to include Gulf War era veterans with other diagnosed medical diseases and difficult-to-diagnose

conditions.

 That the Department of Defense and the Department of Veterans Affairs collaborate in

establishing a comprehensive federal Gulf War research plan and a strategy to coordinate and

manage federal programs to ensure that priority research objectives are satisfactorily achieved.
310  Research Priorities and Recommendations
Highest Priority Gulf War Research  311

5| Research Priorities and Recommendations

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 that affect

Gulf War veterans as a result of their military service remains the obligation of the federal government

and all who are indebted to the 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 veterans have waited for answers

and assistance.

The Committee was directed to determine what has been learned about the health consequences of

military service in the 1990-1991 Gulf War and to recommend research directed toward improving the

health of Gulf War veterans. As described throughout this report, an extensive amount of research has

provided important progress and improved understanding of the nature and causes of Gulf War illness

and, more generally, the health of Gulf War veterans. Important questions remain, however. In

reviewing the broad range of studies and topics related to the health of Gulf War veterans, the Committee

identified many scientific issues for which additional research is needed and provided specific

recommendations for each topic considered. Those research recommendations are brought together and

summarized below, listed by categories of priority. Guidelines are also provided for improvements in

clinical and epidemiologic research on Gulf War veterans, based on limitations commonly identified in

existing studies.

While the Committee believes that all of the recommended research is important, it places highest priority

on research that can most directly contribute to the objective of improving the health of Gulf War

veterans. The corollary objective, of achieving a clearer and more comprehensive understanding of the

health consequences of the Gulf War, also remains essential both to assist Gulf War veterans and their

families, and to avoid similar consequences in future military deployments.

Highest Priority Gulf War Research

1. Identification of effective treatments for Gulf War illness. Highest priority is given to

research conducted to identify beneficial treatments for Gulf War illness. The primary objective is the

conduct of well-designed clinical trials of treatments that hold promise for providing substantial benefit

for veterans with Gulf War illness or identifiable subgroups. This research should include:

 Studies that identify and systematically evaluate the effectiveness of currently available

treatments used for Gulf War illness or conditions with similarities to Gulf War illness.

Preliminary research should include pilot trials and/or observational studies capable of identifying

promising treatments suitable for evaluation in larger clinical trials.
312  Research Priorities and Recommendations

 Research to identify specific pathophysiological mechanisms underlying Gulf War illness that are

potentially amenable to treatment interventions.

 Research to evaluate novel therapies based on scientific findings as they emerge.

2. Identification of objective measures that distinguish veterans with Gulf War illness

from healthy veterans. The Committee places a high priority on identification of biological markers

for Gulf War illness and measurable differences between groups of symptomatic and healthy Gulf War

veterans. In light of findings from current and ongoing studies describing associations between Gulf War

illness and neurological, immune, endocrine, genetic, and biochemical alterations, the Committee

recommends the following research:

 Studies that utilize state-of-the-art neuroimaging technologies to characterize aspects of brain

structure and function that may distinguish veterans with Gulf War illness, including illness or

exposure subgroups, from healthy Gulf War veterans.

 Comprehensive evaluation of autonomic nervous system function associated with Gulf War illness,

as well as illness and exposure subgroups.

 Research that investigates biological and genetic variability potentially linked to differences in

vulnerability to Gulf War exposures, including studies that evaluate associations between Gulf War

illness and genetic polymorphisms and activity levels of enzymes associated with uptake and

metabolism of neurotoxic exposures.

 Studies that evaluate alterations in central proinflammatory and inflammatory processes in Gulf

War veterans affected by Gulf War illness.

 Comprehensive evaluation of immune parameters associated with Gulf War illness, including

parameters that may differ among illness and/or exposure subgroups.

 Comprehensive evaluation of hypothalamic-pituitary-adrenal axis and other neuroendocrine

parameters in association with Gulf War illness, including parameters that may differ among illness

and/or exposure subgroups.

 Studies that determine the extent to which other physiological characteristics that distinguish CFS,

FM, and MCS patients from healthy controls are also associated with Gulf War illness.

 Studies that use the most reliable methods available to determine rates of latent or active

leishmania (particularly l. tropica) and mycoplasma infection in veterans with Gulf War illness and

healthy controls.

 Studies that utilize new technologies (proteomic, genomic, and metabolomic methods) capable of

identifying unique molecular characteristics of Gulf War illness, and of illness and exposure

subgroups.
Highest Priority Gulf War Research  313

3. Studies that characterize effects of neurotoxic exposures associated with Gulf War

illness. Due to the consistency of findings relating Gulf War illness to neurotoxic exposures during the

war, the Committee gives high priority to studies that further characterize specific effects of Gulf Warrelated neurotoxic exposures, and recommends the following research:

 Studies that utilize animal models to characterize persistent molecular, cellular, systemic, and

behavioral effects of individual and combined exposure to pyridostigmine bromide, pesticides

and insect repellants used in the Gulf War, and low-level sarin.

 Studies that utilize animal models to characterize persistent effects of Gulf War-related

exposures, alone and in combination, on central proinflammatory processes and their biological

mediators in the central nervous system and target organs.

 Studies that identify markers indicative of past exposure to Gulf War-related neurotoxic

compounds that can be applied to Gulf War veterans. This might include studies that utilize

technologies capable of detecting toxins or secondary metabolites retained for many years

following exposure, studies that identify persistent or “downstream” changes in biochemical

processes in relation to past neurotoxicant exposure, and studies that identify persistent changes

in the central nervous system and autonomic function associated with exposure to Gulf Warrelated neurotoxicants.

4. Research to determine if Gulf War veterans are affected by excess rates of

neurological diseases and to further characterize neurological abnormalities in Gulf War

veterans. Research studies indicating that Gulf War veterans have a significantly higher rate of

amyotrophic lateral sclerosis (ALS) than their nondeployed peers raise concerns about other chronic

neurological conditions for which no studies have been conducted. The committee therefore recommends

the following research:

 Epidemiologic studies to identify rates of diagnosed neurological diseases (including multiple

sclerosis, Parkinson’s disease, ALS, and brain cancers), as well as central nervous system

conditions that are difficult to precisely diagnose, in Gulf War veterans and appropriate

comparison groups.

 Greater focus of VA’s ALS Registry and Gulf War brain tissue bank on projects related to Gulf

War veterans, and expansion of both programs to include Gulf War veterans with other diagnosed

neurological diseases and difficult-to-diagnose neurological conditions. In addition, the brain

tissue bank should be expanded to specifically include veterans with Gulf War multisymptom

illness and appropriate controls.
314  Research Priorities and Recommendations

Other Research Areas of Importance for Addressing Gulf War Health Issues

Epidemiologic research: general. The Committee considers information provided by VA’s national

longitudinal study of Gulf War veterans and continued monitoring of the health of Gulf War veterans over

time to be extremely important. It therefore recommends that VA:

 Make results from the national longitudinal study of Gulf War veterans publicly available at the

earliest possible time, including comprehensive findings related to multisymptom illness,

treatments and practices used by veterans to address their symptoms, and reported rates of

medical diagnoses. Results should include outcomes assessed according to the guidelines for

epidemiologic research provided below.

 Continue current research evaluating cancer rates in Gulf War era veterans, and assess cancer

rates among subsets of veterans identified as being exposed to chemical nerve agents, depleted

uranium, and smoke from the Kuwaiti oil well fires.

 Provide current information on overall and cause-specific mortality rates in Gulf War veterans,

and update this information, at minimum, at five year intervals. This should include information

on mortality in subgroups of Gulf War veterans identified by deployment locations, branch of

service, and exposures reported in the National Survey of Gulf War Era Veterans and Their

Families.

 Conduct additional analyses of available data from existing large population-based studies to

more thoroughly evaluate rates of Gulf War illness, cancer, respiratory conditions, and other

health outcomes in relation to self-reported and modeled exposures, individually and in

combination, appropriately controlling for effects of other exposures in theater.

 Make available comprehensive information on family members of Gulf War veterans from the

national study of Gulf War era veterans and family members. This should include information on

diagnosed conditions, multisymptom illness, behavioral problems, and birth defects. Health

parameters should also be assessed in subgroups of interest, such as family members of veterans

with/without Gulf War illness and subgroups defined by characteristics of veterans’ wartime

service.

 Continue to monitor health and disease outcomes among veterans assessed in the National Survey

of Gulf War Era Veterans and Their Families, conducting longitudinal surveys and appropriate

clinical follow-up studies at five year intervals.

 Further evaluate indications of possible increased risk of specific types of birth defects, as well as

other health problems in children of Gulf War veterans, using innovative study designs.

Studies to further characterize effects of Gulf War exposures

 Conduct an epidemiologic investigation to evaluate health outcomes in an expanded cohort of Gulf

War veterans who had the greatest exposure to depleted uranium during deployment, and an

appropriate comparison group. Evaluated health outcomes should include detailed information on

symptoms, Gulf War illness, functional status, diagnosed medical conditions, and reproductive

outcomes.
Other Research Areas of Importance  315

 Commission a case-control study to determine whether Gulf War illness is associated with elevated

levels of squalene antibodies.

 Evaluate the association of anthrax vaccine adsorbed (AVA) with chronic symptoms,

multisymptom illness, and diagnosed disease by conducting a retrospective cohort study of military

personnel known to have received/not received AVA during the Gulf War and/or in the early years

of the AVIP program.

 Conduct an epidemiologic investigation to determine if personnel who served with the Army

National Guard’s 325th Maintenance Company in the Gulf War suffer excess health problems

associated with exposure to CARC paint during deployment, alone or in combination with other

Gulf War-related exposures.

Guidelines for Clinical and Epidemiologic Research on Gulf War Veterans

 Studies of Gulf War veterans should use well-constructed and clearly-described case definitions for

Gulf War illness and illness subgroups. Pending more widespread acceptance of an established

case definition, preferred case definitions are those that most clearly distinguish the pattern of

symptoms in Gulf War veterans from those in nondeployed era veterans, such as the Kansas Gulf

War illness case definition.

 In addition to general comparisons between Gulf War and nondeployed veterans, Gulf War

research studies should analyze results in relation to Gulf War veteran subgroups of interest,

including ill vs. well veterans and subgroups defined according to veterans’ locations in theater,

exposures, and other military and deployment characteristics potentially relevant to the outcomes

evaluated.

 Associations between deployment-related exposures and health outcomes in Gulf War veterans

should be evaluated using analytic methods that appropriately control for the effects of

confounding introduced by multiple exposures during deployment.

 Research studies whose principal focus is on psychiatric disorders such as posttraumatic stress

disorder or effects of psychological stressors are not directly relevant to Gulf War illness and

should not be considered Gulf War illness research.
316 
Acknowledgements  317

| Acknowledgements

Since its inception, the work of the Committee has relied on the assistance and input provided by research

scientists, veterans, government officials, and members of the general public. The Committee could not

have executed its charge in the comprehensive manner required had it not been for this support. We have

been continually gratified by the generosity with which individuals from many sectors have

enthusiastically provided their expertise and time in this important endeavor.

We would first like to acknowledge former members of the Committee who have contributed greatly to

its work in the years since the last major report, but whose names do not appear as authors of the present

report. These past members include Mr. Adrian Atizado, Dr. Nicola Cherry, Dr. Robert Haley, Dr. Pierre

Pellier, Mr. Steve Robinson, and Dr. Hugh Tilson. This report, in no small part, reflects their

contributions. We also welcome new members LTC Adam Such and Dr. Dedra Buchwald, who recently

joined the Committee. Because they did not participate in discussions and approval of the present report,

neither former members nor new members are responsible for the report’s specific findings or content.

The Committee was mandated by Congress, and charged with advising the federal government on Gulf

War research, directing its advice specifically to the Secretary of Veterans Affairs, who chairs the

interagency group on the health of Gulf War veterans, the Deployment Health Working Group. We

express our thanks to the Secretaries of Veterans Affairs we have advised and under whom we have

served: Secretary Anthony J. Principi, Secretary R. James Nicholson, and Secretary James B. Peake. We

appreciate their support and continuing interest in our work and, more broadly, in issues concerning the

health of Gulf War veterans. We have also appreciated inquiries from members of Congress, and their

ongoing interest in and support of the Committee’s work.

There are many individuals, both officials and staff members, in the Department of Veterans Affairs (VA)

and the Department of Defense (DOD) who have been most helpful in providing information and

assistance to the Committee. Within VA, we express our gratitude to officials at the Office of Research

and Development: Chief Research and Development Officer Dr. Joel Kupersmith, Director of the Clinical

Science Research and Development Service Dr. Timothy O’Leary, and portfolio manager for VA’s Gulf

War illness research program Dr. William Goldberg, who also serves as the Committee’s Designated

Federal Officer. We also thank Mr. Phil Riggin, Special Assistant to the Secretary, who oversees VA’s

Office of Advisory Committees. Within the Department of Defense, we are grateful for the assistance of

Dr. Michael Kilpatrick, Deputy Director of the Office of Force Health Protection and Readiness and Dr.

Francis O’Donnell, medical consultant in that office. We also thank COL Janet Harris and CAPT Melissa

Kaime, past and current directors of the Army’s Office of Congressionally Directed Medical Research

Programs.

The Committee recognizes, with special appreciation, the Gulf War veterans and other members of the

public who have attended our meetings. We have considered their experiences and ideas—shared in

public testimony and in private conversations—to be extremely useful in charting our course, and keeping

us on course. Many veterans who have attended our meetings have themselves been chronically ill and

their participation has often required considerable personal effort and expense. Their continuing efforts

on behalf of their fellow veterans, 17 years after the war, have been an inspiration and a valuable asset in

the Committee’s work. Here we acknowledge veterans and members of the public who have offered

public testimony at Committee meetings since 2004: Mr. Mark Anderson, Ms. Lauren Billings, Mr.

Edward Bryan, Mr. Ed Butler, Ms. Becky Cann, Mr. Wesley Crawford, Mr. Albert Donnay, Ms. Julia

Dyckman, Mr. Andrew Eddowes, Mr. Dan Fahey, Ms. Connie Gonzales, Mr. Mike Hood, Ms. Alison

Johnson, Ms. Kathi Krome, Mr. Kirt Love, Dr. Ruth McGill, Dr. Meryl Nass, Mr. Harold Nelson,
318  Gulf War Illness and the Health of Gulf War Veterans

Ms. Angela Newbold, Mr. Kevin Smith, Mr. Erwin Steffen, Mr. James Thew, Ms. Venus Val-Hammack,

and Mr. Cheyne Worley. We would like to single out for special acknowledgement Ms. Denise Nichols,

retired Air Force Major, nurse, and Desert Storm veteran, for her tireless participation in nearly every

meeting held by the Committee since its inception.

One of the most valuable assets in the Committee’s work has been our small but dedicated research staff.

Their work in providing both scientific and administrative support to the Committee’s activities has been

exemplary and we are grateful for their commitment and efforts. Our thanks to Ms. Laura Palmer, Ms.

Barbara LaClair, Dr. Kim Sullivan, and Ms. Callie Comtois. We also thank Dr. Jeff Levin for his

assistance with staff activities, including technical assistance in preparing this report.

We give special recognition and thanks to Dr. Lea Steele, who served as the Committee’s Scientific

Director throughout most of the period of review and deliberations covered by this document. We

appreciate her prodigious contribution in overseeing the scientific activities of the Committee during this

period, including preparation of this report.

The Committee is also greatly indebted to the scientists and government officials who have generously

provided presentations to our meetings, taken part in scientific discussions, and often provided helpful

insights and suggestions after their meeting participation. Their names are listed below, and the

Committee could not have conducted its work without their expertise and thoughtful assistance. We are

also grateful to the countless other scientists who have conferred with the Chair, Scientific Director, and

Committee members on a wide variety of scientific matters in relation to this work. Their insights have

helped to shape our consideration of important topics and identify useful resources. Although it is not

possible to name them all here, we are most grateful for their input and advice.

We thank the scientists and government officials listed below who have provided presentations at

Committee meetings since 2004. Detailed information on presentations and discussions is provided in

each meeting’s minutes, which can be found on the Committee’s website: www.va.gov/RAC-GWVI.

February 23-24, 2004 (Washington, D.C.):

Dr. John Concato West Haven VA, Yale University

Mr. Roger Kaplan, Mr. Joe Gough,

Ms. Preeti Hans

VA Office of Research and Development

Dr. Alan Magill Walter Reed Army Institute of Research

Dr. Ya Fang Liu Boston University School of Medicine

Dr. Mohan Sopori Lovelace Respiratory Research Institute

Dr. John Ottenweller East Orange, NJ, VA War-Related Illness and Injury Study Center

Dr. Mark Peakman King’s College School of Medicine

Mr. Al Marshall Sandia National Laboratories

Dr. Terry Pellmar DOD Armed Forces Radiobiology Research Institute

Dr. Johnnye Lewis University of New Mexico

Dr. Melissa McDiarmid Baltimore VA Depleted Uranium Program

Dr. Sam Donta Boston VA (retired), Donta Infectious Diseases
Acknowledgements  319

June 28-29, 2004 (East Orange, New Jersey)

Dr. Benjamin Natelson,

Dr. Tom Findley, Dr. John

Ottenweller, Dr. Dane Cook,

Dr. Kevin Beck, Dr. Karen Quigley,

Dr. Liesel Copeland, Dr. Drew

Helmer, Dr. Gudrun Lange, Dr.

Helena Chandler, Dr. Don Ciccone,

Dr. Ronald Teichman

East Orange, NJ, VA War-Related Illness and Injury Study Center

Mr. Roger Kaplan VA Office of Research and Development

Dr. John Concato West Haven VA, Yale University

Dr. Paul Greengard, Dr. Sharon

Mates, Dr. Allen Fienberg

Intra-Cellular Therapies, Inc.

October 25-26, 2004 (Washington, D.C.)

Dr. Jack Heller, Mr. Warren

Wortman, Mr. Jeff Kirkpatrick,

MAJ Christine Moser

U.S. Army Center for Health Promotion and Preventive Medicine

CAPT Eugene Goodwin U.S. Navy Medical Service Corps

Dr. David Cowan Walter Reed Army Institute of Research

Dr. Charles Engel Walter Reed Army Medical Center

Dr. Stephan Fihn VA Office of Research and Development

Dr. Quentin Deming

Mr. Bill Weiss

April 6-8, 2005 (Washington, D.C.)

Dr. Iris Bell University of Arizona School of Medicine

Dr. William Reeves U.S. Centers for Disease Control and Prevention

Dr. Daniel Clauw University of Michigan School of Medicine

LTC Mark Melanson USACHPPM Health Physics

Ms. Mary Ann Parkhurst Battelle Pacific Northwest National Laboratory

Dr. Wayne Briner University of Nebraska

Dr. David Barber University of Florida

COL John Grabenstein Military Vaccine Agency, U.S. Army Medical Command

Dr. Phillip Pittman U.S. Army Medical Research Institute of Infectious Diseases

Dr. Brian Schuster VA Office of Research and Development

September 19-21, 2005 (Washington, D.C.)

Dr. Gary Friedman Texas Lung Institute

Dr. Bellina Veronesi U.S. Environmental Protection Agency

Dr. Mark Witten University of Arizona College of Medicine
320  Gulf War Illness and the Health of Gulf War Veterans

September 19-21, 2005 (Washington, D.C.) (cont.)

Dr. Glen Ritchie Battelle

Dr. Susan Proctor Boston VA

Dr. Mihaela Aslan,

Dr. Peter Peduzzi

West Haven VA

Mr. Tim Bullman Washington, D.C., VA

Dr. Paul Levine George Washington University

Dr. Joel Kupersmith,

Dr. Timothy O’Leary

VA Office of Research and Development

Dr. Han Kang Washington, D.C., VA

December 12-13, 2005 (Washington, D.C.)

Dr. Joel Kupersmith, Dr. William

Goldberg

VA Office of Research and Development

May 15-16, 2006 (Washington, D.C.)

Dr. Mohamed Abou-Donia Duke University Medical Center

Dr. Robert Haley University of Texas Southwestern School of Medicine

Secretary James Nicholson U.S. Department of Veterans Affairs

Dr. James Baraniuk Georgetown University School of Medicine

Dr. William Goldberg VA Office of Research and Development

August 14-15, 2006 (Washington, D.C.)

Dr. Kevin Tracey Feinstein Institute for Medical Research

Dr. Nancy Klimas Miami VA, University of Miami School of Medicine

Dr. Mariana Morris Wright State University Boonshoft School of Medicine

Dr. Mohan Sopori Lovelace Respiratory Research Institute

Dr. Jau-Shyong Hong National Institute for Environmental Health Sciences

Dr. Tomas Guilarte Johns Hopkins School of Hygiene and Public Health

Dr. Michael Kussman VA Principal Deputy Undersecretary for Health

COL Janet Harris U.S. Army Congressionally Directed Medical Research Programs

Dr. Joseph Francis, Dr. William

Goldberg

VA Office of Research and Development

November 6-7, 2006 (Dallas, Texas)

Ms. Kathleen Considine,

Mr. Vince Iannacchione

Research Triangle Institute

Dr. Robert Haley, Dr. Jeffrey

Spence, Dr. Richard Briggs, Dr.

Christopher Sinton, Dr. James Bibb,

University of Texas Southwestern School of Medicine
Acknowledgements  321

November 6-7, 2006 (Dallas, Texas) (cont.)

Dr. George DeMartino, Dr. Philip

Thomas, Dr. Ilya Bezprozvanny

University of Texas Southwestern School of Medicine

Dr. Louis Fiore Boston VA MAVERIC Program

Dr. Anil Prasad Tucson VA

Dr. Joel Kupersmith, Dr. William

Goldberg

VA Office of Research and Development

April 24-25, 2007 (Washington, D.C.)

Dr. Douglas Wallace University of California at Irvine

Dr. Julia Golier Bronx VA

Dr. Kristin Heaton U.S. Army Research Institute of Environmental Medicine

Dr. William Goldberg VA Office of Research and Development

COL Janet Harris U.S. Army Congressionally Mandated Medical Research Programs

July 18-19, 2007 (Dallas, Texas)

Dr. Jonathan Kerr St. George’s University of London

Dr. Robert Haley, Dr. Wendy Ringe,

Dr. Richard Briggs, Dr. Tom Ferree,

Dr. Sergei Cheshkov, Dr. Roderick

McColl, Dr. K.S. Gopinath, Dr.

Michael Motes

University of Texas Southwestern School of Medicine

Dr. John Hart, Dr. James Bartlett University of Texas at Dallas

Dr. William Goldberg VA Office of Research and Development

April 7-8, 2008 (Boston, Massachusetts)

Dr. Ronald Bach Minneapolis VA

Dr. Ashok Tuteja Salt Lake City VA

Dr. Fred Gorelick, Dr. Avlin Imaeda West Haven VA, Yale University

General Richard Valente Rhode Island Persian Gulf War Information and Relief Commission

Dr. Allen Fienberg Intra-Cellular Therapies, Inc.

Dr. William Goldberg VA Office of Research and Development

Dr. Louis Fiore VA Boston MAVERIC Program

September 15-16, 2008 (Washington, D.C.)

Dr. Edward Kasarskis Lexington VA

Dr. Ronnie Horner University of Cincinnati

Dr. Eugene Oddone Durham VA, Duke University Medical Center

Dr. Marie Lynn Miranda Duke University Medical Center

Dr. Paul Levine George Washington University
322  Gulf War Illness and the Health of Gulf War Veterans

September 15-16, 2008 (Washington, D.C.) (cont.)

Dr. William Goldberg VA Office of Research and Development

Dr. Robert Haley University of Texas Southwestern School of Medicine

Dr. Mitchell Wallin Washington, D.C., VA

CAPT Melissa Kaime U.S. Army Congressionally Directed Medical Research Programs

Dr. Han Kang Washington, D.C., VA

Dr. Karen Quigley, Dr. Helena

Chandler, Dr. Gudrun Lange

East Orange, NJ, VA War-Related Illness and Injury Study Center

Secretary James Peake U.S. Department of Veterans Affairs
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| Appendices

| Appendix A

Association of Gulf War Experiences and Exposures

with Chronic Symptoms and Multisymptom Illness:

Results from Studies of Gulf War Veterans
396  Results from Studies of Gulf War Veterans
Appendix A-1 . Association of CA

R

C

Paint with Multisymptom Illness  397

Appendix A-1. CARC (Chemical Agent Resistant Coating) Paint: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with CARC Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Haley Haley Syndrome 1 RR (CI) = 0.9 (0.1-6.9)

1997

249 Seabees,

24th NMCB

Near enough to smell

CARC paint sprayed Haley Syndrome 2 RR (CI) = 3.2 (1.3-8.0)*

Haley Syndrome 3 RR (CI) = 1.6 (0.5-5.1)

Kang

2002

10,423 U.S.

GWV

CARC paint GW-unique neurological

symptom complex

OR (CI) = 5.4 (4.2-6.9)* ⁪

Spencer Painted with CARC CMI OR (CI) = 1.9 (0.7-5.0)

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 2.1 (0.9-5.0)

_________________________________________________

CARC = Chemical Agent Resistant Coating; GW = Gulf War; GWV = Gulf War veterans; CMI = chronic multisymptom illness;

464 GWUI = Gulf War unexplained illness;

OR = odds ratio; RR = risk ratio; CI = 95% confidence interval; p = p value;

* statistically significant; ⁪calculated from reported data
398 

Results from

Studies of Gulf War Veterans
Appendix A-2 . Association of Chemical Agent Variables with Multisymptom Illness  399

Appendix A-2. Chemical Agent-related Variables: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Possible Chemical Agent Exposures

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Blanchard

2006

1,035 GWV

veterans

In DOD-modeled

Khamisiyah exposure area

CMI-any

CMI-severe

OR (CI) = 1.6 (1.0-.2.6)

sign.*

Boyd

2003

978 GWV in

GW Registry

Days gas mask worn

at least 4 hours

High symptom vs. low

symptom groups

p < 0.01*

Days gas mask worn at all p = 0.12

Chemical/biological warfare p < 0.01*

Goss Gilroy Chemical warfare agents Cognitive symptoms ns

1998

3,113

Canadian GWV Chronic fatigue symptoms ns

Fibromyalgia symptoms ns

Gray

2002

3,831 U.S.

Navy Seabees

Use of gas masks GWI (study-defined) OR (CI) = 2.6 (2.1-3.1)* OR(CI) = 1.4 (1.1-1.8)*

Haley Haley Syndrome 1 RR (CI) = 1.3 (0.4-3.9)

1997

249 Seabees,

24th NMCB

Experienced likely chemical

attack Haley Syndrome 2 RR (CI) = 7.8 (2.4-25.9)* ±

p < 0.001*

Haley Syndrome 3 RR (CI) = 2.3 (1.0-5.3)

In sector 7 on 20 Jan 1990 Haley Syndrome 1 undefined

Haley Syndrome 2 RR (CI) = 4.3 (1.9-10.0)* ±p = 0.004*

Haley Syndrome 3 undefined

Saw explosion suspected Haley Syndrome 1 RR (CI) = 2.2 (0.3-15.2)

chemical land mine Haley Syndrome 2 RR (CI) = 5.6 (2.3-13.6)* ns

Haley Syndrome 3 RR (CI) = 1.1 (0.2-7.6)

Found enemy's chemical or Haley Syndrome 1 RR (CI) = 6.0 (1.6-23.1)*

biological weapons Haley Syndrome 2 RR (CI) = 3.2 (0.9-11.4)

Haley Syndrome 3 RR (CI) = 1.4 (0.2-9.4)
400 

Results from

Studies of Gulf War Veterans

Appendix A-2. Chemical Agent-related Variables: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Possible Chemical Agent Exposures

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Iowa Chemical warfare agents Cognitive symptoms Prev diff = 6.8, p< 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 8.1, p< 0.001*

Ishoy Nerve gas Gastrointestinal symptoms ns

1999

686 Danish

GWV Other chemical warfare trend test, p < 0.05* ns

Mustard gas ns

Kang

2002

10,423 U.S.

GWV

Nerve gas GW-unique neurological

symptom complex

OR(CI) = 15.1 (11.6-19.7)* ⁪

Kelsall

2004

Chemical weapons area Number of symptoms ARM (CI) = 1.3 (1.2-1.5)*

McCauley

2001

2,918 U.S.

GWV

Within 50 km. of Khamisiyah

(DOD determined)

24 symptoms ns

Participated in or within sight

of Khamisiyah

6 of 24 symptoms sign.,

ORs = 1.6-2.0

Nisenbaum CMI-Mild/moderate OR (CI) = 2.5 (1.8-3.5)* OR (CI) = 2.3 (1.5-3.3)*

2000

1,002 U.S. Air

Force GWV

Thought biological or

chemical weapons used CMI-Severe OR (CI) = 6.1 (3.4-10.7)* OR (CI) = 3.5 (1.7-6.9)*

Page

2006

5,234 U.S.

Army GWV

In DOD-modeled

Khamisiyah exposure area

mild-moderate symptoms

severe symptoms

ns

2 of 47 symptoms sign.

Proctor 252 U.S. GWV Dermatological symptoms ns

1998

Chemical, biological

warfare agents Musculoskeletal symptoms sign corr, p = 0.001* p = 0.015*

Neurological symptoms sign corr, p = 0.013* sign corr*

Neuropsych symptoms sign corr, p = 0.009* sign corr*

Psychiatric symptoms sign corr, p = 0.001* sign corr*
Appendix A-2 . Association of Chemical Agent Variables with Multisymptom Illness  401

Appendix A-2. Chemical Agent-related Variables: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Possible Chemical Agent Exposures

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Reid Chemical nerve gas attack CFS OR (CI) = 1.7 (0.9-3.4) OR (CI) = 1.5 (0.7-3.1)

2001

3,531 U.K.

GWV MCS OR (CI) = 3.8 (1.9-7.6)* OR (CI) = 3.2 (1.5-6.7)*

Mustard gas CFS OR (CI) = 2.5 (0.9-7.1) OR (CI) = 1.4 (0.4-4.6)

MCS OR (CI) = 4.2 (1.4-12.0)* OR (CI) = 2.5 (0.8-7.9)

Schumm

2005

650 Ohio GWV

reservists

Located in areas potentially

affected by Khamisiyah

CMI

GWI (Kansas definition)

sign.*

ns

Spencer CMI OR (CI) = 3.2 (1.3 -7.8)*

2001

1,119 GWV

from OR, WA

Inadequate protection during

chemical/SCUD alarms GWUI (study-defined) OR (CI) = 2.4 (1.0-5.6)*

Worked around chemical

warfare agents

CMI OR (CI) = 1.9 (0.7-5.3)

Steele

2000

1,548 Kansas

GWV

Notified by DOD of possible

Khamisiyah exposure

GWI (Kansas definition) OR (CI) = 1.5 (1.1-1.9)* OR (CI) = 1.3 (0.9-1.7)

Suadicani Nerve gas Neurological symptoms ns

1999

667 Danish

GWV Other chemical warfare ns

Mustard gas trend test, p < 0.05* ns

SCUD explosion w/in 2 km ns

Unwin NBC suits CMI OR (CI) = 2.7 (2.3-3.3)*

1999

2,735 U.K.

GWV Heard chemical alarms OR (CI) = 2.2 (1.9-2.6)*

Chemical nerve gas attack OR (CI) = 2.6 (1.9-3.5)*

Wolfe

1998

2,119 U.S.

Army GWV

Poison gas exposure More than 5 symptoms

reported

OR (CI) = 6.3 (1.2-33.3)*
402 

Results from

Studies of Gulf War Veterans

Appendix A-2. Chemical Agent-related Variables: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Possible Chemical Agent Exposures

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

945 U.S.

Army GWV

Placed on formal alert for

chemical attack

Wolfe

2002

3-10 times CMI-Mild-mod. OR (CI) = 1.2 (0.8-1.8)

CMI-Severe OR (CI) = 1.1 (0.7-1.7)

CMI - Mild, mod, severe ns

more than 10 times CMI-Mild-mod. OR (CI) = 1.9 (1.4-2.7)*

CMI-Severe OR (CI) = 2.7 (2.0-3.7)*

CMI - Mild, mod, severe ns

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War Illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome; MCS = multiple chemical sensitivity;

OR = odds ratio; RR = risk ratio; corr = correlation; prev diff = prevalence difference; ARM = adjusted ratio of means; CI = 95% confidence interval; p = p value; sign. = statistically significant;

ns = not significant; * statistically significant; ⁪calculated from reported data;

±

limited number of selected exposures in model
Appendix A-3. Association of Contaminated Food and Water with Multisymptom Illness  403

Appendix A-3. Contaminated and Local Food and Water: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Local or Contaminated Food/Water

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Boyd

2003

978 GWV in

GW Registry

Ate/drank local food

or water

High symptom vs. low

symptom groups

p < 0.01*

Gray Drank contaminated water GWI (study-defined) OR (CI) = 3.8 (3.1-4.7)* OR (CI) = 1.7 (1.3-2.2)*

2002

3,831 U.S.

Navy Seabees Food poisoning in unit OR (CI) = 2.1 (1.8-2.6)* OR (CI) = 1.4 (1.1-1.8)*

Water from desert bag OR (CI) = 2.0 (1.7-2.4)* OR (CI) = 1.4 (1.1-1.7)*

Got food poisoning OR (CI) = 2.5 (1.9-3.3)* ns

Bathed in local

pond/river/Gulf

OR (CI) = 1.8 (1.5-2.1)* ns

Ate local food OR (CI) = 1.3 (1.1-1.6)* ns

Haley Haley Syndrome 1 RR (CI) = 2.6 (0.9-7.7)

1997

249 Seabees,

24th NMCB

Drinking water had

petroleum taste Haley Syndrome 2 RR (CI) = 2.8 (1.3-6.3)*

Haley Syndrome 3 RR (CI) = 2.6 (1.2-5.6)*

Ishoy Ingested contaminated food Gastrointestinal symptoms trend test, p < 0.001* ns

1999

686 Danish

GWV Ingested local food trend test, p < 0.01* ns

Bathed in or drank

contaminated water

trend test, p < 0.001* ns

Brushed teeth with

contaminated water

trend test, p < 0.001* ns

Bathed/swam in local lake,

pond, Gulf

ns

Kang

2002

10,423 U.S.

GWV

Ate food contaminated

with smoke, oil

GW-unique neurological

symptom complex

OR (CI) = 10.6 (8.1-13.9)* ⁪

Bathed in or drank

contaminated water

OR (CI) = 6.3 (4.9-8.1)* ⁪

Reid Ate local food CFS OR (CI) = 0.8 (0.5-1.4) OR (CI) = 0.9 (0.5-1.6)

2001

3,531 U.K.

GWV MCS OR (CI) = 0.8 (0.4-1.6) OR (CI) = 0.9 (0.5-1.7)
404 

Results from

Studies of Gulf War Veterans

Appendix A-3. Contaminated and Local Food and Water: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Local or Contaminated Food/Water

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Spencer Drank local alcohol CMI OR (CI) = 0.5 (0.2-1.6)

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 0.8 (0.3-1.8)

Suadicani

1999

667 Danish

GWV

Ingested contaminated food

(fumes, oil, chemicals)

Neurological symptoms trend test, p < 0.001* ns

Bathed in/drank contam

water (fumes, oil, chemicals)

trend test, p < 0.001* OR (CI) = 2.9 (1.8-4.6)*

Ingested local food trend test, p < 0.001* ns

Brushed teeth using

contaminated water

trend test, p < 0.001* ns

Unwin

1999

2,735 U.K.

GWV

Ate local food CMI OR (CI) = 1.1 (0.9-1.3)

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome;

MCS = multiple chemical sensitivity; OR = odds ratio; RR = risk ratio; corr = correlation; prev diff = prevalence difference; CI = 95% confidence interval; p = p value; sign. = statistically significant;

ns = not significant; * statistically significant; ⁪calculated from reported data
Appendix A-4. Association of Depleted Uranium

with Multisymptom Illness  405

Appendix A-4. Depleted Uranium: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Depleted Uranium Exposure

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Haley Any exposure to DU Haley Syndrome 1 RR (CI) = 0.7 (0.1-5.2)

1997

249 Seabees,

24th NMCB Haley Syndrome 2 RR (CI) = 2.4 (0.9-6.0)

Haley Syndrome 3 RR (CI) = 0.8 (0.2-3.1)

Walked past DU munitions Haley Syndrome 1 RR (CI) = 0.8 (0.1-5.6)

Haley Syndrome 2 RR (CI) = 2.6 (1.0-6.5)

Haley Syndrome 3 RR (CI) = 0.8 (0.2-3.3)

Stood 6 feet from DU Haley Syndrome 1 RR (CI) = 0.9 (0.1-6.9)

munitions Haley Syndrome 2 RR (CI) = 1.7 (0.6-5.4)

Haley Syndrome 3 RR (CI) = 1.0 (0.3-4.1)

Ishoy

1999

686 Danish

GWV

Inside destroyed Iraqi tanks Gastrointestinal symptoms trend test, p < 0.01* ns

Kang

2002

10,423 U.S.

GWV

DU exposure GW-unique neurological

symptom complex

OR (CI) = 5.7 (4.4-7.6)* ⁪

Kelsall

2004

1,456

Australian GWV

DU Number of symptoms ARM (CI) = 1.0 (0.9-1.1)

Spencer DU exposure CMI OR (CI) = 4.5 (1.7-11.4)*

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 3.7 (1.5-8.8)*

Suadicani Inside destroyed Iraqi tank Neurological symptoms trend test, p < 0.01*

1999

667 Danish

GWV DU exposure trend test, p < 0.001* OR (CI) = 2.3 (0.9-5.7)

________________________________________________

DU = depleted uranium; GW = Gulf War; GWV = Gulf War veterans; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 OR = odds ratio; RR = risk ratio; ARM = adjusted

ratio of means; CI = 95% confidence interval; p = p value; ns = not significant; * statistically significant; ⁪calculated from reported data
406 

Results from

Studies of Gulf War Veterans
Appendix A-5. Association of Fuel Exposures with Multisymptom Illness  407

Appendix A-5. Fuel Exposures: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Fuel Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Jet fuel burned in tent

heaters

Gray GWI (study-defined) OR (CI) = 2.1(1.8-2.5)* ns

2002

3,831 U.S.

Navy Seabees

Oil sprayed on ground OR (CI) = 2.2 (1.9-2.6)* ns

Haley Haley Syndrome 1 RR (CI) = 0.7 (0.2-2.2)

1997

249 Seabees,

24th NMCB

Burned jet fuel in stove or

lantern in tent Haley Syndrome 2 RR (CI) = 0.9 (0.4-2.1)

Haley Syndrome 3 RR (CI) = 0.7 (0.3-1.7)

Worked on sand sprayed Haley Syndrome 1 RR (CI) = 1.8 (0.6-5.6)

with petroleum Haley Syndrome 2 RR (CI) = 2.1 (0.9-4.9)

Haley Syndrome 3 RR (CI) = 0.9 (0.4-2.0)

Iowa Solvents/petrochemicals Cognitive symptoms Prev diff = 8.6, p < 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 6.7, p < 0.001*

Ishoy

1999

686 Danish

GWV

Diesel, kerosene, other

fumes

Gastrointestinal symptoms ns

Evaporated fuel on ground

to suppress dust

trend test, p < 0.01* ns

Skin contact with fuel trend test, p < 0.001* ns

Proctor 252 U.S. GWV Vehicle exhaust Cardiac symptoms sign corr, p = 0.026* ns

1998 Neuro symptoms sign corr, p = 0.024* ns

Smoke from tent heaters Cardiac symptoms sign corr, p < 0.001* p = 0.011*

Neuro symptoms sign corr, p = 0.001* ns

Pulmonary symptoms sign corr, p < 0.001* p = 0.007*
408 

Results from

Studies of Gulf War Veterans

Appendix A-5. Fuel Exposures: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Fuel Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Reid Exhaust from heaters CFS OR (CI) = 1.3 (0.7-2.3) OR (CI) = 1.4 (0.7-2.6)

2001

3,531 U.K.

GWV MCS OR (CI) = 2.0 (0.9-4.8) OR (CI) = 2.8 (1.1-7.5)*

Diesel on skin CFS OR (CI) = 2.1 (1.2-3.6)* OR (CI) = 1.8 (1.0-3.5)*

MCS OR (CI) = 1.7 (0.9-3.2) OR (CI) = 1.7 (0.8-3.6)

Spencer Kerosene tent heater CMI OR( CI) = 1.9 (0.9-4.0)

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 2.1 (1.1-4.0)*

Diesel tent heater CMI OR (CI) = 1.8 (0.9-3.4)

GWUI (study-defined) OR (CI) = 1.6 (0.9-2.9)

Potbelly tent heater CMI OR (CI) = 2.3 (1.1-4.7)*

GWUI (study-defined) OR (CI) = 2.0 (1.1-3.7)*

Cleaned tent heater CMI OR (CI) = 2.4 (1.3-4.5)*

GWUI (study-defined) OR (CI) = 2.2 (1.2-3.8)*

Direct contact with

diesel/petroleum fuel

1-5 times CMI OR (CI) = 1.5 (0.8-3.0)

6+ times OR (CI) = 3.8 (2.0-7.1)*

1-5 times GWUI (study-defined) OR (CI) = 1.5 (0.9-2.8)

6+ times OR (CI) = 3.6 (2.0-6.3)*

Suadicani

1999

667 Danish

GWV

Diesel, kerosene or other

fumes

Neurological symptoms trend test, p < 0.01* ns

Evaporated diesel oil used

on ground

trend test, p < 0.01* ns

Skin contact with diesel,

other petrochemical fuel

trend test, p < 0.001* ns
Appendix A-5. Association of Fuel Exposures with Multisymptom Illness  409

Appendix A-5. Fuel Exposures: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Fuel Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Diesel or petrochemical

fumes

Unwin CMI OR (CI) = 2.1 (1.7-2.5)*

1999

2,735 U.K.

GWV

Exhaust from heaters or

generators

CMI OR (CI) = 1.9 (1.6-2.2)*

Diesel or petrochemical

on skin

CMI OR (CI) = 1.8 (1.5-2.1)*

Wolfe Diesel fuel odor CMI-Mild-moderate OR (CI) = 1.9 (1.4-2.6)*

2002

945 U.S.

Army GWV CMI-Severe OR (CI) = 2.7 (1.9-3.9)*

CMI-Mild,mod,severe ns

Heater in tent CMI-Mild-moderate OR (CI) = 1.1 (0.8-1.5)

CMI- Severe OR (CI) = 1.6 (1.1-2.2)*

CMI-Mild,mod,severe OR (CI) = 1.4 (1.0-1.8)*

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome;

MCS = multiple chemical sensitivity; OR = odds ratio ; RR = risk ratio; corr = correlation; prev diff = prevalence difference; CI = 95% confidence interval; p = p value;

sign. = statistically significant; ns = not significant;

* statistically significant; ⁪calculated from reported data
410 

Results from

Studies of Gulf War Veterans
Appendix A-6. Association of Oil Well Fires with Multisymptom Illness  411

Appendix A-6. Oil Well Fires: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Oil Well Fire Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Cherry

2001

7,791 U.K.

GWV

Days exposed to oil fire

smoke

Overall symptom severity sign. corr, p < 0.001*

Gray

1999

527 U.S.

Navy Seabees

Oil fire smoke 23 individual symptoms 15 of 23 symptoms sign;

ORs = 2.1-5.7

Gray Oil fire smoke GWI (study-defined) OR (CI) = 2.2 (1.9-2.7)* ns

2002

3,831 U.S.

Navy Seabees Oil fire smoke

(modeled: yes/no)

OR (CI) = 1.5 (1.3-1.8)* OR (CI) = 0.4 (0.3-0.7)*

Haley Haley Syndrome 1 RR (CI) = 0.9 (0.1-6.3)

1997

249 Seabees,

24th NMCB

Lived/worked in air filled with

oil well smoke Haley Syndrome 2 RR (CI) = 1.6 (0.2-11.0)

Haley Syndrome 3 RR (CI) = 1.6 (0.2-11.5)

Scaled smoke exposure Haley Syndrome 1 trend test, p = 0.854

Haley Syndrome 2 trend test, p = 0.021*

Haley Syndrome 3 trend test, p = 0.072

Iowa Smoke/combustion products Cognitive symptoms Prev diff = 5.1, p < 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 5.7, p < 0.001*

Ishoy

1999

686 Danish

GWV

Fumes from burning

oil wells

Gastrointestinal symptoms ns

Kang

2002

10,423 U.S.

GWV

Food contaminated with

oil, smoke

GW-unique neurological

symptom complex

OR (CI) = 10.6 (8.1-13.9)* ⁪

Nisenbaum CMI - Mild-moderate OR (CI) = 1.3 (1.0-1.7) OR (CI) = 1.3 (0.9-1.8)

2000

1002 U.S. Air

Force GWV

Direct contact with smoke/

crude oil from oil well fires CMI - Severe OR (CI) = 2.0 (1.2-3.5)* OR (CI) = 1.6 (0.8-3.4)
412 

Results from

Studies of Gulf War Veterans

Appendix A-6. Oil Well Fires: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Oil Well Fire Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Proctor Oil fire smoke Cardiac symptoms ns

1998

252 U.S. GWV

Neuro symptoms ns

Pulmonary symptoms ns

Reid Oil fire smoke CFS OR (CI) = 0.9 (0.5-1.4) OR (CI) = 1.1 (0.6-2.0)

2001

3,531 U.K.

GWV MCS OR (CI) = 4.3 (1.6-12.2)* OR (CI) = 4.6 (1.6-13.3)*

Spencer

2001

1,119 GWV

from OR, WA

Eye irritation from burning oil

wells

1-5 days GWUI (study-defined) OR (CI) = 1.5 (0.9-2.8)

6+ days OR (CI) = 3.6 (2.0-6.3)*

1-5 days CMI OR (CI) = 2.6 (1.3-5.2)*

6+ days OR (CI) = 4.5 (2.1-9.6)*

Unwin

1999

2,735 U.K.

GWV

Oil fire smoke CMI OR (CI) = 1.8 (1.5-2.1)*

Wolfe Oil fire smoke odor CMI - Mild-moderate OR (CI) = 2.1 (1.5-2.9)*

2002

945 U.S.

Army GWV CMI - Severe OR (CI) = 2.9 (2.1-4.1)*

CMI - Mild, mod, severe OR (CI) = 1.6 (1.2-2.1)*

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome;

MCS = multiple chemical sensitivity; OR = odds ratio ; RR = risk ratio; corr = correlation; prev diff = prevalence difference; CI = 95% confidence interval; p = p value;

sign. = statistically significant; ns = not significant; * statistically significant; ⁪calculated from reported data
Appendix A-7. Association of Pesticides with Multisymptom Illness  413

Appendix A-7. Pesticides and Insect Repellants: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Pesticide Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Cherry Days handling pesticide Overall symptom severity sign. corr, p < 0.001*

2001

7,971 U.K.

GWV Peripheral symptoms sign. corr, p < 0.002*

Neurological symptoms sign. corr, p < 0.003*

Peripheral neuropathy OR = 1.3, p < 0.001*

Widespread pain Ns

Days using insect repellant Overall symptom severity sign. corr, p < 0.005*

Peripheral symptoms sign. corr, p < 0.006*

Neurological symptoms sign. corr, p < 0.007*

Peripheral neuropathy sign. corr, p < 0.008*

Widespread pain OR = 1.2, p < 0.001*

Gray Pesticides GWI (study-defined) OR (CI) = 3.5 (2.5-4.9)* OR (CI) = 1.9 (1.2-2.9)*

2002

3,831 U.S.

Navy Seabees Wore flea collar OR (CI) = 3.8 (2.7-5.2)* ns

Wore treated uniform OR (CI) = 3.4 (2.7-4.2)* ns

Wore flea collar Haley Syndrome 1 RR (CI) = 8.7 (3.0-24.7)* ± Haley p = 0.001*

1997

249 Seabees,

24th NMCB Haley Syndrome 2 RR (CI) = 2.9 (1.1-7.6)*

Haley Syndrome 3 RR (CI) = 2.7 (1.0-7.2)

DEET scale, govt. repellant Haley Syndrome 1 trend test, p = 0.14

users Haley Syndrome 2 trend test, p = 0.4

Haley Syndrome 3 trend test, p = 0.004* ±p < 0.001*

DEET scale, Off! users Haley Syndrome 1 trend test, p = 0.06

Haley Syndrome 2 trend test, p = 0.19

Haley Syndrome 3 trend test, p = 0.06 ns

DEET scale, Skin-so-soft Haley Syndrome 1 trend test, p = 0.01*

users Haley Syndrome 2 trend test, p = 0.40

Haley Syndrome 3 trend test, p = 0.19 ns
414 

Results from

Studies of Gulf War Veterans

Appendix A-7. Pesticides and Insect Repellants: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Pesticide Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Haley (cont.) Wore treated uniform Haley Syndrome 1 RR (CI) = 6.0 (1.6-23.1)*

Haley Syndrome 2 undefined

Haley Syndrome 3 RR (CI) =1.4 (0.2-9.4)

Sprayed pesticides Haley Syndrome 1 RR (CI) = 3.0 (0.9-10.3)

Haley Syndrome 2 RR (CI) = 2.8 (1.1-7.0)*

Haley Syndrome 3 RR (CI) = 2.0 (0.7-5.4)

Residence sprayed with Haley Syndrome 1 RR (CI) = 7.3 (0.9-55.4)

pesticides Haley Syndrome 2 RR (CI) = 0.5 (0.2-1.1)

Haley Syndrome 3 RR (CI) = 1.0 (0.4-2.2)

Personally sprayed Haley Syndrome 1 RR (CI) = 2.5 (0.8-7.6)

residence with pesticides Haley Syndrome 2 RR (CI) = 0.6 (0.2-1.5)

Haley Syndrome 3 RR (CI) = 1.2 (0.5-2.8)

Iowa Pesticides Cognitive symptoms Prev diff = 14.2, p < 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 11.0, p < 0.001*

Ishoy Lotions, sprays against fleas Gastrointestinal symptoms trend test, p < 0.001* ns

1999

686 Danish

GWV Insecticides against

cockroaches

trend test, p < 0.001* OR(CI) = 2.3 (1.2-4.4)*

Kelsall Pesticides Number of symptoms ARM (CI) = 1.3 (1.2-1.4)*

2004

1,456 Australian

GWV Insect repellents ARM (CI) = 1.2 (1.1-1.3)*

Kelsall Pesticides ARM (CI) = 1.7 (1.4-2.0)*

2005

1,424 Australian

GWV Insect repellents

Number of neurological

symptoms ARM (CI) = 1.3 (1.1-1.5)*
Appendix A-7. Association of Pesticides with Multisymptom Illness  415

Appendix A-7. Pesticides and Insect Repellants: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Pesticide Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Nisenbaum CMI- Mild to moderate OR (CI) = 2.0 (1.5-2.6)* OR (CI) = 1.7 (1.2-2.3)*

2000

1,002 U.S. Air

Force GWV

Used insect repellent on

regular basis CMI- Severe OR (CI) = 3.4 (2.0-6.0)* OR (CI) = 2.4 (1.3-4.5)*

Proctor 252 U.S. GWV Pesticides Dermatological symptoms ns

1998 Gastrointestinal symptoms ns

Musculoskeletal symptoms sign. corr, p = 0.001* p = 0.011*

Neurological symptoms sign. corr, p = 0.007* ns

Neuropsych symptoms ns

Psychiatric symptoms ns

Reid Personal pesticides CFS OR (CI) = 1.2 (0.7-2.1) OR (CI) = 1.0 (0.6-1.8)

2001

3,531 U.K.

GWV MCS OR (CI) = 10.6 (2.6-43.9)* OR (CI) = 10.9 (2.6-45.8)*

Pesticides on clothing CFS OR (CI) = 1.4 (0.9-2.2) OR (CI) = 1.2 (0.7-3.1)

MCS OR (CI) = 11.3 (4.8-27.0)* OR (CI) = 12.3 (5.1-30.0)*

Frequency of pesticides

sprayed in billeting area

CMI

GWI (Kansas definition)

sign.*

ns

Schumm

2005

650 Ohio GWV

reservists

Frequency of personal

pesticide use

CMI

GWI (Kansas definition)

sign.*

sign.*

Spencer DEET CMI OR (CI) = 3.3 (1.8-6.3)*

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 2.7 (1.5-4.7)* OR±

(CI) = 1.5 (0.8-2.8)

Sprayed pesticide CMI OR (CI) = 3.6 (1.8-6.9)*

GWUI (study-defined) OR (CI) = 3.1 (1.7-5.7)*

Burned surplus insecticide CMI OR (CI) = 2.3 (0.7-7.6)

GWUI (study-defined) OR (CI) = 2.9 (1.0-8.3)
416 

Results from

Studies of Gulf War Veterans

Appendix A-7. Pesticides and Insect Repellants: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Pesticide Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Lotions or spray against

e.g. fleas

Suadicani Neurological symptoms trend test, p < 0.001* ns

1999

667 Danish

GWV

Insecticides against

cockroaches

trend test, p < 0.001* ns

Unwin Personal pesticides CMI OR( CI) = 2.2 (1.9-2.6)*

1999

2,735 U.K.

GWV Pesticides on clothing or

bedding

OR (CI) = 1.9 (1.6-2.2)*

Wolfe Insecticide odor CMI - Mild-moderate OR (CI) = 1.4 (1.0-2.1)

2002

945 U.S.

Army GWV CMI - Severe OR (CI) = 3.1 (2.2-4.3)*

CMI - Mild, mod, severe ns

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome;

MCS = multiple chemical sensitivity; OR = odds ratio; RR = risk ratio; corr = correlation; prev diff = prevalence difference; CI = 95% confidence interval; p = p value;

sign. = statistically significant; ns = not significant; * statistically significant;

±

limited number of selected exposures in model
Appendix A-8. Association of Psychological Stressors with Multisymptom Illness  417

Appendix A-8. Psychological Stressors: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Psychological Stressors During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

MSE score = 0-4 ARM = 1.0

MSE score = 5-8

Total number of symptoms

ARM (CI) = 1.3 (1.2-1.5)*

Australia DVA

2003

MSE score = 9-12 ARM (CI) = 1.8 (1.6-2.0)*

1,456

Australian

GWV

MSE score > 12 ARM (CI) = 2.5 (2.3-2.8)*

Dose response p < 0.001*

Blanchard

2006

1,035 U.S.

GWV

Mean combat exposure

score

CMI p < 0.001*

Boyd Traumatic event p = 0.03*

2003

978 GWV in

GW Registry Battle experiences

High symptom vs. low symptom

groups p = 0.15

Combat Overall symptom severity ns

Peripheral symptoms ns

Neurological symptoms ns

Respiratory symptoms ns

Cherry

2001

7,971 U.K.

GWV

Gastrointestinal symptoms ns

Ford Combat exposure score OR (CI) = 1.0 (1.0-1.1)*

2001

237 cases,

113 controls

Unexplained illness case,

confirmed by physician exam

Cognitive symptoms POR (CI) = 2.1 (1.7-2.5)*

Chronic fatigue symptoms POR (CI) = 2.2 (1.5-3.1)*

Goss Gilroy

1998

3,112

Canadian GWV

Psychological stressors

Fibromyalgia symptoms POR (CI) = 1.9 (1.5-2.4)*

Gray Seeing someone killed GWI (study-defined) OR (CI) = 3.1 (2.4-4.1)* OR(CI) = 1.6 (1.1-2.2)*

2002 Seeing dead bodies OR (CI) = 2.6 (2.2-3.1)* ns

3,831 U.S.

Navy Seabees

Direct combat OR (CI) = 2.6 (2.1-3.2)* ns
418 

Results from

Studies of Gulf War Veterans

Appendix A-8. Psychological Stressors: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Psychological Stressors During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Haley Haley Syndrome 1 trend test, p=0.024*

1997

Combat stress index

Haley Syndrome 2 trend test, p=0.260

249 Seabees,

24th NMCB

Haley Syndrome 3 trend test, p=0.892

Iraqi artillery shell exploded Haley Syndrome 1 RR (CI) = 2.0 (0.5-8.4)

w/in 1 km Haley Syndrome 2 RR (CI) = 4.9 (2.2-10.9)* ns

Haley Syndrome 3 RR (CI) = 0.5 (0.1-3.3)

Haley Syndrome 1 RR (CI) = 2.2 (0.3-15.2)

Haley Syndrome 2 RR (CI) = 5.6 (2.3-13.6)* ns

Saw explosion, suspected

chem land mine

Haley Syndrome 3 RR (CI) = 1.1 (0.2-7.6)

Scud missile exploded w/in Haley Syndrome 1 RR (CI) = 1.0 (0.2-4.5)

5 km Haley Syndrome 2 RR (CI) = 4.1 (0.6-29.4)

Haley Syndrome 3 RR (CI) = 2.0 (0.5-8.4)

Iowa

1997

1,896 Iowa

GWV

Psychological stressors Fibromyalgia symptoms Prev diff = 3.4, p =0.003*

Ishoy

1999

686 Danish

GWV

SCUD explosion within

2 km

Gastrointestinal symptoms ns

Kang Sexual assault OR (CI) = 8.3 (3.9-17.9)* ⁪

2002

10,423 U.S.

GWV Sexual harassment

GW-unique neurological

symptom complex OR (CI) = 6.7 (4.7-9.6)* ⁪

Came under attack CMI - Mild-moderate OR (CI) = 1.1 (0.9-1.5) OR (CI) = 0.7 (0.5-1.0)

CMI - Severe OR (CI) = 2.4 (1.3-4.3)* OR (CI) = 1.2 (0.5-3.1)

CMI - Mild-moderate OR (CI) = 1.3 (0.8-2.0) OR (CI) = 1.0 (0.6-1.7)

Nisenbaum

2000

1,002 U.S. Air

Force GWV

Saw casualties

CMI - Severe OR (CI) = 2.2 (1.0-4.6) OR (CI) = 1.1 (0.4-2.8)
Appendix A-8. Association of Psychological Stressors with Multisymptom Illness  419

Appendix A-8. Psychological Stressors: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Psychological Stressors During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Nisenbaum CMI - Mild-moderate OR (CI) = 1.7 (1.0-2.8) OR (CI) = 1.6 (0.9-2.9)

(cont.)

Family member had

significant health event CMI - Severe OR (CI) = 2.8 (1.2-6.5)* OR (CI) = 2.2 (0.8-5.7)

Change in marital status CMI - Mild-moderate OR (CI) = 1.1 (0.7-1.6) OR (CI) = 0.9 (0.6-1.5)

CMI - Severe OR (CI) = 1.7 (0.8-3.7) OR (CI) = 1.3 (0.6-3.2)

Dismembered bodies CFS OR (CI) = 1.9 (1.1-3.4)* OR (CI) = 1.6 (0.8-3.0)

Maimed soldiers OR (CI) = 2.1 (1.3-3.5)* OR (CI) = 2.0 (1.2-3.6)*

Reid

2001

3,531 U.K.

GWV

Witnessed death OR (CI) = 2.3 (1.4-3.6)* OR (CI) = 2.2 (1.3-3.8)*

SCUD explosion OR (CI) = 2.2 (1.4-3.6)* OR (CI) = 2.6 (1.5-4.6)*

Small arms fire OR (CI) = 1.3 (0.8-2.1) OR (CI) = 1.3 (0.8-2.3)

Artillery close by OR (CI) = 1.8 (1.2-2.9)* OR (CI) = 2.4 (1.4-4.1)*

Dismembered bodies MCS OR (CI) = 4.5 (1.8-11.4)* OR (CI) = 4.2 (1.6-11.0)*

Maimed soldiers OR (CI) = 3.8 (1.9-7.6)* OR (CI) = 3.2 (1.6-6.5)*

Witnessed death OR (CI) = 2.3 (1.3-4.1)* OR (CI) = 2.2 (1.2-4.2)*

SCUD explosion OR (CI) = 1.8 (1.0-3.4) OR (CI) = 1.6 (0.8-3.0)

Small arms fire OR (CI) = 2.1 (1.2-3.7)* OR (CI) = 2.1 (1.1-3.9)*

Artillery nearby OR (CI) = 2.8 (1.5-5.0)* OR (CI) = 2.7 (1.4-5.0)*

CES subscore CMI OR (CI) = 1.1 (1.0-1.2)*

(continuous) GWUI (study-defined) OR (CI) = 1.1 (1.0-1.1)*

Spencer

2001

CES: low-mod stress GWUI (study-defined) OR±(CI) = 1.3 (0.7-2.5)

mod-heavy stress OR±(CI) = 2.4 (0.8-7.6)

Heard SCUD alarms CMI

1-5 times OR (CI) = 1.3 (0.5-3.3)

1,119 GWV

from OR, WA

6-30 times OR (CI) = 1.6 (0.8-3.2)

31+ times OR (CI) = 1.5 (0.8-2.9)
420 

Results from

Studies of Gulf War Veterans

Appendix A-8. Psychological Stressors: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Psychological Stressors During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Spencer Heard SCUD alarms GWUI (study defined)

(cont) 1-5 times OR (CI) = 1.3 (0.6-2.8)

6-30 times OR (CI) = 1.3 (0.7-2.4)

31 + times OR (CI) = 1.4 (0.8-2.5)

Saw SCUD detonate CMI

1-5 times OR (CI) = 1.1 (0.6-2.1)

6-30 times OR (CI) = 1.9 (0.9-3.9)

31 + times OR (CI) = 2.3 (0.8-6.0)

Saw SCUD detonate GWUI (study-defined)

1-5 times OR (CI) = 1.0 (0.6-1.8)

6-30 times OR (CI) = 1.9 (1.0-3.6)

31 + times OR (CI) = 1.6 (0.7 - 4.1)

Witnessed combat Neurological symptoms trend test, p < 0.01*

Saw assaults on civilians trend test, p < 0.01*

Suadicani

1999

667 Danish

GWV

Saw wounded/ dead trend test, p < 0.05*

Threatened with arms trend test, p < 0.01*

Saw colleagues threatened

or shot at

trend test, p < 0.001* ns

Was shot at trend test, p < 0.01*

Pointed gun/shot other trend test, p < 0.001*

Dismembered bodies CMI OR (CI) = 2.0 (1.7-2.3)*

Maimed soldiers OR (CI) = 1.7 (1.5-2.0)*

Combat injury OR (CI) = 2.9 (2.1-4.2)*

Witness death OR (CI) = 1.6 (1.4-1.9)*

Unwin

1999

2,735 U.K.

GWV

SCUD exploded w/in 1 mile OR (CI) = 1.6 (1.4-1.9)*

Under small arms fire OR (CI) = 1.5 (1.3-1.7)*
Appendix A-8. Association of Psychological Stressors with Multisymptom Illness  421

Appendix A-8. Psychological Stressors: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Psychological Stressors During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Wolfe

1998

2,119 GWV High combat exposure

score

High symptom endorsement OR (CI) = 3.2 (2.3-4.4)* ns

Score > 6 on expanded

combat exposure scale

CMI - Mild-moderate OR (CI) = 1.5 (1.1-2.1)*

CMI - Severe OR (CI) = 1.5 (1.1-2.1)*

Wolfe

2002

945 U.S.

Army GWV

CMI - Mild, mod, severe ns

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome;

MCS = multiple chemical sensitivity; MSE = Military Service Experience score; CES = Keane Combat Exposure Scale; DVA = Department of Veterans Affairs;

OR = odds ratio; RR = risk ratio; corr = correlation; prev diff = prevalence difference; CI = 95% confidence interval; p = p value; sign. = statistically significant; ns = not significant;

* statistically significant;

±

limited number of selected exposures in model; ⁪calculated from reported data
422 

Results from

Studies of Gulf War Veterans
Appendix A-9. Association of Pyridostigmine Bromide with Multisymptom Illness  423

Appendix A-9. Pyridostigmine Bromide: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Use of Pyridostigmine Bromide

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Boyd Days taking any PB p = 0.07

2003

978 GWV in

GW Registry Days taking > 3 PB pills

High symptom vs. low

symptom groups p = 0.08

Cherry Days used NAPs Overall symptom severity sign. corr; p < 0.001*

2001

7,971 U.K.

GWV

Side effects from NAPs Overall symptom severity sign. corr; p < 0.001*

Peripheral symptoms sign. corr; p < 0.001*

Gastrointestinal symptoms sign. corr; p < 0.001*

Peripheral neuropathy OR = 1.4, p < 0.001*

Widespread pain OR = 1.5, p < 0.001*

Gray

2002

3,831 U.S.

Navy Seabees

Took PB tablets GWI (study defined) OR (CI) = 3.0 (2.4-3.7)* OR (CI) = 1.4 (1.1-1.9)*

Haley Took PB tablets Haley Syndrome 1 RR (CI) = 0.6 (0.1-4.3)

1997

249 Seabees,

24th NMCB Haley Syndrome 2 undefined

Haley Syndrome 3 RR (CI) = 0.6 (0.1-2.1)

Scale of advanced side Haley Syndrome 1 trend test, p = 0.413

effects of PB Haley Syndrome 2 trend test, p < 0.001* p

±

< 0.001*

Haley Syndrome 3 trend test, p < 0.001* p

±

< 0.001*

Scale of mild side effects Haley Syndrome 1 trend test, p= 0.670

of PB Haley Syndrome 2 trend test, p= 0.003* ns

Haley Syndrome 3 trend test, p= 0.067

Iowa PB tablets used Cognitive symptoms Prev diff = 12.0, p < 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 16.4, p < 0.001*
424 

Results from

Studies of Gulf War Veterans

Appendix A-9. Pyridostigmine Bromide: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Use of Pyridostigmine Bromide

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Kelsall Any PB Number of symptoms ARM (CI) = 1.4 (1.2-1.5)*

2004

1,456

Australian GWV 1-80 PB tablets ARM (CI) = 1.3 (1.1-1.5)*

81-180 PB tablets ARM (CI) = 1.4 (1.2-1.6)*

>180 PB tablets ARM (CI) = 1.4 (1.2-1.7)*

Dose-response ARM (CI) = 1.1 (1.1-1.2)*

Kelsall Any PB ARM (CI) = 1.5 (1.2-1.8)*

2005

1,424

Australian GWV 1-80 PB tablets

Number of neurological

symptoms ARM (CI) = 1.4 (1.0-1.8)

81-180 PB tablets ARM (CI) = 1.6 (1.2-2.1)*

>180 PB tablets ARM (CI) = 1.6 (1.2-2.1)*

Dose-response ARM (CI) = 1.2 (1.1-1.3)*

Nisenbaum CMI - Mild-moderate OR (CI) = 1.4 (1.1-1.8)* OR (CI) = 1.6 (1.1-2.2)*

2000

1,002 U.S. Air

Force GWV

Took PB to protect from

nerve gas CMI - Severe OR (CI) = 3.0 (1.7-5.2)* OR (CI) = 2.9 (1.4-6.1)*

Proctor 252 U.S. GWV Anti-nerve gas pills Dermatological symptoms ns

1998 Gastrointestinal symptoms ns

Musculoskeletal symptoms ns

Neurological symptoms ns

Neuro-psych symptoms ns

Psychiatric symptoms ns

Reid PB CFS OR (CI) = 1.6 (0.8-3.2) OR (CI) = 1.5 (0.6-3.4)

2001

3,531 U.K.

GWV MCS OR (CI) = 1.5 (0.6-3.5) OR (CI) = 1.6 (0.6-4.0)

Amount of PB taken CMI

GWI (Kansas definition)

sign.*

sign.*

Schumm

2005

650 Ohio GWV

reservists
Appendix A-9. Association of Pyridostigmine Bromide with Multisymptom Illness  425

Appendix A-9. Pyridostigmine Bromide: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Use of Pyridostigmine Bromide

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Spencer < 21 PB pills CMI OR (CI) = 3.2 (1.7-5.8)*

2001

1,119 GWV

from OR, WA 22+ PB pills OR (CI) = 4.4 (2.1-9.4)*

< 21 PB pills GWUI (study-defined) OR (CI) = 2.2 (1.3-3.8)* OR±(CI) = 1.6 (0.9–2.9)

22+ PB pills OR (CI) = 3.8 (2.0-7.4)* OR±(CI) = 2.2 (1.0–4.6)*

Unwin PB CMI OR (CI) = 2.6 (2.2-3.1)*

1999

2,735 U.K.

GWV

Wolfe 1-21 PB pills CMI - Mild-moderate OR (CI) = 1.9 (1.4-2.7)*

2002

945 U.S.

Army GWV CMI - Severe OR (CI) = 2.3 (1.6-3.3)*

CMI - Mild, mod, severe OR (CI) = 1.4 (1.0-1.9)*

>21 PB pills CMI - Mild-moderate OR (CI) = 2.5 (1.6-3.9)*

CMI -Severe OR (CI) = 3.7 (2.4-5.6)*

CMI - Mild, mod, severe OR (CI) = 2.1 (1.4-3.1)*

_________________________________________________

PB = pyridostigmine bromide; NAPs = nerve agent pretreatment sets; GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; GWUI = Gulf War unexplained illness;

CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome; MCS = multiple chemical sensitivity; OR = odds ratio; RR = risk ratio; corr = correlation; prev diff = prevalence difference;

CI = 95% confidence interval; p = p value; sign. = statistically significant; ns = not significant;

* statistically significant;

±

limited number of selected exposures in model
426 

Results from

Studies of Gulf War Veterans
Appendix A-10. Association of Sand with Multisymptom Illness  427

Appendix A-10. Sand-related Variables: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Sand Exposures During Deployment

Study Veterans Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Gray

1999

527 U.S.

Navy Seabees

Sandstorms 23 symptoms 7 of 23 symptoms sign.;

ORs 2.3-4.1

Gray

2002

3,831 U.S.

Navy Seabees

Sandstorms GWI (study-defined) OR (CI) = 2.6 (2.1-3.3)* OR (CI) = 1.7 (1.3-2.3)*

Ishoy

1999

686 Danish

GWV

Sand or dust storm Gastrointestinal symptoms trend test, p < 0.01 ns

Nisenbaum Sandbagging/digging CMI - Mild-moderate OR (CI) = 1.8 (1.4-2.4)* OR (CI) = 1.4 (1.0-1.9)

2000

1,002 U.S. Air

Force GWV CMI -Severe OR (CI) = 3.1 (1.7-5.5)* OR (CI) = 1.5 (0.7-2.9)

Walk/hike in sand CMI - Mild-moderate OR (CI) = 1.6 (1.1-2.4)* OR (CI) = 1.1 (0.7-1.7)

CMI -Severe OR (CI) = 6.4 (1.5-26.7)* OR (CI) = 2.6 (0.6-11.7)

Suadicani

1999

667 Danish

GWV

Sand or dust storm Neurological symptoms trend test, p < 0.01* ns

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWI = Gulf War illness; CMI = chronic multisymptom illness;

464 OR = odds ratio; CI = 95% confidence interval; sign. = statistically significant;

ns = not significant; * statistically significant
428 

Results from

Studies of Gulf War Veterans
Appendix A-11. Association of Solvents with Multisymptom Illness  429

Appendix A-11. Solvents: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Solvent Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Iowa Solvents/petrochemicals Cognitive symptoms Prev diff = 6.6, p < 0.001*

1997

1,896 Iowa

GWV Fibromyalgia symptoms Prev diff = 4.6, p < 0.001*

Ishoy

1999

686 Danish

GWV

Other paint, solvents or

kerosene products

Gastrointestinal symptoms trend test, p < 0.05* ns

Kelsall

2005

1,424

Australian GWV

Solvents Neurological symptoms ARM (CI) = 1.8 (1.3-2.5)*

Reid Other paints or solvents CFS OR (CI) = 1.3 (0.8-2.2) OR (CI) = 1.4 (0.8-2.5)

2001

3,531 U.K.

GWV MCS OR (CI) = 2.2 (1.1-4.4)* OR (CI) = 2.4 (1.1-5.1)*

Spencer Vehicle repair CMI OR (CI) = 3.3 (1.9-5.8)*

2001

1,119 GWV

from OR, WA GWUI (study-defined) OR (CI) = 3.0 (1.8-4.9)*

Battery repair CMI OR (CI) = 2.7 (1.3-5.5)*

GWUI (study-defined) OR (CI) = 2.1 (1.1-4.1)*

Generator repair CMI OR (CI) = 2.1 (1.2-3.9)*

GWUI (study-defined) OR (CI) = 1.6 (1.0-2.8)

Refrig service CMI OR (CI) = 2.9 (0.9-9.2)

GWUI (study-defined) OR (CI) = 2.1 (0.7-6.3)

Electronic/ radio repair CMI OR (CI) = 1.2 (0.6-2.2)

GWUI (study-defined) OR (CI) = 1.3 (0.7-2.2)

Degreasing machinery CMI OR (CI) = 2.4 (1.3-4.2)*

GWUI (study-defined) OR (CI) = 2.5 (1.5-4.1)*

Cleaned hydraulic leaks CMI OR (CI) = 2.5 (1.3-4.6)*

GWUI (study-defined) OR (CI) = 2.5 (1.4-4.3)*

Weapons repair CMI OR (CI) = 1.2 (0.5-2.9)

GWUI (study-defined) OR (CI) = 1.5 (0.7-3.1)
430 

Results from

Studies of Gulf War Veterans

Appendix A-11. Solvents: Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Solvent Exposures During Deployment

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Unwin Other paints or solvents CMI OR (CI) = 1.7 (1.5-2.0)*

1999

2,735 U.K.

GWV

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; GWUI = Gulf War unexplained illness; CMI = chronic multisymptom illness;

464 CFS = chronic fatigue syndrome; MCS = multiple chemical sensitivity;

OR = odds ratio; CI = 95% confidence interval; p = p value; prev diff = prevalence difference; sign. = statistically significant; ns = not significant;

* statistically significant
Appendix A-12a. Association of Vaccines (Individual Types) with Multisymptom Illness  431

Appendix A-12a. Vaccines (Individual Types): Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Individual Types of Vaccines

Study

Veterans

Studied Vaccine/Shot Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Boyd Botulism OR = 1.8, p = 0.02*

2003

978 GWV in

GW Registry Meningococcus

High symptom vs.

low symptom groups OR = 1.6, p = 0.10

Anthrax OR = 1.7, p = 0.03*

Plague OR = 1.3, ns

Typhoid OR = 1.4, ns

IgG OR = 1.2, ns

Goss Gilroy Cognitive symptoms OR (CI) = 1.3 (1.1-1.5)*

1998

3,113

Canadian GWV

Non-routine immunizations

(anthrax, plague) Chronic fatigue symptoms OR (CI) = 1.9 (1.5-2.5)*

Fibromyalgia symptoms ns

Anthrax 23 individual symptoms 12 of 23 symptoms sign.;

ORs 2.0-4.5

Gray

1999

527 U.S.

Navy Seabees

IgG 11 of 23 symptoms sign.;

ORs 2.1-8.1

Botulism 16 of 23 symptoms sign.;

ORs 2.7-5.2

Gray Meningococcus GWI (study-defined) OR (CI) = 3.6 (2.5-5.2)* OR (CI) = 1.3 (1.0-1.6)*

2002

3,831 U.S.

Navy Seabees Botulism OR (CI) = 4.9 (3.5-7.0)* ns

Anthrax OR (CI) = 3.7 (2.6-5.4)* ns

Plague OR (CI) = 3.2 (2.2-4.8)* ns

IgG OR (CI) = 1.9 (1.4-2.5)* ns

Typhoid OR (CI) = 2.3 (1.5-3.6)* ns
432 

Results from

Studies of Gulf War Veterans

Appendix A-12a. Vaccines (Individual Types): Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Individual Types of Vaccines

Study

Veterans

Studied Vaccine/Shot Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Hotopf Received predeployment CMI

2000 Anthrax OR (CI) = 1.3 (0.8-2.0)

923 U.K. GWV

with vaccine

records Plague OR (CI) = 1.2 (0.6-2.2)

Pertussis OR (CI) = 1.0 (0.5-1.7)

Tetanus OR (CI) = 0.9 (0.6-1.3)

Cholera OR (CI) = 0.9 (0.6-1.2)

Hepatitis A OR (CI) = 1.3 (0.8-2.1)

Hepatitis B OR (CI) = 0.8 (0.5-1.3)

Polio OR (CI) = 0.7 (0.5-1.2)

Yellow fever OR (CI) = 1.3 (0.9-1.9)

Typhoid OR (CI) = 1.0 (0.7-1.4)

Received during deployment CMI

Anthrax OR (CI) = 1.3 (0.9-2.0)

Plague OR (CI) = 0.9 (0.6-1.4)

Pertussis OR (CI) = 1.3 (0.9-2.0)

Tetanus OR (CI) = 2.7 (1.0-7.2)*

Cholera OR (CI) = 2.9 (1.0-7.9)*

Hepatitis A OR (CI) = 1.3 (0.5-3.2)

Hepatitis B OR (CI) = 0.7 (0.3-1.4)

Polio OR (CI) = 1.2 (0.3-4.3)

Yellow fever OR (CI) = 0.8 (0.2-3.7)

Typhoid OR (CI) = 0.7 (0.3-2.0)

Kang

2002

10,423 U.S.

GWV

Botulism vaccine GW-unique neurological

symptom complex

OR (CI) = 3.5 (2.7-4.7)* ⁪

Mahan

2004

11,441 U.S.

GWV

Anthrax vaccine

(verified by DOD records)

10 severe symptoms 5 of 10 symptoms sign.;

ORs =1.5-1.6
Appendix A-12a. Association of Vaccines (Individual Types) with Multisymptom Illness  433

Appendix A-12a. Vaccines (Individual Types): Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Individual Types of Vaccines

Study

Veterans

Studied Vaccine/Shot Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Schumm

2005

650 Ohio GWV

reservists

Anthrax GWI (Kansas definition) sign.*

Unwin Anthrax CMI OR (CI) = 1.5 (1.3-1.7)*

1999

2,735 U.K.

GWV Plague OR (CI) = 1.3 (1.1-1.6)*

Pertussis OR (CI) = 1.1 (0.9-1.4)

Any biological vaccine OR (CI) = 1.5 (1.3-1.7)*

Hepatitis A OR (CI) = 1.1 (0.8-1.5)

Hepatitis B OR (CI) = 1.0 (0.8-1.3)

Yellow fever OR (CI) = 1.3 (1.1-1.7)*

Typhoid OR (CI) = 1.0 (0.8-1.3)

Poliomyelitis OR (CI) = 1.2 (1.0-1.5)

Cholera OR (CI) = 1.1 (0.9-1.4)

Tetanus OR (CI) = 1.3 (1.1-1.5)*

Any routine vaccine OR (CI) = 1.2 (1.1-1.4)*

Wolfe Anthrax CMI - Mild-moderate OR (CI) = 1.5 (1.1-2.1)*

2002

945 U.S.

Army GWV CMI - Severe OR (CI) = 1.9 (1.4-2.6)*

CMI - Mild, mod, severe OR (CI) = 1.5 (1.1-2.0)*

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; CMI = chronic multisymptom illness;

464 OR = odds ratio; CI = 95% confidence interval; sign. = statistically significant; ns = not significant;

* statistically significant; ⁪calculated from reported data
434 

Results from

Studies of Gulf War Veterans
Appendix A-12b. Association of Vaccines (Number Received) with Multisymptom Illness  435

Appendix A-12b. Vaccines (Number Received): Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Number of Vaccines Received

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Cherry Number of inoculations Overall symptom severity sign. corr; p < 0.001*

2001

7,971 U.K.

GWV Peripheral symptoms sign. corr; p < 0.001*

Hotopf Received predeployment CMI

2000 0/1 vaccine OR = 1.0

923 U.K. GWV

with vaccine

records 2 vaccines OR (CI) = 1.0 (0.6-1.6)

3 vaccines OR (CI) = 0.8 (0.5-1.4)

4 vaccines OR (CI) = 1.3 (0.8-2.2)

5+ vaccines OR (CI) = 1.1 (0.6-2.0)

trend test, p = 0.38

Received during deployment

0/1 vaccine OR = 1.0

2 vaccines OR (CI) = 2.2 (1.3-3.7)*

3 vaccines OR (CI) = 2.4 (1.4-4.0)*

4 vaccines OR (CI) = 2.2 (1.4-3.4)*

5+ vaccines OR (CI) = 5.0 (2.5-9.8)*

trend test, p < 0.001

Kelsall Any immunization Number of symptoms ARM (CI) = 1.0 (0.9-1.2)

2004

1,456

Australian GWV 1-4 immunizations ARM (CI) = 0.9 (0.7-1.0)

5-9 immunizations ARM (CI) = 1.0 (0.9-1.2)

10+ immunizations ARM (CI) = 1.3 (1.1-1.6)*

>5 in one week ARM (CI) = 1.1 (1.0-1.2)

Dose response ARM (CI) = 1.0 (1.0-1.1)*
436 

Results from

Studies of Gulf War Veterans

Appendix A-12b. Vaccines (Number Received): Association with Symptoms and Multisymptom Illness in Studies of Gulf War Veterans

Association of Health Outcomes with Number of Vaccines Received

Study

Veterans

Studied Exposure Assessed Health Outcome Crude (no adjustments)

Adjusted only for military,

demographic variables

Adjusted for other

deployment exposures

Kelsall Any immunization ARM (CI) = 1.1 (0.8-1.5)

2005

1,424

Australian GWV 1-4 immunizations

Number of neurological

symptoms ARM (CI) = 0.8 (0.6-1.1)

5-9 immunizations ARM (CI) = 1.1 (0.8-1.5)

10+ immunizations ARM (CI) = 1.5 (1.1-2.3)*

>5 in one week ARM (CI) = 1.1 (0.8-1.5)

Dose response ARM (CI) = 1.1 (1.0-1.1)*

Unwin All veterans CMI

1999

2,735 U.K.

GWV 1-2 vaccinations OR (CI) = 0.9 (0.7-1.2)

3-6 vaccinations OR (CI) = 1.2 (1.0-1.4)

7+ vaccinations OR (CI) = 1.8 (1.5-2.2)*

trend test, p < 0.001

Veterans with shot records CMI

1-2 vaccinations OR (CI) = 1.2 (0.7-2.0)

3-6 vaccinations OR (CI) = 1.1 (0.8-1.6)

7+ vaccinations OR (CI) = 1.9 (1.3-2.8)*

trend test, p < 0.001

_________________________________________________

GW = Gulf War; GWV = Gulf War veterans; CMI = chronic multisymptom illness;

464 OR = odds ratio; CI = 95% confidence interval; ARM = adjusted ratio of means; p = p value;

sign. = statistically significant; ns = not significant;

* statistically significant
| Appendix B

Charter of the Research Advisory Committee

on Gulf War Veterans’ Illnesses
438  Research Advisory Committee on Gulf War Veterans’ Illnesses
Committee Charter  439

| Committee Charter

DEPARTMENT OF VETERANS AFFAIRS

CHARTER OF THE

RESEARCH ADVISORY COMMITTEE ON

GULF WAR VETERANS’ ILLNESSES

A. OFFICIAL DESIGNATION: Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC-GWVI).

B. OBJECTIVES AND SCOPE OF ACTIVITY: The Department of Veterans Affairs (VA) Research Advisory

Committee on Gulf War Veterans’ Illnesses shall provide advice and make recommendations to the Secretary of

Veterans Affairs on proposed research plans and strategies related to understanding and treating the health

consequences of military service in the Southwest Asia theater of operations during the 1990-1991 Gulf War

(Operations Desert Shield and Desert Storm). The Committee shall not conduct scientific research or review

research proposals submitted to VA prior to funding. VA may, however, request individual Committee members with

appropriate scientific expertise to participate in the review of such proposals.

The guiding principle for the work of the Committee shall be the premise that the fundamental goal of Gulf Warrelated government research, either basic or applied, is to ultimately improve the health of ill Gulf War veterans, and

that the choice and success of research efforts shall be judged accordingly. The Committee shall assess the overall

effectiveness of government research to answer central questions on the nature, causes, and treatments for health

consequences of military service in the Southwest Asia theater of operations during the1990-1991 Gulf War.

The Committee shall meet in public session to review all relevant funded research, investigations, and processes for

funding research conducted previously and assess their methods, results, and implications. The Committee shall

review all proposed Federal research plans, initiatives, procurements, grant programs, and other activities in support

of research projects on health consequences of military service in the Southwest Asia theater of operations during

the 1990-1991 Gulf War. The Committee, consistent with law, shall have access to all VA documents and other

sources of information it finds relevant to such review.

C. PERIOD OF TIME NECESSARY FOR THE COMMITTEE TO CARRY OUT ITS PURPOSE: The Committee

was established in compliance with statutory instructions contained in § 104 of Public Law 105-368. It has no

termination date.

D. OFFICIAL TO WHOM THE COMMITTEE REPORTS: The Committee shall report to the Secretary of

Veterans Affairs.

E. OFFICE RESPONSIBLE FOR PROVIDING THE NECESSARY SUPPORT TO THE COMMITTEE: The

Veterans Health Administration of the Department of Veterans Affairs will provide support for the Committee. A VA

employee shall be the Designated Federal Officer. Technical support for the Committee shall be provided by a staff

that reports to the Committee chair, who may appoint a technical director for the staff to supervise its operation. Staff

members may be VA employees, employees of other government agencies, or independent agents employed as

temporary VA employees.

F. DUTIES OF THE COMMITTEE: The Committee shall provide to the Secretary of Veterans Affairs, not later

than December 1 of each year, an annual report summarizing its activities for the preceding year. The Committee is

authorized to develop additional reports and recommendations regarding relevant research. During its review of

such research and in compliance with governing law, the Committee shall have access to all VA documents and
440  Research Advisory Committee on Gulf War Veterans’ Illnesses

other information sources it finds relevant to such review. Recommendations contained within a formal Committee

report shall be submitted to the Secretary and other appropriate officials, as directed by the Secretary. All such

reports shall be approved by the Committee, meeting in open public session, prior to submission to the Secretary.

The Secretary shall, to the extent provided by law, seek support from other Federal departments and agencies to

provide the Committee with information and research findings it may require for purposes of carrying out its functions.

To augment the expertise of the Committee, the Secretary may, at the request of the chair of the Committee, contract

through VA for the services of non-governmental consultants who may prepare reports and background papers or

prepare other materials for consideration by the Committee, as appropriate.

The Committee shall be comprised of members of the general public, including Gulf War veterans, representatives of

such veterans, and members of the medical and scientific communities representing appropriate disciplines such as,

but not limited to, biomedicine, epidemiology, immunology, environmental health, neurology, and toxicology.

Members shall be appointed for two- or three-year terms. The Secretary may renew the terms of members. The

Secretary shall appoint the chair of the Committee. The term of office for the chair shall be two years, also

renewable by the Secretary. The Committee will be composed of approximately fifteen (15) members. Several

members may be Regular Government Employees (RGE), but the majority of the Committee’s membership will be

Special Government Employees (SGE).

The Committee may establish subcommittees to carry out specific projects or assignments. The Committee chair

shall notify the Secretary, through the Designated Federal Officer for the Committee, upon the establishment of any

subcommittee, including its function, membership and estimated duration.

The Secretary may establish a panel of experts representing appropriate medical and scientific disciplines to assist

the Committee in its work. Panelists may be called on by the Secretary for advice and consultation, and may advise

the Committee on research or conduct other appropriate activities for the Committee, at the request of the Committee

chair. Panelists shall report directly to the chair or such Committee members designated by the chair, but they shall

not be members of the Committee. Panelists will be nominated by the Committee chair and appointed by the

Secretary.

G. ESTIMATED ANNUAL OPERATING COSTS IN DOLLARS AND STAFF-YEARS: The estimated annual cost

for operating the Committee and its support staff is $400,000 and 4 FTE. All members will receive travel expenses

and a per diem allowance in accordance with the Federal Travel Regulation for any travel made in connection with

their participation in Committee meetings.

H. ESTIMATED NUMBER AND FREQUENCY OF MEETINGS: The Committee is expected to meet not less than

twice annually. Meetings of the subcommittee(s) shall be convened as necessary. The Designated Federal Officer

(DFO), a full time VA employee, will approve the schedule of Committee meetings. The DFO or a designee will be

present at all meetings, and each meeting will be conducted in accordance with an agenda approved by the DFO.

The DFO is authorized to adjourn any meeting when he or she determines it is in the public interest to do so.

I. COMMITTEE TERMINATION DATE: None.

J. DATE CHARTER IS FILED:

APPROVED: _ James B. Peake, M.D._____ Date: ___05/08/08_______

Secretary of Veterans Affairs
| Appendix C

Members of the Research Advisory Committee

on Gulf War Veteran’s Illnesses
442  Research Advisory Committee on Gulf War Veterans’ Illnesses
Committee Members  443

| Committee Members

James H. Binns (Committee Chair)

Mr. Binns is former Principal Deputy Assistant Secretary of Defense for International Security Policy,

and a Vietnam veteran. He is also former chairman of Parallel Design and past president of A.D.R.

Ultrasound, two medical imaging manufacturing companies which he led from startup to merger with

major corporations. He is a graduate of Stanford University and Harvard Law School.

Carrolee Barlow, MD, PhD

Dr. Barlow is Vice President of Research for BrainCells, Inc., and previously conducted neuroscience

research at the National Institutes of Health, the Salk Institute of Biological Studies, and Merck Research

Laboratories. Dr. Barlow is an expert in neuroscience and clinical applications of basic research to

neurological and neuropsychiatric diseases. She has authored numerous articles and book chapters in

areas ranging from neurogenomics to the implications of basic research for understanding genetic

diseases affecting the brain.

Floyd E. Bloom, MD

Dr. Bloom is Professor Emeritus in the Molecular and Integrative Neuroscience Department at The

Scripps Research Institute. He is a distinguished neuroscientist who pioneered the use of modern

molecular biological and database techniques in brain research. Dr. Bloom is a past president of the

American Association for the Advancement of Science (AAAS) and a member of the National Academy

of Sciences, the Institute of Medicine, the American Philosophical Society, and the Royal Swedish

Academy of Science. He has authored or co-authored over 700 scientific articles and was Editor-in-Chief

of Science Magazine from 1995 – 2000.

Daniel J. Clauw, MD

Dr. Clauw is Assistant Dean for Clinical and Translation Research and Professor of Medicine at the

University of Michigan. He is director of the Chronic Pain and Fatigue Research Center and the Center

for the Advancement of Clinical Research. His primary research interest focuses on overlapping chronic

pain syndromes such as fibromyalgia and Gulf War illness and the role of central nervous system

dysfunction in the development of these syndromes. He leads a multidisciplinary team of collaborators

committed to identifying chronic pain syndrome risk factors and the establishment of programs aimed at

the most effective treatment and prevention of this spectrum of illnesses.

Beatrice A. Golomb, MD, PhD

Dr. Golomb is Associate Professor of Medicine and of Family and Preventive Medicine at the University

of California at San Diego, Research Associate Professor of Psychology at the University of Southern

California, and a Robert Wood Johnson Generalist Physician Faculty Scholar. Her research focuses on the

risks and benefits of medical interventions, especially cholesterol drugs, and on Gulf War veterans'

illnesses. As a RAND scientist she traveled to the Middle East on a fact finding mission related to this

issue, and has authored several RAND reports on the relation of exposures to illness in Gulf War

veterans. Dr. Golomb served as Scientific Director of the Committee in 2002 and 2003.
444  Research Advisory Committee on Gulf War Veterans’ Illnesses

Joel C. Graves, DMin

Rev. Graves is a Lutheran minister, hospice chaplain and Gulf War veteran. He retired from the U.S.

Army in 1997 as a captain, after serving as enlisted for nine years and an armor officer for nine years.

During the war, he was a member of the 1st Battalion, 67th Armored Battalion, 1st "Tiger" Brigade

Independent Task Force, which took the northern part of Kuwait City. He has Gulf War illness.

Anthony Hardie

Mr. Hardie is Executive Assistant of the Wisconsin Department of Veterans Affairs where he oversees the

agency's relations with the state legislature, Congress, the media, stakeholders, and the public. He is a

Gulf War and Somalia veteran and is a former officer with the National Gulf War Resource Center. He

has worked extensively on policy issues related to Gulf War veterans' illnesses and deployment health.

He is a former Congressional staff member, a graduate of the University of Wisconsin, and the 2005

recipient of Wisconsin's Disabled American Veterans Department Distinguished Service Award.

Marguerite L. Knox, MN, NP

LTC Knox serves on the South Carolina Army National Guard's Medical Command and is a senior sales

representative for Teva Neuroscience. During the Gulf War she served with the 251st Evacuation

Hospital at King Khalid Military City, Saudi Arabia. During her tenure as Assistant Professor at the

University of South Carolina College of Nursing, she served on the Presidential Advisory Committee on

Gulf War Veterans' Illnesses (1995-1998).

William J. Meggs, MD, PhD

Dr. Meggs is Professor and Chief of the Division of Toxicology, Department of Emergency Medicine at

the Brody School of Medicine at East Carolina University, where he also serves as Senior Vice Chair for

Academic Affairs. His research interests include the role of neurogenic inflammation in chemical

sensitivity, and the effects of low-level exposures to organophosphorous compounds. Dr. Meggs is a

fellow of the American College of Medical Toxicology and the American College of Emergency

Medicine, and served on the National Academy of Science's subcommittee on immunotoxicology.

Mary Dekker Nettleman, MD, MS

Dr. Nettleman is the Chair of the Department of Medicine at Michigan State University. She is dually

boarded in Internal Medicine and Infectious Diseases, with a Master's Degree in Preventive Medicine.

Her research focuses on disease epidemiology, with special emphasis on nosocomial infections, sexually

transmitted diseases, and early pregnancy. She has served on national committees, study sections, and

editorial boards related to infectious diseases, quality of care, and general internal medicine.

James P. O'Callaghan, PhD

Dr. O'Callaghan is Distinguished Consultant and Head of the Molecular Neurotoxicology Laboratory in

the Toxicology and Molecular Biology Branch of the Health Effects Laboratory Division at the U.S.

Centers for Disease Control and Prevention (CDC). Prior to joining CDC, Dr. O'Callaghan founded the

molecular and cellular neurotoxicology program in the Neurotoxicology Division, U.S. Environmental

Protection Agency in Research Triangle Park, North Carolina. He directs a research program dedicated

to the discovery and implementation of biomarkers of neurotoxicity.
Committee Members  445

Steve Smithson

Mr. Smithson is Deputy Director for Claims Services for the American Legion, where he oversees matters

related to the Veterans Benefits Administration. He served on active duty in the United States Marine

Corps from 1988-92, including a seven-month tour of duty in Saudi Arabia and Kuwait during the Gulf

War. Mr. Smithson was previously an Assistant Director for Gulf War and deployment-related issues

with the American Legion.

Lea Steele, PhD

Dr. Steele is Adjunct Associate Professor in the College of Human Ecology at Kansas State University.

She is an epidemiologist and human ecologist whose research interests focus on the study of complex

medical conditions that are difficult to diagnose and treat. Dr. Steele previously directed the Kansas

Persian Gulf War Veterans Health Initiative, a state-sponsored research and service program, and was

principal investigator of the Kansas Gulf Veterans Health Study. She served as Scientific Director of the

Committee from 2003 through early 2008.

Roberta F. White, PhD

Dr. White is Professor and Chair of the Department of Environmental Health at Boston University School

of Public Health. She is a neuropsychologist with expertise in environmental and occupational

epidemiology. Author of numerous scientific publications, her research interests include evaluation of

chronic effects of exposure to neurotoxicants, the use of imaging in behavioral toxicology, and

environmental factors that influence the development of neurodegeneration. Dr. White currently serves

as Scientific Director of the Committee.

Consultant to the Committee

Jack Melling, PhD

Dr. Melling is former Chief Executive of the U.K. Microbiological Research Authority. He was

previously Director of the Salk Institute of Biologicals Development Center, Director of the Karl

Landsteiner Institute for Vaccine Development, and a Senior Program Manager at the Battelle Memorial

Institute. He is currently a consultant to the United States Government Accountability Office.
446  Gulf War Illness and the Health of Gulf War Veteranss
Abbreviations and Acronyms
448  Gulf War Illness and the Health of Gulf War Veterans
Abbreviations and Acronyms  449

| Abbreviations and Acronyms

ACE angiotensin converting enzyme

ACh acetylcholine, a neurotransmitter

AChE acetylcholinesterase, an enzyme that breaks down acetylcholine

ACTH adrenocorticotropic hormone

AFRRI U.S. Armed Forces Radiobiology Research Institute

AFTAC Air Force Technical Assistance Center, U.S. Air Force

ALS amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease

ANS autonomic nervous system

ARM adjusted ratio of means

ATP adenosine triphosphate

AVA anthrax vaccine adsorbed

AVEC Anthrax Vaccine Expert Committee, U.S. Department of Health and Human Services

AVIP Anthrax Vaccine Immunization Program, U.S. Department of Defense

BChE butyrylcholinesterase

BDRC Birth Defect Research for Children

BIRLS Beneficiary Identification and Records Locator Subsystem, U.S. Department of Veterans Affairs

BT botulinum toxoid

CAM chemical agent monitor

CAPS Clinician-Administered PTSD Scale

CARC chemical agent resistant coating

CATI computer assisted telephone interview

CBT cognitive behavioral therapy

CBW chemical and biological warfare agents

CCEP Comprehensive Clinical Evaluation Program, U.S. Department of Veterans Affairs

CDC U.S. Centers for Disease Control and Prevention

CDMRP Congressionally Directed Medical Research Program, U.S. Department of Defense

CENTCOM Central Command, U.S. Department of Defense

CFS chronic fatigue syndrome

CI confidence interval

CIA U.S. Central Intelligence Agency

CIDI Composite International Diagnostic Interview

CMI chronic multisymptom illness

CMV Cytomegalovirus

CN chloroacetophenone, a form of tear gas

CNS central nervous system

CO carbon monoxide

CO2 carbon dioxide
450  Gulf War Illness and the Health of Gulf War Veterans

corr correlation

CPAP Continuous Positive Airway Pressure, used to treat sleep apnea

CRH corticotropin-releasing hormone

CS chlorobenzylidenemalononitrile, tear gas

CT computed tomography scan

DC District of Columbia

DEET N,N-diethyl-meta-toluamide, an insect repellant

DEX dexamethasone, a synthetic glucocorticoid

DFP diiosopropylfluorophosphate

DHWG Deployment Health Working Group, U.S. federal interagency group

DMSS Defense Medical Surveillance System

DNA deoxyribonucleic acid

DOD U.S. Department of Defense

DS2 decontamination solution 2

DSM-III-R Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised

DU depleted uranium

EEG electroencephalogram

EBV Epstein-Barr virus

EEG electroencephalogram

EF edema factor, a protein in the anthrax vaccine

ELISA Enzyme-Linked ImmunoSorbent Assay

EPA U.S. Environmental Protection Agency

FDA U.S. Food and Drug Administration

FM fibromyalgia

fMRI functional magnetic resonance imaging

FVC forced vital capacity

FY fiscal year

GABA gamma aminobutyric acid, a neurotransmitter

GAO U.S. General Accounting Office, renamed the U.S. Government Accountability Office in 2004

GFAP glial fibrillary acidic protein

GH growth hormone

GIS geographical information systems

GW Gulf War

GWI Gulf War illness

GWUI Gulf War-related unexplained illness

GWV Gulf War veterans

GWVIS Gulf War Veterans Information System, U.S. Department of Veterans Affairs

HDI hexamethylene diisocyanate, a hardening compound in CARC paint

HHS U.S. Department of Health and Human Services

HHV human herpes virus
Abbreviations and Acronyms  451

HHV6 human herpes virus 6

5-HIAA 5-hydroxyindoleacetic acid, a metabolite of serotonin

HIV human immunodeficiency virus

HLA human leukocyte antigen

1H MRS proton magnetic resonance spectroscopy

HPA hypothalamic-pituitary-adrenal axis

HPRT hypoxanthine-guanine phosphoribosyl transferase, used to assay genetic mutations

HRV heart rate variability

HSC Health Symptom Checklist

HSV herpes simplex virus

5-HT 5-hydroxytryptamine, or serotonin

HVA homovanillic acid, a dopamine metabolite

IAEA International Atomic Energy Agency

IBS irritable bowel syndrome

IFN interferon

IG Inspector General

IgE immunoglobulin E

IgG immunoglobulin G

IL-2 interleukin 2

IL-10 interleukin 10

IM intramuscular

IND investigational new drug

IOM Institute of Medicine, National Academy of Sciences

IP intraperitoneal

ISG Iraq Survey Group

IV intravenous

JP-4, JP-5, JP-8 jet propulsion fuel types 4, 5, and 8

KKMC King Khalid Military City, Saudi Arabia

KLH keyhole limpet hemocyanin

km kilometer

KS GWI Kansas case definition for Gulf War illness

L leucine, an amino acid

LD50 dosage that is lethal to 50 percent of exposed animals

LF lethal factor, a protein in the anthrax vaccine

LSD lysergic acid diethylamide, a hallucinogenic drug

M methionine, an amino acid

M1, M2, M3 types of acetylcholine muscarinic receptors

MAP Medical Assessment Program, U.K. Ministry of Defence

MAVERIC Massachusetts Veterans Epidemiology Research and Information Center (VA)

MBPI Michigan Biological Products Institute
452  Gulf War Illness and the Health of Gulf War Veterans

MCS multiple chemical sensitivity

MDA malondialdehyde

MDPH Michigan Department of Public Health

2ME ethylene glycolmonomethyl ether, a solvent

MEG magnetoencephalography

MF59 a vaccine adjuvant that contains squalene

MHPG 3-methoxy-4-hydroxyphenylglycol

MOD Ministry of Defence, U.K.

MOPP Mission Oriented Protective Posture, protective garments worn at different levels of chemical threat

MPTP 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

MRI magnetic resonance imagining

MRS magnetic resonance spectroscopy

mRNA messenger ribonucleic acid

MS multiple sclerosis

NAA/Cr N-acetyl-aspartate/creatine ratio

NADH nicotinamide adenine dinucleotide

NAPPs nerve agent pyridostigmine pretreatment sets

NAPs nerve agent pretreatment sets

NAS The National Academy of Sciences

NATO North Atlantic Treaty Organization

NBC nuclear, biological, and chemical

NCO noncommissioned officer

NHRC Naval Health Research Center, U.S. Navy

NIH National Institutes of Health

NK cells natural killer cells

NMH neurally mediated hypotension

NOx oxides of nitrogen

NTE neuropathy target esterase

O3 ozone

ODS Operation Desert Storm

OEF Operation Enduring Freedom

OIF Operation Iraqi Freedom

OP organophosphate

OPIDN organophosphate induced delayed neuropathy

OR odds ratio, a measure of association between a risk factor and health outcome

ORD Office of Research and Development, U.S. Department of Veterans Affairs

OSAGWI Office of the Special Assistant to the Deputy Secretary of Defense for Gulf War Illnesses

p p value, a test of statistical significance

PA protective antigen, immunogenic component of the anthrax vaccine

PAC Presidential Advisory Committee on Gulf War Veterans’ Illnesses
Abbreviations and Acronyms  453

PAHs polycyclic aromatic hydrocarbons

2-PAM 2-pralidoxine chloride, used as an antidote following nerve agent exposure

PB pyridostigmine bromide

PBMC peripheral blood mononuclear cells

PCR polymerase chain reaction

PET positron emission tomography

PGVCB Persian Gulf Veterans Coordinating Board

PL public law

PM10 particulate matter, 10 microns or smaller

PON1 paraoxonase

Prev diff prevalence difference

PSOB Presidential Special Oversight Board for Department of Defense Investigations of Chemical and

Biological Incidents

PTSD post traumatic stress disorder

Q glutamine, an amino acid

R arginine, an amino acid

RAC-GWVI Research Advisory Committee on Gulf War Veterans’ Illnesses

RAND RAND National Defense Research Institute

RCT randomized, controlled trial

REM rapid eye movement, a stage in the sleep cycle

RFA Request for Applications

RFP Request for Proposals

ROS reactive oxygen species

RR risk ratio, a measure of association between a risk factor and health outcome

SCID Structured Clinical Interview for DSM-III-R

SCUD Subsonic Cruise Unarmed Decoy

SF36 Medical Outcomes Study Short Form Survey

SF36 PCS Physical component score of the Medical Outcomes Study Short Form Survey

sign. statistically significant

SIU Special Investigation Unit on Gulf War Illnesses, U.S. Senate

SO2 sulfur dioxide

SOx oxides of sulfur

SPECT single photon emission tomography

SR self-reported

SRI Stanford Research Institute

SSG Staff Sergeant (U.S. Army)

SSgt Staff Sergeant (U.S. Air Force)

subQ subcutaneous

TCPs tricresyl phosphates

Th1 T-helper cells associated with cell-mediated immunity and phagocyte-dependent inflammation
454  Gulf War Illness and the Health of Gulf War Veterans

Th2 T-helper cells associated with humoral immunity and allergy

TNF tumor necrosis factor

TSPs total suspended particulates

U.K. United Kingdom

U.N. United Nations

UNSCOM United Nations Special Commission on Iraq

USACHPPM U.S. Army Center for Health Promotion and Preventive Medicine (formerly USAEHA)

USAEHA U.S. Army Environmental Hygiene Agency

USAMRMC U.S. Army Medical Research and Materiel Command

UTSW University of Texas Southwestern Medical School

VA U.S. Department of Veterans Affairs

VAERS Vaccine Adverse Event Reporting System

VAMC VA Medical Center

VBA Veterans Benefits Administration, U.S. Department of Veterans Affairs

VHA Veterans Health Administration, U.S. Department of Veterans Affairs

VHI Veterans Health Initiative, U.S. Department of Veterans Affairs

VOCs volatile organic compounds

VZV varicella zoster virus

WMD weapons of mass destruction

WRAIR Walter Reed Army Institute of Research

WRIISC War Related Injury and Illness Study Center, U.S. Department of Veterans Affairs