Scientific Progress in Understanding 

Gulf War Veterans’ Illnesses: 

Report and Recommendations

 

Research Advisory Committee 

on Gulf War Veterans’ Illnesses 

September, 2004 
Scientific Progress in Understanding 

Gulf War Veterans’ Illnesses: 

Report and Recommendations

 

Research Advisory Committee 

on Gulf War Veterans’ Illnesses 

September, 2004 

The Research Advisory Committee on Gulf War Veterans’ Illnesses 

James H. Binns, Committee Chair 

Nicola Cherry, M.D., Ph.D. 

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

Joel C. Graves 

Robert W. Haley, M.D. 

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

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

Pierre J. Pellier, M.D. 

Stephen L. Robinson 

Steve Smithson 

Lea Steele, Ph.D., Scientific Director 

Consultant to the Committee: 

Jack Melling, Ph.D. 

Table of Contents 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations 

Table of Contents 

Executive Summary.............................................................................................. 1

Introduction......................................................................................................... 15

Findings and Recommendations 

Finding 1 A substantial proportion of Gulf War veterans are ill with multisymptom 

conditions not explained by wartime stress or psychiatric illness....................... 21

Finding 2 Treatments that improve the health of veterans with Gulf War illnesses are 

urgently needed....................................................................................

Recommendations.................................................................................

29

36

Finding 3 A growing body of research indicates that an important component of Gulf War 

veterans’ illnesses is neurological in character..............................................

Recommendations................................................................................

38

45

Finding 4 Evidence supports a probable link between exposure to neurotoxins and the 

development of Gulf War veterans’ illnesses ...............................................

Recommendations .................................................................................

47

66

Finding 5 Other wartime exposures may also have contributed to Gulf War veterans’ 

illnesses................................................................................................

Recommendations.................................................................................

68

70

Finding 6 The health of Gulf War veterans must be carefully monitored to determine if 

Gulf War service is associated with excess rates of specific diseases, diseasespecific deaths, or overall mortality............................................................

Recommendations.................................................................................

72

75

Finding 7 Important questions concerning the health of children and other family members 

of Gulf War veterans remain unanswered...................................................

Recommendations.................................................................................

77

83

Finding 8 Progress in understanding Gulf War veterans’ illnesses has been hindered by 

lack of coordination and availability of data resources maintained by the 

Department of Defense and the Department of Veterans Affairs.......................

Recommendations.................................................................................

84

86

Finding 9 Research on Gulf War veterans’ illnesses has important implications for current 

and future military deployments and for homeland security..............................

Recommendations.................................................................................

87

91
Table of Contents 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations 

Finding 10 Further progress in understanding and treating Gulf War veterans’ illnesses 

requires federal research programs that are properly focused, well-managed, 

and adequately funded...........................................................................

Recommendations.................................................................................

93

100

Conclusions......................................................................................................... 103

Acknowledgments................................................................................................ 105

References.......................................................................................................... 107

Appendices 

Appendix A Members of the Research Advisory Committee on Gulf War Veterans’ Illnesses 133

Appendix B 2002-2004 Members of the Expert Advisory Panel for the Research Advisory 

Committee on Gulf War Veterans’ Illnesses................................................ 137

Appendix C Charter of the Research Advisory Committee on Gulf War Veterans’ Illnesses... 139

Abbreviations...................................................................................................... 142
Tables 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

 2004 Report and Recommendations 

Tables 

Table 1 Proportion of U.S Gulf War-era Veterans Reporting Symptoms in a National Survey...... 22

Table 2 Diagnosed Conditions Reported at Significantly Higher Rates by Gulf Veterans than 

Nondeployed Veterans ..................................................................................... 24

Table 3 Prevalence Estimates of Multisymptom Illness in Gulf and Non-Gulf Veterans.............. 28

Table 4 Federal Research on Treatments for Gulf War Veterans’ Illnesses.............................. 30

Table 5 Age-Specific ALS Rates in Gulf Veterans, Nondeployed Veterans, and a Comparison 

Population.................................................................................................... 39

Table 6 Neurological Symptom Groups/Factors Identified in Gulf Veteran Populations............. 40

Table 7 Studies of Chronic Effects of Low-Dose Sarin Exposure in Animals............................. 52

Table 8 Products Used During the Gulf War Identified by the Deployment Health Support 

Directorate as Pesticides of Potential Concern....................................................... 58

Table 9 Animal Studies Evaluating Synergistic Effects of Gulf War-Related Exposures.............. 60

Table 10 Population Studies Assessing Relationships of Multiple Exposures in Theater to Gulf 

War Veterans’ Illnesses................................................................................... 63

Table 11 Exposures Suggested as Possible Contributors to Gulf War Veterans’ Illnesses ............. 68

Table 12 Proportion of Gulf War and Nondeployed Veterans Reporting Birth Defects Resulting 

from First Live Births Occurring after June 30, 1991............................................... 79

Table 13 Projected Federal Funding for Gulf War Veterans’ Illnesses Research through Fiscal 

Year 2003..................................................................................................... 96

Table 14 Projected VA Gulf War Research Expenditures for Fiscal Year 2003........................... 98

Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 1

Executive 

Summary 

 

 More than thirteen years after the end of Operation Desert Storm, a 

substantial proportion of veterans of the 1990-1991 Gulf War continue to 

experience chronic and often debilitating conditions characterized by 

persistent headaches, cognitive problems, somatic pain, fatigue, 

gastrointestinal difficulties, respiratory conditions, and skin abnormalities. 

Veterans have looked to government officials, scientists, and healthcare 

providers for answers to their many questions concerning these conditions, 

often without receiving adequate response or assistance. Research studies 

conducted since the war have consistently indicated that psychiatric illness, 

combat experience, or other deployment-related stressors do not explain 

Gulf War veterans’ illnesses in the large majority of ill veterans. Promising 

scientific advances in recent years have begun to unravel the mysteries of 

these conditions, providing important new insights into the effects of toxic 

substances encountered in theater and the physiological processes 

underlying veterans’ illnesses. These advances point the way to continued 

progress that can be made by a renewed federal research effort focused on a 

more precise understanding of the chronic effects of exposures encountered 

in the Gulf War and identification of treatments that improve the health and 

lives of ill veterans. 

 The Research Advisory Committee on Gulf War Veterans’ Illnesses was 

established by Congress by Section 104 of Public Law 105-368, and 

appointed by the Secretary of Veterans Affairs in 2002 to advise the 

Secretary on research relating to the health consequences of service in the 

Gulf War. According to its charter, the Committee measures all research 

on Gulf War veterans’ illnesses against a single standard: the potential for 

that research to improve the health of ill veterans. In the years since the 

war, thousands of Gulf War veterans have been evaluated and treated by 

government and private physicians. But the federal research effort has not 

succeeded in identifying treatments that substantially improve the health of 

ill veterans. Further, there are no programs in place to evaluate the 

effectiveness of treatments currently being used or to identify and develop 

treatments that may hold promise for these conditions. 

 Many of the veterans who served in the Gulf War were exposed to a 

variety of potentially toxic substances during their deployment. Among 

these were several neurotoxins—chemical nerve agents, pills taken to 

protect veterans from the deadly effects of nerve agents, and multiple types 

of pesticides—that belong to a single class of compounds that adversely 

affect the nervous system. A growing body of research now indicates that 

ill Gulf War veterans differ from healthy controls on objective measures of 

neurological pathology and impairment. Particularly troubling are findings 

that Gulf veterans have developed amyotrophic lateral sclerosis (ALS), or 

Lou Gehrig’s disease, at twice the rate of their nondeployed peers. This 

information parallels recent findings from a large number of animal studies 

indicating that, contrary to previous assumptions, exposure to nerve agents 

at levels too low to produce acute symptoms can result in chronic adverse 

effects on the nervous and immune systems. Additional research has 

shown that combinations of the types of neurotoxins encountered in the 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 2

Finding 1 

Persian Gulf theater can work synergistically, producing greater toxicity 

than would result from the chemicals individually. 

 This report provides the Committee’s key findings and 

recommendations about the nature and scope of Gulf War veterans’ 

illnesses and the urgent need for treatments that improve the health of ill 

veterans. It includes findings from the Committee’s review of information 

regarding neurological aspects of veterans’ illnesses and their potential 

linkages to neurotoxic exposures encountered during the Gulf War. 

Additional recommendations relate to the importance of monitoring the 

health of veterans over time, the need for additional information regarding 

the health of veterans’ family members, the importance of making full use 

of existing federal data resources related to Gulf War veterans’ health and 

military service, and the relevance of research in this area to future 

deployments and homeland security. The report also addresses the overall 

effectiveness of the federal research effort on Gulf War veterans’ illnesses, 

and recommends the immediate implementation of a targeted research plan 

focused on treatments and the effects of Gulf War-related exposures. 

 The conditions affecting Gulf War veterans appear to be complex, 

involving diverse symptoms associated with multiple organs and 

physiological systems, possibly as a result of multiple overlapping causes. 

They present a difficult scientific and administrative challenge for federal 

agencies responsible for addressing them. Despite recent impressive 

research breakthroughs, the Committee found, overall, that the federal 

research effort has not succeeded in answering fundamental questions 

about Gulf War veterans’ illnesses. This has been due, in large part, to lack 

of effective follow-through in implementing studies that satisfactorily 

address key research questions, and a continuing focus on stress as the 

primary explanation for these conditions. Additional progress in 

addressing Gulf War veterans’ illnesses is not likely to come from a 

haphazard mix of studies. It will require a comprehensive and focused 

effort, managed to achieve success in answering priority research questions 

and capitalizing on scientific advances as they emerge. Progress made in 

recent years by government and non-government researchers indicates that 

the goal of understanding and treating Gulf War veterans’ illnesses is 

within reach. A renewed effort to effectively address these conditions is 

particularly important now, given its immediate relevance to current 

military deployments and homeland security. 

A substantial proportion of Gulf War veterans are ill with 

multisymptom conditions not explained by wartime stress or 

psychiatric illness. Gulf War veterans experience significantly more 

chronic and often debilitating symptoms, illnesses, and diagnosed 

conditions than veterans who did not serve in the Gulf War. Cumulative 

evidence from multiple studies has demonstrated that Gulf War veterans’ 

illnesses are not adequately explained by deployment stress or wartime 

trauma and that the large majority of ill veterans have no identifiable 

psychiatric conditions. Population-based studies consistently indicate that 

between 26 and 32 percent of Gulf veterans experience a multisymptom 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 3

Finding 2 

pattern of illness, over and above rates experienced by veterans who did not 

serve in the Gulf War. 

Treatments that improve the health of veterans with Gulf War 

illnesses are urgently needed. Expert panels and government 

committees have consistently identified treatments for Gulf War veterans’ 

illnesses to be a top federal research priority. However, no treatments have 

yet been shown to improve the health of a substantial number of ill 

veterans, and no programs are in place to identify treatments that may hold 

promise. The Committee recommends that the Department of Veterans 

Affairs (VA) immediately establish a comprehensive program specifically 

tasked with evaluating treatment-related information and research, and 

developing data and pilot studies as necessary to identify promising 

candidate treatments for clinical trials for Gulf War veterans’ illnesses. 

This program would employ a multi-faceted approach and should be 

staffed and managed by professionals with expertise in investigating 

complex illnesses and in evidence-based methodological approaches to 

treatment development and evaluation. 

The recommended program would include the following components: 

• Identification of treatments used by clinicians and veterans for Gulf 

War veterans’ illnesses. Current and previously used treatments can be 

identified in a variety of ways, including compilation of existing 

clinical data on treatments administered by VA clinicians and 

systematic surveys of veterans and clinicians regarding treatments. 

• Collection of retrospective and prospective observational data on 

clinical outcomes associated with treatments used by clinicians, 

particularly treatments used in VA specialty clinics for Gulf War 

veterans, and those recommended for use by VA clinical practice 

guidelines for medically unexplained fatigue and pain. 

• Development of a plan for developing and testing innovative but 

untried treatment strategies. Priority among treatments to be developed 

and tested should be determined by such considerations as plausibility 

of benefit based on likely pathophysiological mechanisms of illness, 

proven effectiveness in treating symptoms or symptom complexes 

similar to those experienced by Gulf War veterans, and potential for 

adverse side effects. This plan should include cooperative research 

with scientists and clinicians outside the VA system with expertise in 

testing or administering innovative therapies not currently available at 

VA. 

• Development of a general protocol for assessing the evidence on the 

potential benefit of treatments for Gulf War veterans’ illnesses in order 

to determine which ones appear to be suitable for clinical trials, which 

require further data development and evaluation, and which appear to 

hold little potential for benefit. 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 4

Finding 3 

• Provision of technical assistance and research support to clinicians—

both those who currently treat Gulf War veterans’ illnesses and those 

with expertise in administering treatments that may hold promise for 

these conditions—in developing evidence regarding the effectiveness 

of treatments. 

• Development of guidelines for standardizing essential parameters of 

Gulf War illness treatment research, including documentation of the 

definition and measures used to define multisymptom illness and 

illness subgroups, documentation of the treatment intervention, and 

measurement of health status before and after the treatment 

intervention. 

A growing body of research indicates that an important 

component of Gulf War veterans’ illnesses is neurological in 

character. Gulf War service is associated with an excess rate of the 

progressive neurodegenerative condition amyotrophic lateral sclerosis 

(ALS). In addition, multiple studies have identified elevated rates of 

neurological symptom complexes in ill Gulf War veterans, as well as 

objective neurological abnormalities demonstrated using specialized 

neuroimaging techniques, tests of autonomic nervous system function, and 

audiovestibular and neuropsychological testing. The Committee 

recommends that VA expand research efforts that investigate and further 

characterize neurological abnormalities in ill Gulf War veterans. 

Specifically, VA should: 

• Enlist the expertise of specialists in the neurosciences to develop a 

comprehensive research initiative capable of examining both 

neurophysiological and neuropsychological function in symptomatic 

Gulf War veterans in comparison to healthy controls. This effort 

should emphasize research protocols capable of identifying specific 

pathways associated with neurological pathology and include 

comparisons between subgroups of ill Gulf War veterans characterized 

by their individual symptom profiles and exposures encountered in 

theater. Protocols should include evaluation of neurological function 

under dynamic as well as static conditions. 

• Expand research efforts that utilize state-of-the-art neuroimaging 

technology to better characterize differences between ill Gulf War 

veterans and comparison groups. This should include studies that 

follow up and extend previously published findings in Gulf War 

veterans and other chemically exposed populations using magnetic 

resonance spectroscopy as well as other imaging techniques suited to 

study brain cell injury and dysfunction, such as functional magnetic 

resonance imaging (fMRI), positron-emission tomography (PET), 

single photon emission tomography (SPECT), 128-channel 

electroencephalography (EEG), and magnetoencephalography (MEG).

• Develop a comprehensive research strategy designed to evaluate and 

expand on the growing body of evidence regarding autonomic 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 5

Finding 4 

dysfunction in ill Gulf War veterans. This effort should give priority to 

protocols capable of determining which specific aspects of the 

autonomic regulatory system are affected in symptomatic veterans. As 

with other studies involving neurological pathology, studies should 

investigate autonomic function in defined veteran subsets, grouped 

according to symptom types and exposures encountered during the war. 

• Establish a brain bank to collect and maintain samples of autopsy 

materials from Gulf War veterans for study. 

Evidence supports a probable link between exposure to 

neurotoxins and the development of Gulf War veterans’ 

illnesses. Government reports have described the extent to which Gulf 

War veterans were exposed to a variety of potentially neurotoxic 

substances during their deployment to Southwest Asia, including different 

amounts and combinations of acetylcholinesterase inhibitors (AChEi) such 

as the nerve agent sarin, pyridostigmine bromide, and carbamate and 

organophosphate pesticides. Multiple avenues of research have 

demonstrated that these substances have the potential to cause long-term 

health effects. Animal research has also indicated that some combinations 

of Gulf War-related exposures can lead to adverse effects that significantly 

exceed those resulting from single exposures. Further, epidemiologic 

studies of Gulf War veterans consistently find that self-reported exposures 

to these compounds during the war is associated with higher rates of 

illness. The Committee recommends that the federal government expand 

research efforts to systematically investigate the chronic effects of exposure 

to neurotoxins encountered during the Gulf War. Specifically, the 

Committee recommends that VA: 

• Establish a comprehensive research program to investigate persistent 

and/or delayed effects of exposure to AChEi, including sarin and other 

nerve agents, at dosages comparable to those that may have been 

encountered in the Gulf War. Such research should focus on 

elaboration of the specific physiological pathways involved in possible 

adverse consequences of these exposures, including those involved in 

synergistic effects of combinations of neurotoxic exposures. 

• Work with scientists with appropriate expertise to comprehensively 

evaluate the role of differences in genotype and activity levels of 

enzymes such as paraoxonase, acetylcholinesterase, and 

butyrylcholinesterase, which are associated with the uptake and 

metabolism of neurotoxins, in susceptibility to wartime exposures and 

the development of Gulf War veterans’ illnesses. 

• Give priority to research studies designed to identify and utilize 

objective biological markers associated with the effects of exposure to 

AChEi. Such measures might pertain to effects in the brain or in 

peripheral areas influenced by acetylcholine such as the neuromuscular 

system, the gastrointestinal system, and the immune system. 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 6

Finding 5 

• Give priority to research studies capable of identifying pathways 

involved in chronic adverse effects of AChEi exposure that may be 

amenable to treatment interventions. 

• Expand VA and collaborative research efforts that capitalize on new 

technologies capable of identifying low-level residues of exposures, 

their metabolites, or persistent alterations in metabolism or genetic 

expression resulting from wartime exposures or associated with chronic 

unexplained illnesses in Gulf War veterans. 

• Analyze data from existing and future epidemiologic studies to 

reevaluate the association of combinations of neurotoxic exposures 

with chronic illness in Gulf War veterans. 

The Committee recommends that the Department of Defense (DOD): 

• Make available to researchers studying Gulf War veterans’ illnesses 

detailed information concerning the locations and dates of incidents 

involving destruction of chemical targets during and after the Gulf War. 

• Continue and expand research efforts that identify possible chronic 

effects of low-level exposure to sarin and other nerve agents, 

pesticides, and pyridostigmine bromide, individually and in 

combination. 

Other wartime exposures may also have contributed to Gulf 

War veterans’ illnesses. In addition to neurotoxins, a variety of 

potentially harmful exposures have been suggested as possible causes or 

contributors to Gulf War veterans’ illnesses. For example, epidemiologic 

studies have consistently identified significant associations between illness 

rates and vaccines received in relation to Gulf War deployment. In the 

coming months, the Committee will investigate in greater detail evidence 

regarding the potential for additional Gulf War-related exposures to have 

contributed to veterans’ illnesses, including research related to infectious 

diseases, depleted uranium, oil well fire smoke and other petroleum 

products, and a more detailed consideration of evidence relating to 

vaccines. 

At this time, the Committee recommends that VA: 

• Support research efforts that investigate well-evidenced hypotheses 

concerning potential linkages between Gulf War veterans’ illnesses and 

wartime exposures, including possible chronic effects of combinations 

of Gulf War-related exposures. 

• Work with federal agencies (Centers for Disease Control and 

Prevention, National Institutes of Health, Department of Defense) 

involved in conducting vaccine trials that include administration of 

anthrax vaccine adsorbed (AVA) to ensure that these trials include 

follow-up assessments of study subjects a minimum of five years after 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 7

Finding 6 

inoculation. Such studies should utilize methods and instruments

capable of capturing chronic symptoms and cognitive difficulties 

similar to those experienced by Gulf War veterans. 

• Conduct a retrospective cohort study that compares chronic symptoms 

and diagnosed conditions experienced by veterans who received AVA 

as part of the military’s mandatory anthrax vaccination program to 

those of a comparable group of veterans who did not receive this 

vaccine. 

The health of Gulf veterans must be carefully monitored to 

determine if Gulf War service is associated with excess rates of 

specific diseases, disease-specific deaths, or overall mortality. 

The excess rate of ALS identified in Gulf War veterans highlights the need 

to determine rates of other serious medical conditions in this population. 

Effects of Gulf War-related exposures on rates of diseases of long latency, 

including cancer and some neurological conditions, may not become 

apparent until 10 or more years after deployment. The Committee 

recommends that rates of medical conditions and disease-specific mortality 

among Gulf War veterans be regularly assessed and reported. Specifically, 

the Committee recommends that VA: 

• Continue to identify ALS cases among Gulf War veterans, and evaluate 

the potential role of toxic exposures encountered in theater or after the 

war in the development or progression of this disease. Publish findings 

regarding any identified risk factors for ALS in Gulf War veterans, and 

provide this information to veterans. 

• Undertake epidemiologic studies to determine the prevalence of other 

serious neurological conditions, including multiple sclerosis (MS), 

Parkinson’s disease, and brain cancers, among Gulf War veterans in 

relation to appropriate comparison groups. Studies should include 

ascertainment of the number of cases of rare and difficult-to-diagnose 

neurological conditions that may have clinical similarities to 

recognized conditions such as ALS, MS, or Parkinson’s disease, but are 

difficult to precisely characterize. 

• Analyze and make available mortality data for U.S. Gulf War and 

nondeployed Gulf War era veterans every 18 months. Data should be 

analyzed for a wide range of ICD-9 categories and the results made 

publicly available, electronically and through published reports. Data 

already available, covering the period 1998 through 2003, should be 

analyzed and published immediately. 

• Utilize troop location information and data collected in VA’s National 

Health Survey of Gulf War-era Veterans and their Families to assess 

mortality among subcategories of Gulf War veterans grouped by 

exposure, location, and demographic and military characteristics. 

Analyses of mortality rates among Gulf War veterans that do not take 

into account differences in deployment experiences and exposures
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 8

Finding 7 

could mask even large mortality excesses associated with conditions 

encountered by a minority of those deployed. 

• Regularly monitor information contained in VA clinical and benefit 

claims data sources and provide annual reports of morbidity and 

mortality by available diagnostic categories. Age and sex-adjusted 

rates of hospitalization and benefits claims should be compared 

between Gulf War and nondeployed Gulf War era veterans, and across 

military subgroups identifiable through available data. 

• Recognizing that assessment of morbidity is difficult for U.S. veterans, 

for whom health care is not universally available from a single 

provider, explore the possibility of examining morbidity patterns in 

allied countries where such data are available. This information may 

help to identify excesses in chronic diseases before they become 

apparent using U.S. mortality data or the recommended surveillance 

activities. 

• Where surveillance of clinical or mortality data indicate a possible 

elevated rate of any condition in Gulf War veterans, undertake 

appropriate epidemiologic studies to determine the rate of occurrence 

of that condition among Gulf War veterans and an appropriate 

comparison group. 

• Where a possible excess of any condition is determined, make efforts to 

identify individuals with that condition among living veterans, 

especially in situations where early detection and treatment would be 

beneficial. 

Important questions concerning the health of children and 

other family members of Gulf War veterans remain 

unanswered. Gulf War veterans have been particularly concerned about 

possible effects of their wartime service on the health of their families, 

including the risk of birth defects in children conceived since the war. 

However, clear information has not been available concerning many 

unanswered questions in this area. The Committee therefore recommends 

that VA: 

• Accelerate efforts to complete analyses and publish results from Phase 

III of the National Health Survey of Gulf War-era Veterans and their 

Families. Reports should contain comprehensive information on the 

health of veterans’ spouses and children, including an accounting of 

specific diagnosed conditions, symptoms, and symptom complexes. 

Special effort should be made to assess childhood health problems or 

abnormalities not apparent at birth, including learning and behavior 

disorders. 

• Analyze data from existing VA studies to evaluate birth defects and 

other health measures for family members of important veteran 

subgroups. Analyses should include comparisons between the health of 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 9

Finding 8 

family members of veterans who are ill and veterans who are well, and 

comparisons among family members of veterans with different 

deployment, location, and exposure histories. 

• Develop studies with innovative designs to test for excess rates of 

specific birth defects, such as Goldenhar syndrome, that occur too 

rarely to address with the types of studies done in the past. 

• Continue to query veterans regarding reproductive outcomes and the 

health of family members in VA’s ongoing longitudinal study of Gulf 

War and nondeployed veterans, and follow up veteran-reported 

information on birth defects and other health conditions with medical 

record reviews. 

• Issue a public report detailing information and data collected in 

connection with VA’s medical evaluation program for family members 

of Gulf War veterans. 

• Provide clear information to veterans and clinicians concerning what is 

known about the risk of birth defects related to Gulf War service, and 

update that information as additional research becomes available. 

Progress in understanding Gulf War veterans’ illnesses has 

been hindered by lack of coordination and availability of data 

resources maintained by the Department of Defense and the 

Department of Veterans Affairs. The Departments of Defense and 

Veterans Affairs collect and maintain a large amount of data relevant to the 

health and military experiences of Gulf War veterans. Progress in 

understanding Gulf War veterans’ illnesses would benefit significantly 

from researchers making full use of data collected and maintained by 

different agencies and departments within the federal government. The 

Committee therefore recommends that VA and DOD: 

• Cooperate fully in individual projects requiring linkages between 

specific Gulf War-associated databases, such as the unit location 

database and healthcare and benefits data, to facilitate the provision of 

integrated data resources for research purposes. 

• Develop a comprehensive data library that houses and integrates federal 

military, deployment, and health data resources relevant to service in 

the Gulf War and the health of Gulf War era veterans. This data library 

would serve as a central data resource capable of providing usable data 

for the purposes of conducting research on specific questions regarding 

Gulf War veterans’ illnesses and monitoring the health of Gulf War 

veterans. 

• Make federal data resources relevant to Gulf War veterans’ health and 

military experiences available to qualified government and

non-government researchers, and adopt appropriate safeguards for the 

use of these data. 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 10

Finding 9 Research on Gulf War veterans’ illnesses has important 

implications for current and future military deployments and for 

homeland security. Many issues pertaining to Gulf War-related 

exposures and government efforts to address Gulf War veterans’ illnesses 

are directly applicable to current and future military deployments. In 

addition, research on Gulf War veterans’ illnesses has immediate relevance 

to the development of medical countermeasures to protect civilian 

populations from the threat of chemical terrorist attack. 

With respect to the relevance of Gulf War illnesses research to current and 

future military deployments, the Committee applauds efforts of the 

Secretary of Veterans Affairs to encourage the Department of Defense to 

maintain comprehensive records of deployment-related health information, 

including receipt of vaccines, in connection with current military 

deployments. The Committee further recommends that: 

• DOD fully implement the military assessment programs mandated in 

1997 by Public Law 105-85, Section 765 (10 U.S.C. §1074f (1997)), 

which directs DOD to conduct detailed medical examinations of all 

military personnel before and immediately after deployment to hostile 

areas, including the collection and storage of blood samples taken 

before and after deployment. 

• DOD take steps to improve record keeping and exposure assessments 

related to military deployments. 

• DOD reassess policies regarding the use of pyridostigmine bromide as 

a prophylactic measure against the possible effects of nerve agents. 

This assessment should include a comprehensive review of scientific 

studies relating to adverse effects of pyridostigmine bromide in 

combination with other exposures, and revisiting policies concerning 

the circumstances and decisions that govern orders for the use of 

pyridostigmine bromide. 

• DOD and VA work cooperatively to immediately share information 

related to current military deployments, including health experiences 

and exposures in theater. 

• DOD and VA continue to work cooperatively to develop and 

implement a unified health data system that will include all health

information of personnel through their military service and transition 

into the VA healthcare system. 

With respect to the relevance of Gulf War illnesses research to preparations 

against chemical terrorism, the Committee recommends that Congress: 

• Establish a comprehensive medical chemical defense research program 

within the NIH counterterrorism research agenda, and provide adequate 

funding to field effective medical countermeasures. Enlist in this effort 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 11

Finding 10 

the capabilities of relevant agencies, including the Department of 

Defense and the Department of Veterans Affairs. 

• Expand funding for research programs sponsored by the Department of 

Defense relevant to chemical defense measures. In particular, continue 

and expand support for research programs that have provided important 

information regarding the chronic health effects of sarin and other 

chemical agents. 

Further progress in understanding and treating Gulf War 

veterans’ illnesses requires federal research programs that are 

properly focused, well-managed, and adequately funded. 

Overall progress in addressing Gulf War veterans’ illnesses has been 

delayed by the lack of a well-coordinated federal research effort managed 

to successfully address key research priorities, and by an ongoing emphasis 

on studies that focus on psychological stress as the primary explanation for 

these conditions. The Department of Defense no longer supports new 

research on Gulf War veterans’ illnesses, resulting in a dramatic decrease 

in federal funding in this area in recent years. Reduced support for this 

research is of particular concern now, as recent breakthroughs provide new 

progress in understanding veterans’ illnesses. 

The Committee therefore recommends that VA: 

• Develop a comprehensive federal research plan to address Gulf War 

veterans’ illnesses in conjunction with other participants in the 

Research Subcommittee of the Deployment Health Working Group and 

with the Research Advisory Committee on Gulf War Veterans’ 

Illnesses. The plan should address priority research topics identified in 

this and future Committee reports. It should also utilize scientific 

resources and funding mechanisms available at each federal agency in 

order to enlist government and non-government scientific experts most 

capable of undertaking research projects that can best address priority 

topics. 

• In the context of the comprehensive federal research plan, adopt a 

strategic VA research program that identifies and addresses key 

research questions regarding the nature, causes, and treatments for Gulf 

War veterans’ illnesses, utilizing research solicitations that address 

specific priority Gulf War illnesses research topics. 

• Maintain a substantial research funding commitment to address the 

health consequences of Gulf War deployment until specific treatments 

and causes for these conditions are identified. Specifically, VA should 

allocate not less than 15 million dollars in each of the next four years in 

support of a comprehensive and well-managed research portfolio. 

• Work with leading scientists—both those within VA and those not 

affiliated with VA—to develop comprehensive research protocols most 

capable of addressing priority Gulf War illnesses research questions. 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 12

• Establish an effective management strategy for the VA Gulf War 

illnesses research portfolio to ensure that studies capable of addressing 

priority research questions are satisfactorily developed and completed. 

The program should be directed by a doctoral-level scientist with 

appropriate expertise in research directly relevant to Gulf War veterans’ 

illnesses. 

• Adopt a mechanism for reviewing and funding Gulf War illnesses 

research proposals that takes into account the relevance of proposed 

projects to identified Gulf War illnesses research priorities, in addition 

to the scientific merit of the proposed research. Merit review panels 

should include scientists familiar with current research on Gulf War 

veterans’ illnesses and established research priorities. 

• Allocate a significant proportion of Gulf War illnesses research funding 

to treatment research, including specific annual allocations for the 

recommended treatment development program and pilot studies, and 

additional funding for small and large clinical trials, as scientifically 

appropriate. 

• Give funding priority to studies that pursue significant research 

breakthroughs, such as those identified throughout this report. Do not

fund studies in areas that accumulated research has found not to be 

useful in understanding the unexplained illnesses affecting Gulf War 

veterans, unless such proposals can be justified by new evidence or 

innovative hypotheses. For example, although psychiatric conditions 

such as posttraumatic stress disorder are appropriate topics for 

deployment health research in general, research proposals on Gulf War 

veterans’ illnesses should not be funded if their principal focus is on 

psychological stress as the primary cause of these conditions. 

• In conjunction with the Committee, regularly review progress on the 

objectives established for the Gulf War illnesses research program, to 

determine which have been adequately addressed, which should be 

revised, and which require additional follow-through with new and/or 

more specific funding announcements. 

The Committee recommends that Congress: 

• Set a national goal to develop treatments for the chronic multisymptom illnesses affecting Gulf War veterans within five years. 

• Establish line-item funding within the appropriations budgets of the 

appropriate federal departments that provides a total annual federal 

Gulf War illnesses research commitment adequate to execute the 

comprehensive Gulf War illnesses research plan, and in no event less 

than 45 million dollars, consistent with the annual funding levels 

invested in Gulf War illnesses research between 1999 and 2001. 
Executive Summary 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 13

• Designate that 15 million dollars of the annual federal Gulf War 

illnesses research funding be specifically added to VA’s current 

research and development budget in support of the recommended 

comprehensive Gulf War illnesses research program. The balance 

should be provided to the Departments of Defense and Health and 

Human Services, as appropriate for the specific projects to be funded 

and, in particular, for research conducted by non-government research 

scientists on a competitive basis. 

Introduction 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 15

Introduction 

 

Unexplained illnesses in the wake of Desert Storm. Veterans who 

served in the 1990-1991 Persian Gulf War have a compelling story. That 

story conveys the tragedy and triumph of war and, for some, a long struggle 

with unexplained and often debilitating health problems experienced in the 

years since the war. Veterans have looked to government officials, 

scientists, and healthcare providers for answers to the many questions they 

have regarding the nature, causes, and treatments for these conditions, often 

without receiving adequate response or assistance. At the writing of this 

report in 2004, this story is ongoing, having begun in the deserts of 

Southwest Asia 14 years ago. 

 In August of 1990, the Iraqi army invaded the small neighboring nation 

of Kuwait, triggering an immediate response from the United States and an 

international coalition of allied countries organized in opposition to Iraq’s 

aggression. Within weeks, Operation Desert Shield, the massive buildup 

and positioning of Coalition troops in the region, was underway. Operation 

Desert Storm began with the first Coalition air strikes on January 16, 1991, 

and continued with the start of the ground war on February 24, 1991. The 

war was swiftly brought to an end by a decisive Coalition victory. Three 

days into the ground war the liberation of Kuwait was achieved, as 

Coalition tanks moved triumphantly into Kuwait City. A ceasefire was 

declared the following day—just four days after the initiation of the ground 

war and six weeks after air strikes had begun. Coalition forces had 

succeeded more completely, more rapidly, and with fewer casualties than 

anyone had expected or hoped for. 

 American troops returned home to parades and accolades, honored for 

their success in accomplishing their mission of liberating Kuwait. In the 

months after their return, however, stories began to circulate from different 

units that some who had served in the Persian Gulf theater of operations 

were now experiencing unexplained health problems. Some of these 

difficulties were said to have begun during deployment or soon after 

veterans had returned home, but had not resolved with time. Other 

problems had not become apparent for months. The symptoms reported by 

different individuals varied in type and severity, ranging from somewhat 

troubling but chronic muscle pain and skin rashes to more serious 

presentations involving a complex of debilitating problems including 

severe headaches, joint pain, difficulties with balance, memory, and 

cognition, and chronic respiratory and gastrointestinal conditions. As time 

went on, similar problems were reported by veterans in different units and 

branches of service, different areas of the United States, and by veterans 

from other Coalition countries. 

 What had caused these health difficulties? Had the many chemical 

alarms sounded in theater signaled that veterans had been exposed to some 

of the same chemical agents the Iraqi regime had used against Iran and 

against its own citizens? Had exposure to the smoke from hundreds of oil 

well fires set in the closing days of the ground war contributed to these 

conditions? Initial impressions of the nature and causes of these conditions 

varied widely, as did reports of the magnitude of the problem. Almost 
Introduction 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 16

from the beginning, different camps developed in which veterans, 

scientists, and government officials variously promoted different causes 

and explanations for Gulf War veterans’ illnesses. The central question in 

this controversy was whether veterans were suffering from the chronic 

effects of one or more exposures experienced during their deployment or if 

these conditions were the consequence of the stress of deployment and the 

trauma of war. 

 Proponents of the stress theory maintained that military populations 

often experience unexplained symptoms after deployment to hostile areas, 

and that an element common to all deployments is the extreme 

psychological stress and trauma associated with a war zone. The 

suggestion was that the health experience of Gulf War veterans was no 

different from that of prior wars and that the medical problems of Gulf War 

veterans were the expected consequence of service in a hostile area. 

Advocates of the view that Gulf War-related exposures had caused these 

conditions pointed out that a relatively low proportion of military personnel 

had experienced serious psychological stress and trauma during the Gulf 

War, and that post-war psychiatric conditions were actually less prevalent 

in Gulf veterans than in veterans of earlier wars. They identified numerous 

wartime exposures that could plausibly have led to the types of health 

problems affecting veterans. 

 

 The controversy and challenges of understanding Gulf War veterans’ 

illnesses have been reflected in the findings and conclusions of numerous 

Congressional reports, special government panels, and scientific review 

committees appointed to look into this problem.130,131,134,137,221,240,241,305,346-

348 These reports have unanimously acknowledged the seriousness of the 

unexplained symptoms affecting Gulf War veterans, but have differed in 

their conclusions regarding the probable nature and causes of these 

conditions. One general theme that has emerged from these reports, 

however, is that progress in understanding Gulf War-related health 

problems has been severely hindered by a lack of information. All have 

pointed to the need for improved monitoring of the health of military 

personnel and exposures during wartime, and improved recordkeeping, to 

provide a better understanding of the health consequences of future 

deployments. Another conclusion reached by several government panels is 

that Gulf War veterans do not appear to be affected by a single syndrome 

unique to the Gulf War, but rather a mix of multisymptom conditions for 

which no singular cause or diagnostic test has been clearly identified. The 

other common thread emerging from earlier reports has been the difficulty 

in drawing clear conclusions regarding the nature of Gulf War veterans’ 

illnesses due to the lack of scientific information regarding the long-term 

health effects of many of the exposures encountered in the Persian Gulf 

theater. 

 The one indisputable fact is that, after the many conclusions and 

recommendations put forward by special committees and panels, and 

research expenditures of hundreds of millions of dollars to investigate this 

problem, Gulf War veterans remain ill. These veterans deployed to the 
Introduction 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 17

Persian Gulf theater as healthy soldiers, airmen, sailors, and marines, but 

returned with unexplained health problems and unanswered questions, 

which continue thirteen years after Desert Storm. 

Research Advisory Committee on Gulf War Veterans’ Illnesses. 

The Research Advisory Committee on Gulf War Veterans’ Illnesses was 

established by Congress in 1998 by Section 104 of Public Law 105-368, in 

order to provide advice to the Secretary of Veterans Affairs on “proposed 

research studies, research plans, or research strategies relating to the health 

consequences of military service in the Southwest Asia theater of 

operations during the Persian Gulf War” (38 U.S.C.§527(b)(1998)). 

Although the legislation required that the Committee be established by 

1999, no action was taken until Secretary of Veterans Affairs Anthony J. 

Principi appointed the Committee in January, 2002. According to its 

charter, the Committee is required to review “all relevant research, 

investigations, and processes for funding research” as well as “all proposed 

research plans, initiatives, procurements, grant programs, and other 

activities in support of research projects on Gulf War-associated illnesses 

and assess the individual research projects and the overall effectiveness in 

answering central questions on the nature, causes, and treatments for Gulf 

War-associated illnesses” (Appendix C). 

 The Committee consists of eleven members that include veterans, 

physicians, and scientists (Appendix A), and is supported in its work by 

one consultant and a small staff. A six-member expert advisory panel 

named by the Secretary to assist the Committee (Appendix B) is consulted 

informally on specific scientific questions, and the Committee regularly 

seeks the advice and input of other scientists and professionals. In 

accordance with its charter, the Committee measures all research on Gulf 

War veterans’ illnesses against a single standard: the potential for the 

research to improve the health of ill veterans. 

 Committee meetings have been held three times per year and have 

primarily consisted of briefings and scientific presentations on research 

related to possible health consequences of Gulf War service and exposures, 

and on governmental programs and activities related to research on Gulf 

veterans’ illnesses. The meetings have often served as symposia on 

specific topics related to Gulf veterans’ health, typically including 

presentations by several scientists on a specific research topic, followed by 

questions and discussions among Committee members and visiting 

scientists. Government officials associated with medical research programs 

are also invited to participate. All Committee meetings are open and 

include time for members of the public to provide comments and 

suggestions on matters relating to Gulf War veterans’ illnesses. 

 In June, 2002, the Committee issued an Interim Report, containing 

preliminary findings and recommendations based on information reviewed 

by Committee members in the first several months of their work. This 

interim report signaled the Committee’s commitment to a reappraisal of 

research on Gulf War veterans’ illnesses, in accordance with the 
Introduction 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 18

Secretary’s call to approach these complex issues from a fresh perspective, 

and to target research opportunities capable of producing maximum 

progress toward improving veterans’ health. Specifically, the Committee 

found that Gulf War illnesses constitute a serious health problem that 

affects a significant proportion of veterans who served in the 1990-1991 

Gulf War, that these conditions cannot be adequately explained by stress or 

psychological factors, and that a growing body of evidence indicates that 

an important component of these conditions appears to be neurological in 

character. 

Scientific progress in understanding Gulf War veterans’ 

illnesses. In the time since the Committee’s Interim Report was issued, 

important scientific developments have taken place that confirm the 

report’s preliminary findings. A flood of new studies from government and 

non-government researchers has begun to unravel the complex 

physiological processes underlying Gulf War illnesses and shed light on the 

potential for Gulf War-related exposures to produce long-term adverse 

health effects. Taken together, this research lays the groundwork for a new 

era in understanding and addressing Gulf War veterans’ illnesses. Pursuit 

of these findings represents an important scientific opportunity to explain 

the mechanisms underlying veterans’ conditions, potentially pointing the 

way to development of medical treatments. 

 In recent years, studies have provided additional objective evidence of 

neurological impairment and injury and altered autonomic function in ill 

Gulf War veterans. During the same period, numerous animal studies have 

found that low-dose exposure to sarin is associated with chronic 

neurological and immunological effects. Such findings dispel previous 

long-held assumptions that nerve agent exposures too low to produce 

immediate symptoms cannot produce long-term health problems. 

Additional recent studies have provided further evidence that the majority 

of symptomatic Gulf War veterans have no diagnosable psychiatric 

conditions and shed new light on the long-term prognosis of Gulf War 

illnesses and the health of veterans’ children. This new research calls into 

question earlier perceptions regarding Gulf War-related illnesses and 

exposures and mandates fundamentally different conclusions from those 

reached by previous review panels. 

 The work of the Committee is ongoing. This report addresses the nature 

and scope of Gulf War illnesses, and focuses on the urgent need to develop 

treatments for these conditions. It also reviews research evidence related to 

neurological aspects of veterans’ illnesses and the possible contribution of 

neurotoxic exposures. Additional recommendations relate to the need to 

monitor the health of Gulf veterans, including the importance of making 

full use of government databases containing information on the health of 

Gulf War veterans. Preliminary findings are presented regarding the 

potential for other deployment-related exposures, including vaccines, to 

have contributed to Gulf War veterans’ illnesses, and on the need for 

additional information on birth defects and the health of veterans’ family 

members. Future reports will expand on preliminary findings in these 
Introduction 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 19

areas, and will review the scientific evidence related to possible health 

effects of additional exposures encountered by military personnel during 

the Gulf War such as depleted uranium, infectious diseases, smoke from oil 

fires, and other potentially toxic substances. Additional topics to be 

addressed in future Committee meetings and reports will include a more 

detailed examination of medically diagnosed conditions affecting Gulf War 

veterans, treatments used for Gulf War veterans’ illnesses, and parallels 

between Gulf War illnesses and conditions found in the general population. 

 

Administrative challenges in addressing Gulf War Veterans’ 

illnesses. While recent scientific progress in understanding Gulf War 

veterans’ illnesses is encouraging, further advances in addressing these 

conditions depends on the commitment and sustained support of federal 

agencies responsible for the health of military and veteran populations. 

Despite the presence since 1995 of a federal interagency working group 

that identified research priorities in this area, a coordinated and focused 

federal research program that asks and answers the central outstanding 

questions regarding Gulf War veterans’ illnesses has not yet been achieved. 

In recent years, prospects for a coordinated federal Gulf War illnesses 

research effort have been overtaken by events. The Department of Defense 

(DOD) had historically provided the bulk of funding for Gulf War illnesses 

research, and many of the recent scientific breakthroughs came from 

studies funded several years ago by DOD. More recently, however, DOD 

has shifted its focus from research on Gulf War veterans’ unexplained 

illnesses to deployment health protective measures related to current and 

future military deployments. As a result, federal funding in this area has 

dramatically declined, and the Department of Veterans Affairs (VA) is now 

the only federal agency sponsoring new research on Gulf War veterans’ 

illnesses. 

 In response to the Committee’s Interim Report, the Department of 

Veterans Affairs announced a renewed commitment to Gulf War illnesses 

research. In October, 2002, VA announced that it was doubling Gulf War 

research funding by making available up to 20 million dollars in fiscal year 

2004 for research related to Gulf War veterans’ illnesses and other 

deployment health concerns.328 Subsequently, several research activities 

responsive to the Committee’s interim recommendations were undertaken, 

but the promise of a major initiative remained unrealized. In February, 

2004, the Secretary of Veterans Affairs directed VA’s Office of Research 

and Development to work directly with the Committee to develop an 

effective program capable of making significant progress. The Committee 

recommended a targeted approach to Gulf War illnesses research that 

directs resources toward areas of highest priority and greatest promise. At 

the writing of this report, plans to initiate such a program have just begun. 

The Committee will continue to review VA’s progress in developing a 

well-planned and comprehensive research effort to address Gulf War 

veterans’ illnesses. Such a program is sorely needed and long overdue, as 

a significant effort is required to achieve the goal of utilizing the best 

science to improve the health of ill Gulf War veterans. 

Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 21

Finding 1 

A substantial 

proportion of Gulf 

War veterans 

are ill with 

 multisymptom 

conditions not 

explained by 

wartime stress or 

psychiatric illness.

 The health problems reported by Gulf War veterans since the end of 

Desert Storm have posed a complex and frustrating challenge for veterans 

who are ill, as well as for clinicians, researchers, and government agencies 

charged with understanding and addressing these conditions. 

Epidemiologic research, the study of patterns of health and disease in 

populations, is often the first scientific approach taken in understanding 

unexplained health problems. Since the Gulf War, population-based 

epidemiologic studies have investigated the health status of many different 

groups of Gulf War veterans, including veterans from different branches of 

service, veterans from different countries and states, and veterans who 

served in different areas of theater.24,51,85,94,97,138,139,158,237,285,293,349 Despite 

the diversity of research approaches and groups studied, a number of 

common threads have emerged from these investigations, providing insight 

to key questions about the characteristics and prevalence of Gulf War 

veterans’ illnesses. 

Epidemiologic findings regarding the nature and prevalence of 

Gulf War veterans’ illnesses. A number of epidemiologic studies 

have compared hospitalization and mortality rates of Gulf War veterans to 

those of era veterans who did not deploy to the Persian Gulf region 

(nondeployed veterans). The earliest studies comparing hospitalization 

rates between Gulf War and nondeployed veterans utilized data from 

military hospitals and found no significant differences between the two 

groups.96,176 These studies were somewhat limited in scope, since they did 

not include veterans no longer serving in the military. Early comparisons 

between Gulf War and nondeployed veterans may also have been affected 

to some extent by the “healthy warrior effect”102 that arises from the fact 

that personnel who meet fitness qualifications required for deployment to 

war tend to be healthier and less likely to require hospitalization than 

personnel who do not deploy.176 In later hospitalization studies, Gulf War 

veterans have been shown to have proportionally higher rates of 

hospitalization in broad categories such as musculoskeletal disorders,34

digestive diseases, respiratory diseases, symptoms, signs and ill-defined 

conditions, and injuries and poisoning,99 and for specific diagnoses that 

include gastroenteritis and colitis, asthma, fractures, and fibromyalgia.99,274 

 Mortality studies in the United States and United Kingdom have found 

Gulf War veterans to have significantly higher death rates due to accidents 

and injuries than nondeployed Gulf War era veterans,153,154,192,301 but no 

differences in death rates due to specific diseases. Research studies have 

not provided empirical explanations for the excess number of deaths due to 

motor vehicle accidents among Gulf War veterans.29 Proposed 

explanations have included higher rates of PTSD or depressive disorders 

associated with Gulf War service,153 an increase in risk-taking behavior 

following veterans’ return from the war154 and Gulf War-associated 

neurological damage leading to impaired attention and driving ability.102 

 It will be important to follow Gulf War veterans for many years in order 

to monitor deaths due to diseases with long latency periods, such as cancer 

and neurodegenerative diseases. At this time, however, epidemiologic 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 22

studies evaluating hospitalization and mortality rates have identified only 

limited distinctions between Gulf War and nondeployed veterans. These 

differences are considerably less striking than those identified in a large 

number of epidemiologic studies that have evaluated rates of post-Gulf 

War health problems not generally associated with either hospitalization or 

death. The most prominent and consistent finding to emerge from 

population-based studies of Gulf War era veterans is that veterans who 

served in the Gulf War experience a wide range of symptoms at 

significantly higher rates than their contemporaries who did not serve in the 

Gulf War. Representative symptoms reported by Gulf and non-Gulf 

veterans from a survey of over 20,000 U.S. veterans are shown in Table 1. 

Table 1. Proportion of U.S. Gulf War-era Veterans 

Reporting Symptoms in a National Survey 

Gulf War Veterans Non-Gulf Veterans 

Headache 54% 37% 

Joint pain 45% 27% 

Fatigue 38% 15% 

Depressed 36% 22% 

Difficulty concentrating 35% 13% 

Muscle pain 33% 17% 

Diarrhea 31% 15% 

Skin rash 29% 13% 

Coughing 24% 14% 

Shortness of breath 24% 11% 

Hair loss 23% 12% 

Abdominal pain 23% 12% 

Dizziness 22% 10% 

Difficulty with speech 10% 3% 

Burning semen 7% 1% 

Source: National Health Survey of Gulf War-era Veterans and their Families158

 As shown, individual symptoms experienced by Gulf War veterans are 

not unique in that they are also reported by veterans in non-Gulf 

comparison groups, albeit at lower rates. The observation that veterans 

who did not serve in the Gulf War report symptoms is not unexpected, 

since it has long been known that some level of symptomatology is found 

in any population group.178,352 But Gulf War veterans report symptoms in 

patterns that are distinct from other veterans and from the general 

population.286,287 Specifically, Gulf War veterans experience a greater 

number of symptoms than comparison groups, more severe symptoms than 

comparison groups, and are more likely to report multiple different types of 

symptoms simultaneously.85,285 In contrast to the occasional headache or 

digestive problem or joint pains that might afflict anyone from time to time, 

it is not uncommon for Gulf veterans to experience severe headaches and 

joint pain and chronic diarrhea all at the same time, perhaps in connection 

with dizziness, memory problems, fatigue, and skin rashes, and for these 

problems to have persisted over many years. 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 23

 Figure 1 shows the proportion of Gulf War and nondeployed veterans 

who reported having multiple or moderate-to-severe symptoms in six 

different symptom domains (fatigue symptoms, pain symptoms, 

neurocognitive symptoms, respiratory symptoms, gastrointestinal 

symptoms, and skin symptoms) from a population-based study of Kansas 

Gulf War era veterans.285 As shown, a similar proportion of Gulf and nonGulf veterans reported a relatively low level of symptoms—that is, 

symptoms in just one or two of the six defined symptom groups. However, 

over 30 percent of Gulf veterans reported having moderate-to-severe 

symptoms in three or more of the symptom domains, compared to less than 

five percent of the comparison group. So, while individual symptoms may 

not be uniquely associated with Gulf War service, the pattern of symptoms 

in Gulf War veterans is distinct, in terms of symptom frequency, severity, 

duration, and the occurrence of multiple symptom types together. 

Figure 1. Proportion of Gulf War era Veterans Reporting 

 Symptoms in Six Symptom Domains 285 

0%

10%

20%

30%

40%

1-2 Types of Symptoms 3-6 Types of Symptoms

Nondeployed era veterans Gulf War veterans

 In addition to undiagnosed symptoms, population-based studies have 

found that Gulf veterans have significantly higher rates of some types of 

diagnosed medical conditions than non-Gulf veterans. Most prominently, a 

2003 epidemiologic study from the Department of Veterans Affairs (VA) 

found that Gulf veterans have developed a serious neurodegenerative 

disease, amyotrophic lateral sclerosis, at twice the rate of nondeployed era 

veterans in the years since the war.117 Moreover, three population-based 

studies have provided information on rates of other medical and psychiatric 

conditions for which veterans report being diagnosed, as shown in Table 

2.98,285,349 Of note, significantly more Gulf veterans report being diagnosed 

with migraine headaches and with skin, gastrointestinal, and respiratory 

conditions than comparison groups, as well as depression and posttraumatic stress disorder. However, Gulf War service has generally not 

been associated with increases in most age-related chronic conditions such 

as cancer and diabetes. 158,191,285 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 24

 

Table 2. Diagnosed Conditions Reported at Significantly Higher Rates 

by Gulf Veterans than Nondeployed Veterans 

Proportion of Gulf Veterans 

Reporting Condition 

Skin conditions98,285,349 20-21% 

Migraines98,285,349 7-18% 

Stomach or intestinal conditions285 15% 

Depression98,285 8-12% 

Bronchitis98,285,349 7-10% 

Arthritis98,285,349 6-11% 

Hypertension98,349 8-9% 

Asthma285,349 4-7% 

Posttraumatic stress disorder98,285 3-6% 

 Population-based studies have also consistently identified excess rates 

of symptom-defined diagnoses such as chronic fatigue syndrome (CFS), 

fibromyalgia, and multiple chemical sensitivity among Gulf War veterans 

in comparison to both nondeployed veterans and the general 

population.98,138,160,243,248,285,349 For example, symptom-based estimates of 

the prevalence of CFS have ranged from two to five percent among Gulf 

War veterans, significantly higher than estimates of zero to 1.8 percent in 

nondeployed veterans and actual CFS rates of 0.2 to 0.4 percent found in 

the general population.145,250 

 

Relationship of veterans’ illnesses to Gulf War service. In light 

of the large body of evidence demonstrating excess morbidity in Gulf War 

veterans, there is now general consensus among researchers and 

government officials that Gulf War veterans are affected by an abnormally 

high rate of chronic multisymptom illnesses. Some reports, however, have 

suggested that these conditions may not result from experiences or 

exposures specific to the Gulf War, since unexplained symptoms have 

occurred after other wars and are also observed in civilians who have 

experienced traumatic events.54,86,129,148,292 Excess rates of both medical 

and psychiatric conditions have been observed in veterans after service in 

many previous conflicts, including conditions resulting from psychological 

trauma, infectious diseases, and chemical and radiological exposures. 

 Several lines of evidence, however, have indicated that Gulf War 

veterans’ illnesses are the result of experiences specific to the Gulf War, 

rather than a nonspecific result of deployment-related stress or trauma. For 

example, many epidemiologic studies have identified significant 

associations between rates of multisymptom illness and specific exposures 

that veterans report during the Gulf War, including smoke from oil well 

fires, receipt of multiple vaccinations, hearing chemical alarms, ingestion 

of pyridostigmine bromide, and use of pesticides.52,107,138,222,244,349 Despite 

the large number of findings relating veterans’ symptoms to wartime 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 25

exposures, this information is generally considered to be inconclusive, due 

to limitations in veterans’ knowledge and recollection of what they might 

have been exposed to during the war, and at what levels. In general, the 

lack of more objective government data on veterans’ exposures in the 

Persian Gulf theater has required investigators to rely on veterans’ selfreported experiences and exposures in order to identify possible linkages 

between individual exposures and Gulf War veterans’ illnesses. 

 

 Other types of evidence relating veterans’ illnesses to events specific to 

the Gulf War come from studies of Kansas and British veterans. A 2000 

study of Kansas veterans found rates of Gulf War illness to differ 

significantly by the locations and time periods in which veterans served 

during the war.285 Gulf War illness rates were lowest (21%) among 

veterans who served primarily on board ship, higher in veterans who served 

on land but remained in support areas (31%), and highest (42%) in veterans 

who entered Iraq or Kuwait, countries in which the ground war and 

Coalition air strikes took place. Illness rates also varied with the time 

periods veterans were present in theater, with the lowest rate (9%) among 

veterans who departed the region before the start of the air war in January, 

1991, and the highest rate (43%) among veterans who were still in theater 

five months after the cease-fire. Differences in illness rates by location and 

time period indicate that veterans’ illnesses are linked to specific 

experiences during deployment, evidence that is independent of veterans’ 

recollections concerning specific exposures. 

 Additional evidence that links Gulf War veterans’ symptoms to 

experiences specific to the Gulf War comes from a large British study that 

found high rates of multisymptom illness in Gulf War veterans, but not in 

veterans who served in the Bosnian conflict.121,349 Striking differences 

between the health of the two groups were first described in 1999 and have 

been sustained over time, as reported in a study that reassessed the health 

of both veteran groups after a four-year follow-up period.122 Such clear 

and consistent differences between the health of Gulf and Bosnia veterans 

evaluated in a comparable manner are another important indication that 

Gulf veterans’ illnesses result not from a generalized reaction to the stress 

of deployment but from experiences specific to service in the Persian Gulf 

theater. 

Deployment stress does not account for the unexplained 

conditions affecting Gulf War veterans. Early reports suggested that 

the unexplained illnesses reported by Gulf War veterans may have resulted 

primarily from wartime stress.179,240,241 As additional research has become 

available, however, it has become evident that these conditions cannot be 

adequately explained by deployment stress, wartime trauma, or psychiatric 

diagnoses such as posttraumatic stress disorder (PTSD). This is not 

surprising, given the general circumstances of the Gulf War. The war was 

short, requiring only four days of ground combat to achieve a decisive 

victory. Casualty rates were very low, and the vast majority of veterans 

were never in combat areas and did not witness any deaths during 

deployment.158,222,285 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 26

 Some individuals did experience traumatic events during the Gulf War, 

and now experience psychological problems as a result. Data from 

multiple sources, however, indicate that, overall, PTSD rates are lower in 

Gulf veterans than in veterans of previous wars,199,357 and are more similar 

to PTSD rates in the general population.173,360,362 Only a fraction of veterans 

reporting chronic health problems since Desert Storm suffer from PTSD. 

For example, VA has reported that less than four percent of veterans 

examined in its Gulf War registry have either a primary or secondary 

diagnosis of PTSD.334 Similarly, a RAND report commissioned by the 

Department of Defense to review the scientific evidence concerning stress 

and Gulf War illnesses concluded that overall rates of PTSD are low in 

Gulf War veterans, and identified little evidence linking wartime stressors 

to medical symptoms.199 

 Research spanning several decades has described the complex 

relationship between medical and psychiatric symptoms and illness.199

Studies of veterans from different wars have consistently found those with 

PTSD to have more symptomatic complaints than those without 

PTSD.42,115,175,354,360 The reverse is also true. Individuals with chronic 

medical conditions such as cancer and multiple sclerosis are known to have 

more psychiatric illnesses than those who are not ill.119,230,284,296

Evaluating the relationship between medical and psychiatric illness, 

especially in conditions identified primarily by symptoms, can be 

complicated by the fact that some symptoms, such as fatigue, cognitive 

difficulties, and depression can result from physical causes (such as head 

injuries or the sequelae of toxic exposures) or from psychological causes 

(such as traumatic experiences, or the stress of chronic illness). 

 

 Unfortunately, early studies that evaluated the health of Gulf veterans 

often did not use research methods capable of distinguishing between 

physical and psychologically-based symptoms, sometimes leading to 

erroneous conclusions about medical and psychiatric aspects of Gulf War 

illnesses. For example, early studies often relied on psychometric 

screening tests to estimate the prevalence of PTSD and “stress-related 

symptoms” in ill Gulf War veterans, rather than more definitive psychiatric 

assessments using diagnostic measures such as the Clinician Administered 

PTSD Scale (CAPS).32,101,199 Psychometric tests used in such studies were 

typically designed to screen for PTSD in individuals known to have 

experienced traumatic events. These screening tests identify PTSD cases 

based on the number of problems veterans endorse from a list of 

nonspecific symptoms—including such problems as fatigue, difficulty 

concentrating, and night sweats—that can be associated with many types of 

medical conditions. As a result, psychometric screening tests can 

erroneously identify veterans with multisymptom medical conditions as 

having PTSD, without reference to whether they had experienced traumatic 

events during their service in the Gulf War. 

 More recent studies, using more sophisticated evaluation and analytic 

approaches, have found that Gulf veterans experience significantly higher 

rates of unexplained symptoms than non-Gulf veterans, even after 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 27

controlling for the effects of wartime stressors and psychiatric 

diagnoses.180,244,297,357,360 For example, a New Jersey study found similar 

levels of physical impairment in Gulf War veterans with and without comorbid psychiatric conditions and concluded that reduced levels of 

physical functioning in Gulf veterans cannot be attributed to psychiatric 

illness.297 A 1998 study of three groups of Army veterans controlled both 

for the effects of in-theater psychological stressors and for PTSD, and 

found excess symptomology in Gulf veterans associated with a variety of 

war zone exposures.244 A related study determined that two-thirds of the 

most symptomatic veterans had no axis I psychiatric disorders.360 In a 

larger follow-up study, stratified multivariate analyses determined that, 

among veterans with low levels of psychological distress, illness was most 

strongly associated with self-reported exposure to oil fire smoke and 

ingestion of more than 21 anti-nerve gas pills.361 More recently, a study of 

British veterans sponsored by the U.S. Department of Defense found that 

about 24 percent of the most disabled Gulf veterans had identifiable 

psychiatric disorders, a proportion similar to that found in a comparison 

group of disabled veterans who had not served in the Gulf War. Seventysix percent of ill Gulf veterans had no identifiable psychiatric condition, 

leading investigators to conclude that “alternative explanations for the 

persistent ill health in Gulf War veterans are needed.”141 

How many veterans are affected by Gulf War-related health 

problems? The question of the number of veterans with unexplained 

health problems is of key importance to veterans, government officials, and 

healthcare providers. As of May, 2004, over 179,000 Gulf veterans, or 30 

percent of eligible veterans who served in the Persian Gulf conflict, had 

been determined by VA to have a service-connected disability.329 This 

figure includes the total number of veterans with approved claims for any 

disability connected to their military service, not only claims specifically 

for undiagnosed conditions linked to service in Desert Storm. Government 

and media reports have frequently reported that about 100,000 of the nearly 

700,000 U.S. Gulf veterans, or 14 percent, are experiencing Gulf Warrelated health problems. This figure appears to be based on enrollment in 

government registries rather than on information from scientific studies. 

As shown by the prevalence figures listed in Table 3, research-based 

estimates of the proportion of veterans who are ill vary widely from study 

to study, depending on how the “Gulf War multisymptom illness” complex 

is defined. 

 Because symptoms reported by Gulf War veterans also occur at lower 

rates among individuals who did not serve in the Gulf War, evaluation of 

the burden of illness associated with Gulf War service should be based on 

the excess rate of multisymptom illness in Gulf veterans—that is, the level 

above that expected had veterans not deployed to the Persian Gulf theater. 

Such information is readily available from population-based studies that 

have compared the rates of multisymptom illness in Gulf War veterans to 

rates in nondeployed era veterans. 
Finding 1 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 28

TABLE 3 here 

 As shown in the right column of Table 3, highly consistent estimates of 

the excess rate of illness in Gulf veterans have emerged from these studies, 

which used different definitions of “multisymptom illness” in different 

veteran populations. Regardless of whether the symptom pattern is defined 

broadly (as in the studies of British and New England veterans) or 

conservatively (as in the study of Kansas veterans), the excess prevalence 

of multisymptom illness in Gulf War veterans compared to non-Gulf 

veterans has consistently been between 26 and 32 percent. The fact that 

these diverse studies have generated consistent estimates of the excess rate 

of illness attributable to Gulf War service suggests that this finding is 

robust, and that between one-fourth and one-third of Gulf veterans have 

experienced a multisymptom pattern of illness since the war, over and 

above the “background” level of symptoms expected had this group not 

served in the Gulf War. 

 In summary, although many questions remain about the nature and 

causes of health problems affecting Gulf War veterans, a number of 

important conclusions can be drawn from existing epidemiologic research. 

Gulf veterans experience significantly more symptoms, illnesses, and 

diagnosed conditions than veterans who did not serve in the Gulf War, 

although these conditions have not generally been associated with 

increased rates of hospitalization or disease-related deaths. The 

multisymptom conditions affecting Gulf veterans cannot be explained by 

wartime stress or psychiatric illness, and affect a substantial proportion of 

veterans. Population-based studies indicate that between 26 and 32 percent 

of Gulf veterans experience a multisymptom pattern of illness, over and 

above the rates experienced by veterans who did not serve in the Gulf War.
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 29

Finding 2

Treatments that 

improve the health 

of veterans with 

Gulf War illnesses 

are urgently 

needed.

 When military personnel become ill or disabled as a consequence of 

their military service, it is the responsibility of the federal government to 

address their medical needs. In the years since the Gulf War, 

Congressional committees, the federal interagency Persian Gulf Veterans 

Coordinating Board, and expert review panels all have identified adequate 

treatment for Gulf veterans’ illnesses to be a top federal 

priority.136,221,236,304,346,348 The charter of the Research Advisory Committee 

recognizes that “the fundamental goal of Gulf War-related government 

research is to ultimately improve the health of ill Gulf War veterans” and 

directs that “the choice and success of research efforts shall be judged 

accordingly” (Appendix C). However, in the 13 years since military 

personnel returned from Desert Storm, little progress has been made in 

identifying treatments that substantially improve the health of veterans with 

Gulf War illnesses. 

 Identifying useful treatments for Gulf War veterans’ illnesses is a 

complex challenge. These conditions are poorly defined, of unknown 

etiology, and are not generally distinguished by objective clinical markers. 

The conditions may result from several overlapping causative factors and 

represent different overlapping pathophysiological processes. It is 

precisely because of these difficulties and the shortage of promising 

treatment research from the larger scientific community that VA has a 

unique responsibility to pursue all scientific and clinical avenues 

potentially capable of identifying and developing treatments that can 

improve the health of ill Gulf War veterans. 

 Successful treatments for medical conditions are generally identified in 

two ways. The first approach relies on clinical observations over time that 

certain illnesses respond favorably to certain treatments. Such clinical 

observations can then be followed by systematic scientific study to evaluate 

a treatment’s effectiveness and determine if it should be recommended for 

wider use. The second approach involves the rigorous scientific 

identification of the specific molecular mechanisms underlying a disease, 

and development of treatments that interfere with the identified disease 

process. The clinical observation approach may, in some circumstances, be 

faster and less expensive, but involves trial and error and a mechanism 

through which clinical experience is converted into systematic scientific 

information. The molecular mechanism approach requires a determined 

scientific effort, often involving substantial commitments of time and 

financial resources. Given the challenges associated with addressing Gulf 

War veterans’ illnesses, it is likely that both approaches will be important 

for making progress in identifying treatments that significantly improve 

veterans’ health. 

 The federal government has expended considerable funding on 

treatment-related research for Gulf War veterans’ illnesses. As shown in 

Table 4, VA and DOD projected spending over 21 million dollars on 

treatment research for veterans’ unexplained illnesses through 2003.73

Over 15 million dollars of this funding was used to conduct two large 

clinical trials of treatments for Gulf War veterans’ illnesses. Additional 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 30

funding was allocated for demonstration projects at several VA medical 

centers. These demonstration projects focused on identifying innovative 

case management strategies that would improve veterans’ quality of life 

and satisfaction with health care. Although a number of the demonstration 

clinics did result in improved ratings of patient satisfaction with the 

enhanced level of services provided, none produced a significant 

improvement in veterans’ overall health status. 

TABLE 4 here 

 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 31

 VA and DOD jointly funded two large multi-center clinical trials for 

Gulf War veterans’ illnesses: the Antibiotic Treatment Trial (ABT) and the 

Exercise/Behavioral Therapy Trial (EBT).56,75 The ABT was undertaken in 

response to reports from Dr. Garth Nicolson that some ill Gulf veterans 

appeared to be infected with mycoplasma, particularly a species previously 

identified in HIV patients, mycoplasma fermentans (incognitus strain).

186,220

Dr. Nicolson indicated that this chronic infection was intracellular, and so 

often could not be detected by conventional serological methods.219 After 

working with a number of ill Gulf veterans, he reported that many 

improved after a prolonged course of antibiotic therapy.220

 The federal ABT trial assessed the efficacy of a 12-month course of the 

antibiotic doxycycline in improving the health and physical functioning of 

symptomatic veterans who tested positive for mycoplasma infection. The 

study included 491 patients at 28 study sites, and is now complete. Study 

results were summarized in a presentation to the Committee in 2003363 and 

have recently been published.76 About 40 percent of ill veterans screened 

for inclusion in the study were found to be positive for mycoplasma 

species. Study results indicated that about 18 percent of mycoplasmapositive veterans who received doxycyline over a 12 month course of 

treatment showed improvement, as indicated by an increase of at least 

seven points in physical function scores assessed using the Medical 

Outcomes Study Survey Form 36 (SF-36) instrument for veterans.170,355

This was nearly identical to the 17 percent of veterans who showed similar 

improvement after 12 months on a placebo. 

 The results of this trial thus appear to indicate that doxycycline therapy 

does not provide significant benefit for Gulf War veterans’ illnesses. 

However, a number of the study findings shared with the Committee were 

puzzling and raise questions about the study’s conclusions. Investigators 

indicated that laboratory testing for mycoplasma species yielded 

inconsistent results between the four laboratories initially tasked with 

testing veterans’ blood. As a result, the study design was modified to use 

testing results provided by just one of the laboratories. The study also 

found that veterans who received doxycycline therapy did appear to show 

significantly greater improvement than those taking placebo after three 

months of therapy. However, differences between the two groups on both 

primary and secondary measures tapered off over the course of the study, 

with no significant differences remaining after six months.76 After 12 

months of treatment, 39 percent of veterans in the doxycycline treatment 

group had no detectable levels of doxycycline in their blood, indicating that 

there may have been a significant problem with adherence to the 

doxycycline regimen. Finally, after 18 months, only about 10 percent of 

veterans in the study tested positive for mycoplasma, independent of 

whether they had received doxycycline or placebo. This finding is 

perplexing in light of the study’s initial assessment indicating that 40 

percent of all ill veterans tested positive for mycoplasma, and the inclusion 

of only mycoplasma-positive patients in the study. 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 32

 The second large government study tested whether exercise and 

cognitive behavioral therapy, individually or together, would improve the 

health of ill veterans. Previous research had found these approaches to 

provide some benefit for chronic fatigue syndrome (CFS) and fibromyalgia 

patients.68,95,238,239,268,359 The EBT study included 1,092 veterans enrolled at 

20 study sites. Results were published in March, 2003, and indicated that 

cognitive behavioral therapy, but not exercise, was associated with 

improvement in a small but statistically significant proportion of veterans. 

Specifically, 18.5 percent of veterans who received cognitive behavioral 

therapy showed at least a seven-point improvement in SF-36 physical 

function scores. This compared to the 11.5 percent who improved with 

“usual care”—that is, without receiving either intervention—and the 11.7 

percent who improved with exercise alone.75 Cognitive behavioral therapy 

is known to improve function in a number of medical and psychiatric 

conditions, including clinical depression.47,89,111,172,201,267 Additional 

analyses are needed to determine whether the modest improvements 

provided by cognitive behavioral therapy in the EBT trial resulted from 

improvements related to comorbid depression in a subset of ill Gulf War 

veterans, or, more generally, to improvements in veterans’ medical 

symptoms. 

 In addition to research on treatments, VA cooperated with DOD, 

beginning in 1999, in convening a multidisciplinary panel of clinicians and 

researchers to develop clinical practice guidelines for the evaluation and 

management of post-deployment health concerns.330 The guidelines provide 

an algorithm for conducting patients’ histories and physical examinations 

and for laboratory tests to be administered, but do not provide information 

regarding specific treatments. VA and DOD also convened an expert panel 

to develop clinical practice guidelines for medically unexplained 

symptoms, including chronic pain and fatigue.331 These guidelines do 

provide specific treatment options and recommendations based on 

published research and the experience and opinions of scientists and 

clinicians on the panel. Identified treatments are those used by some 

clinicians to treat CFS and fibromyalgia. Some have not been evaluated in 

scientific studies for their effectiveness with these conditions, and none 

have been evaluated for their effectiveness in treating Gulf War illnesses. 

In addition, no studies or monitoring programs have been established to 

follow up veterans treated by government physicians who use these 

guidelines to determine whether the recommended treatments provide 

benefit to veterans with unexplained multisymptom illnesses. 

 There has been little effort to date to systematically utilize the combined 

experience of the many VA clinicians currently treating Gulf veterans in 

VA medical facilities. No mechanism is currently in place for compiling 

data on treatments and outcomes documented in the medical records of ill 

veterans seen by VA clinicians. Research studies of medical outcomes are 

utilized for other conditions by VA scientists and clinicians,170,225,257 but no 

programs are in place to monitor health outcomes associated with 

therapeutic approaches used in treating ill Gulf veterans either at local VA 

medical centers or at VA’s specialty referral clinics for deployment-related 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 33

health conditions. And, as previously mentioned, no new programs have 

been established to evaluate the effectiveness of the therapeutic approaches 

recommended in VA’s clinical practice guidelines for medically 

unexplained symptoms. 

 

 In theory, funding for treatment studies of Gulf veterans’ illnesses has 

long been available to VA researchers interested in pursuing this type of 

research. VA has maintained an open solicitation for treatment proposals 

for Gulf veterans’ unexplained illnesses since 1997, and further encouraged 

the submission of treatment proposals in its 2002 program funding 

announcement for deployment health research. However, with the 

exception of the two large multi-center trials, VA has funded no studies 

designed to evaluate the effectiveness of specific treatments for Gulf 

veterans’ unexplained illnesses. The only treatment study currently 

underway at VA that includes Gulf War veterans is a study comparing two 

types of psychotherapy for PTSD in women veterans.332 

 VA’s usual process for sponsoring treatment studies for Gulf War 

illnesses and other conditions is, in many respects, passive. That is, the VA 

Office of Research and Development does not generally direct researchers 

to conduct specific studies that address specific research questions or 

evaluate specific treatments. Rather, it requires that VA clinicianresearchers with sufficient interest and expertise in treating unexplained 

illnesses come forward with credible proposals for clinical trials with some 

level of evidence indicating that the treatment to be studied may be 

beneficial. There are no VA programs or investigators tasked with 

identifying innovative treatments for Gulf War illnesses that are potentially 

beneficial and should receive high priority for study. Nor are there 

programs or mechanisms in place whereby treatment strategies already 

utilized by VA or private clinicians can be identified and systematically 

studied. 

 Thousands of Gulf veterans are treated for unexplained illnesses every 

year in VA and DOD clinics and by private physicians. A number of 

plausible treatment candidates have been suggested by different clinicians 

as having possible benefit for Gulf War veterans’ illnesses, based on case 

reports, effectiveness in treating similar conditions, and effects on likely 

mechanisms of illness. But little effort has been made to systematically 

evaluate these therapies to determine which candidate treatments appear to 

be suitable for clinical trials, which require further data development, and 

which appear to hold little potential for benefit. Where there are 

insufficient data on a potentially promising treatment to warrant moving 

ahead with large clinical trials, no programs are currently in place to 

develop such information. Thus, promising treatment candidates 

perpetually remain only treatment candidates. 

 Other federal agencies have developed protocols for assessing the 

effectiveness of treatments used clinically that have not been systematically 

evaluated or studied. These include the “Best Case Series” approach 

developed and used at the National Cancer Institute,214,356 and the 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 34

“Prospective Outcomes Evaluation and Monitoring System” developed at 

the National Center for Complementary and Alternative Medicine at the 

National Institutes of Health.251 These protocols have been used to make 

preliminary assessments of the usefulness of unstudied treatments and to 

provide a framework for making decisions to determine when additional 

study is warranted. 

 In 1998, VA asked the Institute of Medicine (IOM) to review existing 

research relevant to treatments for Gulf War illnesses and similar 

conditions. Because no treatment research on Gulf War veterans’ illnesses 

had been completed at that time, the 2001 IOM report and 

recommendations focused on treatment research methodology and research 

on conditions with some similarities to Gulf War veterans’ illnesses, 

including CFS, fibromyalgia, headache, and depression. The IOM report 

called for a comprehensive approach to treatment guidelines and research 

on Gulf War veterans’ illnesses that relies on a “hierarchy of evidence,” 

that is, evidence from a range of study designs that provide different types 

and strengths of information.136 

 Treatment recommendations for veterans’ illnesses must be based on the 

best available scientific evidence. Similarly, decisions made regarding the 

selection of potentially useful treatments for evaluation in large clinical 

trials should be based on the best available evidence. As described in the 

2001 IOM report, a range of study designs is available to researchers that 

provides different levels of evidence regarding treatment effectiveness, 

ranging from expert opinion and unsystematic observation, the lowest level 

of evidence, to multiple well-conducted randomized trials or outcomes 

studies, the highest level. The report noted that observational designs 

(including outcomes monitoring studies and well-conducted cohort studies) 

and small clinical trials can provide important and useful evidence 

regarding treatment effectiveness. Such studies can often be completed at a 

fraction of the time and expense of large clinical trials. 

 In attempting to identify treatments for Gulf War veterans’ illnesses, 

VA has focused its efforts on the lowest and highest levels of evidence—

that is, on the consensus judgment of experts, and on large, multi-center 

trials. Both have required an enormous amount of effort on the part of 

government officials, clinicians, and scientists, and have consumed 

considerable time and financial resources. But unfortunately, neither effort 

has succeeded in identifying treatments for which there is evidence of 

substantial health benefits for veterans with unexplained multisymptom 

conditions. 

 As indicated, VA generally funds research proposals initiated by 

researchers in the field, rather than utilizing a “top down” approach that 

directs specific research questions to be studied using specific protocols. 

The two large treatment trials of Gulf War veterans’ illnesses were an 

exception, however, developed in response to an initiative from VA’s 

Office of Research and Development. The Committee considered this 

exception to be a positive indication that VA was prepared to take decisive 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 35

 

action in identifying treatments that might benefit ill Gulf War veterans. 

However, the Committee was concerned that both large clinical trials were 

undertaken with little systematically generated evidence that the treatments 

being studied were potentially beneficial for Gulf War veterans. Directives 

from Congressional committees and government panels that VA identify 

treatments for Gulf War illnesses likely resulted in considerable political 

pressure for VA to move forward with these studies. This may explain, in 

part, why the approaches taken appear to have lacked the level of 

preliminary development required to optimally study treatments for which 

investigators had little research or experience on which to rely. In the case 

of the antibiotic treatment trial, for example, no corroborating evidence was 

developed prior to the treatment trial to first indicate that the infection in 

question could be reliably identified and was disproportionately present in 

ill veterans. Second, if the infection was shown to be present in a 

substantial number of veterans, it would have been prudent to first conduct 

one or more studies of smaller size and/or shorter duration to determine 

whether antibiotic therapy was associated with symptomatic improvement 

in ill veterans and to optimize a protocol to be used in larger studies. 

Similarly, smaller studies could also have been used to determine first 

whether ill veterans appeared to benefit from cognitive behavioral therapy 

and/or exercise therapy, and to refine the protocols that seemed most 

capable of producing benefits for ill veterans.118 

 The results of these studies have been disappointing to ill veterans and 

to healthcare providers seeking treatments that hold promise for providing 

substantial benefits for veterans’ multisymptom conditions. The 

Committee concludes that federal efforts have not been successful in 

identifying effective therapies for Gulf War illnesses, nor in developing a 

mechanism for identifying and evaluating candidate treatments for 

assessment in clinical trials. The considerable funding and human 

resources required to conduct one large multi-center clinical trial might be 

more productively used to sponsor a range of scientific research activities 

aimed at identifying, prioritizing, and evaluating treatment options for Gulf 

War veterans’ illnesses. Such activities would include observational 

research studies, pre-clinical studies, and smaller trials capable of providing 

crucial preliminary information on the effectiveness of treatments and 

guidance for optimal application and study of those treatments. 

Preliminary efforts should include identification of well-defined veteran 

subgroups for which the treatment under study is most likely to be 

effective. Such efforts would not preclude the use of large, rigorous 

clinical trials for evaluating treatments for Gulf War illnesses. Rather, they 

would establish an evidence-based framework for identifying and 

prioritizing treatment candidates for clinical trials and enhance the 

probability that large, expensive trials of useful therapies will be 

successful. 

 In light of the difficulties involved and the lack of success to date, it is 

particularly important that VA take a new and reinvigorated approach to 

identifying treatments that will benefit ill Gulf War veterans. This
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 36

Finding 2 

Recommendations 

approach must be scientifically rigorous and well-planned and managed, 

but it must also be bolder and more comprehensive than past efforts. 

 The Committee recommends that VA immediately establish a 

comprehensive program specifically tasked with evaluating treatmentrelated information and research, and developing data and pilot studies as 

necessary to identify promising candidate treatments for clinical trials for 

Gulf War veterans’ illnesses. This program would employ a multi-faceted 

approach using and developing evidence from a variety of study types, 

from case series reports and outcomes research to randomized trials. It 

should be staffed and managed by professionals with expertise in 

investigating complex illnesses and in evidence-based methodological 

approaches to treatment development and evaluation. This initiative would 

include support for pilot studies of potentially promising treatments for 

Gulf War veterans’ illnesses and would augment VA’s current strategy of 

supporting clinical trials of scientific merit as they are proposed by VA 

scientists in the field. 

 The recommended program would include the following components: 

• Identification of treatments used by clinicians and veterans for Gulf 

War veterans’ illnesses. Current and previously used treatments can be 

identified in a variety of ways, including compilation of existing 

clinical data on treatments administered by VA clinicians and 

systematic surveys of veterans and clinicians regarding treatments. 

• Collection of retrospective and prospective observational data on 

clinical outcomes associated with treatments used by clinicians, 

particularly treatments used in VA specialty clinics for Gulf War 

veterans, and those recommended for use by VA clinical practice 

guidelines for medically unexplained fatigue and pain. 

• Development of a plan for developing and testing innovative but 

untried treatment strategies. Priority among treatments to be developed 

and tested should be determined by such considerations as plausibility 

of benefit based on likely pathophysiological mechanisms of illness, 

proven effectiveness in treating symptoms or symptom complexes 

similar to those experienced by Gulf War veterans, and potential for 

adverse side effects. This plan should include cooperative research 

with scientists and clinicians outside the VA system with expertise in 

testing or administering innovative therapies not currently available at 

VA. 

• Development of a general protocol for assessing the evidence on the 

potential benefit of treatments for Gulf War veterans’ illnesses in order 

to determine which ones appear to be suitable for clinical trials, which 

require further data development and evaluation, and which appear to 

hold little potential for benefit. 
Finding 2 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 37

• Provision of technical assistance and research support to clinicians—

both those who currently treat Gulf War veterans’ illnesses and those 

with expertise in administering treatments that may hold promise for 

these conditions—in developing evidence regarding the effectiveness 

of treatments. 

• Development of guidelines for standardizing essential parameters of 

Gulf War illness treatment research, including documentation of the 

definition and measures used to define multisymptom illness and 

illness subgroups, documentation of the treatment intervention, and 

measurement of health status before and after the treatment 

intervention.
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 38

Finding 3

A growing body of 

research indicates 

that an important 

component of Gulf 

War veterans’ 

illnesses is 

neurological in 

character. 

 Gulf War veterans have reported symptoms suggestive of neurological 

dysfunction since their return from Desert Storm in 1991.69,150,303

However, without specific information about the types and concentrations 

of exposures experienced by individual veterans, consideration of a link 

between Gulf War service and neurological pathology must rely on two 

types of evidence. First, it must be determined whether Gulf War veterans, 

in fact, do exhibit excess neurological pathology or functional impairment 

relative to comparison groups. Several different lines of research have 

addressed questions regarding neurological impairment in Gulf veterans, 

and are summarized below. Second, it is important to consider evidence 

concerning the potential for events or exposures associated with service in 

the Persian Gulf theater to have caused chronic neurological sequelae, as 

summarized in Finding 4 of this report. After reviewing research and 

testimony relating both to neurological impairment in Gulf War veterans 

and to neurotoxic exposures in theater, the Committee concludes that a 

growing body of evidence indicates that an important component of Gulf 

War veterans’ illnesses is neurological in character. 

Increased risk of amyotrophic lateral sclerosis in Gulf War 

veterans. The most sobering indication of neurological disease in Gulf 

veterans comes from two studies released in 2003 which determined that 

Gulf veterans have developed amyotrophic lateral sclerosis, commonly 

referred to as ALS or Lou Gehrig’s disease, at about twice the rate of 

comparison populations in the years since Desert Storm.103,117 ALS is a 

progressive neurodegenerative disease, with less than 10 percent of patients 

surviving more than five years after initial diagnosis.70,277 

 One of the two studies investigating the rate of ALS in Gulf veterans 

indicated that the excess risk among deployed veterans may be of particular 

concern among younger veterans—that is, those under age 45, who are 

generally least likely to develop this disease.103 The study found that the 

rate of ALS among younger veterans was similar to that of the general 

population in the first four years after the war, but increased progressively 

from 1995 through 1998, the last year in which data were assessed. Twothirds of the young veterans with ALS in this study were reported to have 

returned from the war with chronic symptoms typical of Gulf War 

veterans’ illnesses, but developed serious progressive ALS symptoms 

between five and eight years later. 

 It is of great concern that the full impact of this disease on Gulf War 

veterans might not be known for decades. In the general population, the 

majority of ALS cases are first diagnosed after age 55.21,202,277 By the end 

of the year 2000, the most recent year included in VA’s ALS study, fewer 

than three percent of Gulf veterans had reached age 55. As shown in Table 

5, data from that study indicate that the rate of ALS in Gulf veterans 

exceeded that in nondeployed veterans in all age groups.226 Estimates from 

this study are based on small numbers, and so must be interpreted with 

caution. But it is important that this condition be monitored in Gulf War 

veterans for many years to come, since it is possible that the excess number 

of ALS cases may continue to rise as veterans age. To address this 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 39

concern, VA now maintains a registry for veterans of all eras who have 

been diagnosed with ALS. VA also provides service-connected disability 

compensation for Gulf War veterans diagnosed with ALS on a case-bycase basis, although no regulation granting presumed service-connection 

for all Gulf War veterans with ALS has been established. 

Table 5. Age-Specific ALS Rates in Gulf Veterans, Nondeployed 

Veterans, and a Comparison Population 

(number of ALS cases per 100,000 population)

Age at ALS 

Onset 

Gulf War 

Veterans226

(40 ALS cases) 

Nondeployed 

Veterans226

(67 ALS cases) 

Men in the state 

of Washington202

(127 ALS cases) 

< 25 0.08 0.00 0.11 

25-34 0.45 0.26 0.79 

35-44 1.77 0.80 1.63 

45-54 5.64 4.81 2.49 

55-64 31.19 8.89 6.42 

Neurological symptoms in Gulf War veterans. With the exception 

of ALS, research studies have not comprehensively assessed rates of 

diagnosed neurological diseases in Gulf War veterans. But symptoms 

suggestive of neurological problems have consistently been among those 

most commonly reported by ill veterans. Such symptoms include chronic 

headaches, memory problems, difficulty concentrating, sleep disturbances, 

problems with balance, numbness and tingling in extremities, and mood 

changes. 

 A number of epidemiologic studies have grouped the many unexplained 

symptoms reported by Gulf veterans into categories using statistical 

techniques. Although specific details vary with the types of symptoms 

queried and the statistical methods used, symptom groups suggestive of 

neurological, neurocognitive, and/or neuropsychological dysfunction are 

consistently identified in population-based studies of Gulf War veterans, as 

summarized in Table 6. 

 Identified neurological symptom complexes generally occur in both 

Gulf-deployed and nondeployed veteran groups, but always at significantly 

higher rates in Gulf War veterans. However, in VA’s national survey of 

over 20,000 veterans, a unique neurological symptom factor was identified 

only in Gulf War veterans, not in nondeployed Gulf War era veterans. 

This cluster of symptoms included blurred vision, loss of balance/dizziness, 

tremors/shaking, and speech difficulty. Gulf War veterans with this 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 40

symptom complex also had significantly elevated rates of seizures, 

migraine headaches, and neuralgias compared to veterans who did not have 

these symptoms.159 

TABLE 6 here 

 As shown in Table 6, symptoms suggestive of neurological problems 

have consistently been reported by ill veterans and characterized in 

research studies. Routine physical examinations and diagnostic tests have 

generally not provided explanations for the nature and causes of these 

symptoms.37,85,106,108 However, more specialized assessments of Gulf War 

veterans conducted in research settings have begun to provide objective 

evidence of neurological abnormalities in symptomatic Gulf War veterans. 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 41

Objective evidence of neurological impairment in Gulf War 

veterans. A growing number of studies, from different research groups 

studying different Gulf War veteran populations, have identified 

neurological abnormalities in ill Gulf War veterans using objective testing 

methods. Associations between veterans’ unexplained symptoms and 

neurological pathology have been demonstrated using specialized 

neuroimaging techniques, tests of autonomic nervous system function, 

audiovestibular testing, and measures of neuropsychological function in 

Gulf veterans relative to comparison groups. 

 

Neuroimaging and neurohormonal studies. In a 1997 case-control 

study, researchers at the University of Texas Southwestern Medical Center 

found no evidence of structural differences between the brains of ill 

veterans and controls on standard magnetic resonance imaging scans 

(MRI).106 But because of similarities between Gulf veterans’ symptoms 

and early symptoms of diseases of the basal ganglia such as Huntington’s, 

Wilson’s, and Fahr’s diseases,183 these investigators conducted more 

specialized neuroimaging studies to assess deep brain structures in ill Gulf 

War veterans. Using long echo time proton (1

H) magnetic resonance 

spectroscopy (MRS), they assessed brain cell health in the brainstem and 

right and left basal ganglia of 22 ill Gulf veterans and 18 matched veteran 

controls.109 Results indicated that the ratio of N-acetyl-aspartate to 

creatine (NAA/Cr), a measure of functional brain cell mass, was 

significantly lower in all three brain regions of ill Gulf veterans than in 

controls. Also importantly, the specific regions of the brain affected 

differed between veterans with different symptom profiles. In the most 

severely disabled veterans (those defined as having Haley Syndrome 2), the 

NAA/Cr ratio was reduced in all three brain regions. Veterans with other 

defined symptom profiles (Haley Syndromes 1 and 3) showed reduced 

functional brain cell mass in either the brainstem or the basal ganglia, but 

not in both. This team was able to replicate these findings in a separate 

group of six Army veterans with Syndrome 2, who were also found to have 

reduced NAA/Cr ratios in all three brain regions.109 Researchers 

concluded that Gulf War veterans with different clinical syndromes have 

biochemical evidence of different anatomical distributions of brain cell 

damage as demonstrated by proton magnetic resonance spectroscopy. 

 Following these reports, scientists at the San Francisco VA Medical 

Center and the University of California at San Francisco undertook an 

independent study to test these findings. In an initial study comparing 11 

ill Gulf veterans whose symptoms met the definition of Haley’s Syndrome 

2 to 11 non-veteran controls, investigators performed a similar protocol of 

long echo time proton MRS on the right basal ganglia, with additional 

methodological refinements. Results showed a reduction in the NAA/Cr 

ratio similar to that observed in the Texas study.205 These researchers are 

currently conducting studies to further investigate these neurological 

abnormalities in a larger sample of ill veterans. 

 In conjunction with the Texas MRS studies, Haley and colleagues 

assessed the level of central dopamine activity in the basal ganglia of ill 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 42

veterans and controls. Dopamine is a neurotransmitter in the brain that 

plays a critical role in the control of movement. In the study, after 

veterans spent six days in a low-stress clinical environment consuming a 

low tyrosine diet, fasting venous blood samples were drawn to assess the 

levels of two chemicals (homovanillic acid and 3-methoxy-4-

hydroxyphenlyglycol) whose ratio provides an index of dopamine 

production in the central nervous system. Veterans who had exhibited 

more brain cell damage in the left basal ganglia (lower NAA/Cr ratio) had 

significantly higher brain dopamine production. This association was not 

found in the right basal ganglia, suggesting that dopaminergic pathways in 

the basal ganglia may have been damaged in a lateralalized pattern. 

Investigators concluded that these results support the view that Gulf War 

illnesses are associated with neurological damage, in part resulting from 

injury to dopaminergic neurons in the basal ganglia.105

 An additional neuroimaging study of interest comes from investigators 

affiliated with the Montgomery VA Medical Center in Jackson, 

Mississippi, who used MRS to evaluate the hippocampus region of the 

brain in a small sample of ill Gulf War veterans.204 The hippocampus is a 

highly vascularized inner brain region involved in a variety of functions, 

including those associated with spatial orientation, memory, and mood. 

The study found that symptomatic Gulf veterans had significantly reduced 

NAA/Cr ratios in both the right and left hippocampus areas, in comparison 

to healthy controls. While preliminary, such findings raise the concern 

that ill Gulf War veterans may have neuronal damage in multiple regions of 

the brain. 

Autonomic nervous system dysfunction. The autonomic nervous 

system is the portion of the nervous system that controls the many 

physiological processes that are virtually “automatic”—that is, not 

generally under our conscious control. These include such diverse 

processes as regulation of heartbeat and blood pressure, response to 

stressful stimuli, digestion of food, sexual function, and regulation of body 

temperature. One of the first scientific studies suggesting possible 

autonomic dysregulation among Gulf War veterans was presented at a 1998 

federal research conference. Investigators provided preliminary data 

indicating that Gulf War veterans had an excess rate of gall bladder disease 

requiring cholecystectomy compared to other veterans, and suggested this 

could have been the result of bile stasis due to autonomic dysfunction.206 

 Function of the autonomic nervous system can be assessed by 

monitoring heart rate and blood pressure in response to different 

challenges. One commonly used approach involves tilt table testing, in 

which blood pressure, heart rate, and symptoms are monitored both in a 

supine position and when subjects are tilted to an upright position. 

Abnormalities on this test have been demonstrated in a number of 

conditions affecting the autonomic nervous system, including chronic 

fatigue syndrome.36,83,91 Investigators from Evans Army Hospital in 

Colorado have reported that symptomatic Gulf veterans were significantly 

more likely to have abnormal adaptive responses to tilt table testing than 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 43

healthy controls.67 Researchers from the East Orange, New Jersey, VA 

Medical Center also found that ill Gulf War veterans have blunted 

cardiovascular responses to stressors compared to healthy veterans.231 In 

addition, Haley and colleagues have reported that high frequency heart rate 

variability was significantly blunted during sleep in ill Gulf veterans 

compared to healthy veterans, another indication of autonomic dysfunction 

in symptomatic veterans.110 

 Early findings of abnormal autonomic regulation in ill Gulf War 

veterans have been supported and expanded by a larger and more 

comprehensive study of autonomic function in Gulf War veterans 

sponsored by the Department of Defense and conducted by investigators at 

Midwest Research Institute.258 Portions of this project are still underway 

and autonomic testing results have not yet been published. In a 

presentation to the Committee, Dr. Antonio Sastre reported that ill Gulf 

veterans significantly differed from controls on a wide range of autonomic 

tests and measures, including heart rate and blood pressure responses to tilt 

table testing. In these tests, autonomic responses were generally blunted in 

symptomatic Gulf veterans relative to controls. Investigators also noted 

that, consistent with an earlier study,266 ill veterans did not exhibit 

abnormalities when tested using the Valsalva maneuver, suggesting that 

this single measure does not adequately characterize autonomic function in 

symptomatic Gulf veterans. If supported by scientific peer review, the 

results of this study will provide a strong indication of autonomic 

dysfunction in symptomatic Gulf War veterans, as evidenced by a 

consistent pattern of differences between ill veterans and controls on a 

broad range of autonomic measures. 

Additional neurophysiological assessment of ill Gulf veterans. 

Dizziness and problems with balance are frequently reported by 

symptomatic Gulf War veterans. In 1997 and 2000, University of Texas 

Southwestern investigators reported results of audiovestibular assessments 

of ill veterans undertaken to determine whether these symptoms are 

neurological or functional in nature.106,255 Audiovestibular tests assess the 

function of auditory pathways from the inner ear through the brainstem. 

Specific identified abnormalities can sometimes be used to determine the 

location of pathology in these pathways. Overall, researchers found that 

symptomatic veterans were significantly more likely to exhibit abnormal 

ocular motility, pathologic eye movements (nystagmus), and asymmetric 

eye reflexes than matched controls, with specific abnormalities differing 

between veterans meeting criteria for Haley’s three defined syndromes. 

Investigators concluded that veterans’ reports of balance difficulties are due 

to a true vertigo that is organic in nature, resulting from a subtle 

abnormality of central vestibular function mediated by neural pathways in 

the brainstem or basal ganglia. 

 Studies of peripheral nerve function in Gulf War veterans have 

produced mixed findings. In 1996, a British study reported the results of 

neurophysiological testing of 14 symptomatic Gulf War veterans and 13 

healthy civilian controls.144 Investigators found significant differences 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 44

between the groups on three measures related to peripheral nerve function. 

Most prominent was a finding that the threshold for detecting subtle 

changes in cold temperatures was significantly higher in Gulf War veterans 

than controls, an indication of impaired function of peripheral small nerve 

fibers or central sensory processing. In 2000, researchers from the East 

Orange, New Jersey, VA Medical Center reported that quantitative sensory 

testing revealed elevated tactile thresholds in symptomatic Gulf veterans 

compared to controls, but no differences in heat pain perception.231,232 In 

contrast, a British study that year found no evidence of impaired 

temperature threshold or other sensory measures in symptomatic Gulf 

veterans compared to comparison groups.266 

Neuropsychological testing in Gulf War veterans. Neuropsychological tests measure brain function by assessing skills associated 

with cognitive tasks such as memory, attention, problem-solving, and 

visual-spatial analysis. Such tests are sensitive to the effects of many types 

of brain injury and disease, including more subtle effects of damage due to 

some neurotoxic exposures.15,80 Patterns of poor performance on specific 

tests can sometimes be used to identify the location of damaged 

neurological structures or pathways, providing useful information 

regarding patients’ functional and rehabilitation needs. 

 Ill Gulf War veterans have regularly reported cognitive symptoms such 

as problems with short-term memory and difficulty thinking or 

concentrating. Some researchers have speculated that the excess risk of 

accidents among Gulf War veterans may be the result of unrecognized or 

untreated attention and cognitive problems.29,102 Numerous studies have 

evaluated the extent to which veterans’ self-reported cognitive symptoms 

are associated with objective measures of impaired neuropsychological 

function. Overall, these studies have found ill Gulf War veterans to exhibit 

deficits on a variety of neuropsychological measures of cognitive 

performance, in comparison to control groups or population 

norms.16,25,43,62,92,106,116,185,207,272,291,294,358 One team of investigators found 

that symptomatic Gulf veterans performed worse on global tests of 

neurocognitive function and intelligence than non-symptomatic controls,116

but the majority of studies have reported that ill Gulf War veterans exhibit 

impairment in more limited domains of neuropsychological performance. 

Overall, studies have found that psychological factors are often associated 

with impaired neuropsychological performance, but do not account for the 

full range of cognitive deficits observed in ill veterans.357 

 

 In 1999, researchers at the Portland VA Medical Center screened a 

sample of ill Gulf War veterans and found them to have slowed 

neurobehavioral performance relative to healthy controls.16 For the most 

part, these abnormalities were limited to a subgroup of about 20 percent of 

the symptomatic veterans, distinguished by their poor performance on 

objective tests of memory, attention, and response speed. Larger follow up 

studies confirmed that, overall, ill Gulf War veterans performed 

significantly worse than controls on these tests,290 and again identified a 

bimodal distribution of neurocognitive impairment in ill Gulf veterans,291
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 45

Finding 3 

Recommendations 

indicating that objective indicators of cognitive dysfunction are 

disproportionately found in a subgroup that is distinct from other 

symptomatic Gulf War veterans. Investigators pointed out that this 

subgroup of ill veterans exhibit a pattern of neurobehavioral performance 

deficits consistent with those observed in organophosphate-poisoned 

workers, and suggested that research in this area focus on this subgroup, 

rather than on all symptomatic Gulf War veterans. 

 More recently, a 2003 study conducted at the Boston VA Environmental 

Hazards Research Center compared the performance of 207 treatmentseeking Gulf War veterans to 53 non-Gulf veteran controls on a battery of 

neuropsychological tests. Gulf War veterans scored significantly worse 

than nondeployed era veterans on measures of attention, visual-spatial 

skills, verbal memory, visual memory, and mood. Performance scores of 

Gulf veterans diagnosed with PTSD were similar to scores of veterans who 

did not have this condition. However, Gulf War veterans who reported 

taking pyridostigmine bromide (PB) during the war scored significantly 

worse on a number of neurocognitive measures than Gulf veterans who had 

not used PB.294 

 In summary, multiple studies have documented similar complexes of 

neurological symptoms among different groups of ill Gulf War veterans, as 

well as objectively-identified neurological abnormalities. Gulf War 

veterans have significantly elevated rates of the progressive 

neurodegenerative disease ALS. In addition, neuroimaging studies, tests of 

autonomic function, and neuropsychological testing have independently 

identified significant differences between symptomatic Gulf veterans and 

healthy comparison groups. Although much additional work remains in 

replicating and expanding these findings, taken together, this body of 

research provides compelling evidence that an important component of the 

unexplained illnesses experienced by Gulf War veterans is neurological in 

character. 

 

 The Committee recommends that VA expand research efforts that 

investigate and characterize possible neurological abnormalities in ill Gulf 

War veterans. Specifically, VA should: 

• Enlist the expertise of specialists in the neurosciences to develop a 

comprehensive research initiative capable of examining both 

neurophysiological and neuropsychological function in symptomatic 

Gulf War veterans in comparison to healthy controls. This effort 

should emphasize research protocols capable of identifying specific 

pathways associated with neurological pathology and include 

comparisons between subgroups of ill Gulf War veterans characterized 

by their individual symptom profiles and exposures encountered in 

theater. Protocols should include evaluation of neurological function 

under dynamic as well as static conditions. 
Finding 3 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 46

• Expand research efforts that utilize state-of-the-art neuroimaging 

technology to better characterize differences between ill Gulf War 

veterans and comparison groups. This should include studies that 

follow up and extend previously published findings in Gulf War 

veterans and other chemically exposed populations using magnetic 

resonance spectroscopy as well as other imaging techniques suited to 

study brain cell injury and dysfunction, such as functional magnetic 

resonance imaging (fMRI), positron-emission tomography (PET), 

single photon emission tomography (SPECT), 128-channel 

electroencephalography (EEG), and magnetoencephalography (MEG).

• Develop a comprehensive research strategy designed to evaluate and 

expand on the growing body of evidence regarding autonomic 

dysfunction in ill Gulf War veterans. This effort should give priority to 

protocols capable of determining which specific aspects of the 

autonomic regulatory system are affected in symptomatic veterans. As 

with other studies involving neurological pathology, studies should 

investigate autonomic function in defined veteran subsets, grouped 

according to symptom types and exposures encountered during the war. 

• Establish a brain bank to collect and maintain samples of autopsy 

materials from Gulf War veterans for study. 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 47

Finding 4

Evidence supports 

 a probable link 

between exposure to 

neurotoxins and the 

development of Gulf 

War veterans’ 

illnesses. 

 Recent findings demonstrating neurological pathology and impairment 

in Gulf War veterans necessitate a consideration of the possible causes of 

those problems in conjunction with the many symptoms reported by ill 

veterans. It has long been known that at least 100,000 troops were 

potentially exposed to low levels of nerve agents in one incident involving 

demolition of a weapons storage site in the days just after the Gulf War 

cease-fire. A recent government report suggests that the number of troops 

potentially exposed as a result of this and other incidents may have been 

even greater. This information is of particular concern in light of recent 

animal studies indicating that, contrary to previous assumptions, exposure 

to low levels of nerve agents can produce chronic neurological and 

immunological effects, even in the absence of obvious immediate 

symptoms of exposure. 

 Epidemiologic studies of Gulf War veterans have linked a number of 

exposures of potential concern in the Persian Gulf theater to higher rates of 

symptoms and illnesses. Among the most prominent risk factors 

consistently identified are substances that can adversely affect the nervous 

system. Chemical nerve agents, pyridostigmine bromide, and some types 

of pesticides all have similar modes of action; they work by inhibiting a 

specific enzyme involved in the metabolism of the neurotransmitter 

acetylcholine. After reviewing a large body of evidence concerning 

exposure to these types of compounds in theater, their potential effects 

alone and in combination, and their associations with illness in studies of 

Gulf War veterans and other populations, the Committee concludes that 

evidence supports a probable link between exposure to neurotoxins during 

the Gulf War, most prominently acetylcholinesterase inhibitors, and the 

development of Gulf War veterans’ illnesses. 

Neurotoxic exposures during the Gulf War. The question of 

whether Gulf War veterans were exposed to chemical weapons has long 

been debated. Prior to the war, military officials were greatly concerned 

that the Iraqi regime would use chemical agents offensively during the war, 

as they had in their recent war with Iran.114 Thousands of chemical alarms 

were reported to have sounded during the war, and when veterans began to 

report unexplained symptoms after they returned home many believed that 

these conditions were the result of chemical exposures. Early government 

reports maintained, however, that there had been no confirmed offensive 

use of chemical weapons during the war, requiring a consideration of other 

explanations. Anecdotal reports from veterans indicated that some had 

become ill when they took NAPP pills, the nerve agent prophylaxis pill 

with the active ingredient pyridostigmine bromide (PB), taken as a 

protective measure in the event of chemical attack. Others voiced concerns 

about the heavy use of multiple types of insect repellants and pesticides 

during deployment, due to the profusion of insects and the risk of infectious 

diseases in the desert environment. Excess pesticide exposure has been 

associated with chronic neurological symptoms in humans, and animal 

research has indicated that some combinations of pesticides, or pesticides 

in combination with PB and/or nerve agents, can produce greater damage 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 48

than exposure to any of these compounds alone. Therefore a number of 

neurotoxins encountered during the Gulf War must be considered for their 

possible contribution to the chronic illnesses and unexplained symptoms 

affecting veterans. For each category of exposure, it is important to 

evaluate evidence relating both to the extent of exposure and the potential 

for such exposures to cause chronic illnesses similar to those experienced 

by veterans. 

Exposure to chemical weapons during the Gulf War. 

19 Jan 91. Seabees of Naval Mobile Construction Battalion 

24, stationed near the port of Al Jubayl, report a bright flash in 

the night sky followed by a detonation-concussion. Chemical 

alarms sound, and troops don MOPP gear. After the all clear, 

troops unmask and experience an acrid smell, choking, 

profuse nasal secretions, facial numbness, a burning 

sensation on exposed skin and a metallic taste in the mouth. 

Two M256 detection kits are positive for chemical blister 

agent. During the weeks following the incident, many of the 

exposed troops develop skin rashes and chronic ailments. 

- Evidence Iraq Used Chemical Weapons 

 During the 1991 Persian Gulf War300

 In the early years following the Gulf War, government reports indicated 

that it was unlikely that exposure to chemical agents during the war could 

have contributed to veterans’ unexplained health problems, since there had 

been no documented use of chemical weapons in theater. Conclusions 

regarding chemical weapons exposures were called into question when, in 

1996, reports emerged verifying that chemical agents had been present in 

theater and that U.S. military personnel had been in the area of a large 

weapons storage depot containing nerve agents near Khamisyah, Iraq, 

when it was destroyed after the ceasefire. Verification of this incident 

brought about a dramatic change in thinking about chemical weapons 

exposures during the war. The Department of Defense reported that the 

weapons depot had contained the nerve agents sarin and cyclosarin, and 

sponsored multiple efforts to estimate how many and which veterans may 

have been exposed and at what levels. Investigators concluded, after 

several intensive modeling efforts, that approximately 100,000 U.S. troops 

may have been exposed to low levels of nerve agents as a result of the 

Khamisiyah demolitions.320 

 While the estimate of 100,000 troops is disturbing, it is still unclear 

whether or not it represents a good approximation of the total number of 

personnel who may have been exposed to nerve agents during the Gulf 

War. Contrary to regulations, military logs detailing nuclear, biological, 

and chemical weapons incidents during Desert Shield and Desert Storm 

were destroyed after the war.306 Reports from government and nongovernment sources have described multiple incidents involving evidence 

of possible chemical weapons exposures in addition to the Khamisiyah 

incident.79,300,307-310,312-319,337,347 Military reports indicate that 75 percent of 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 49

chemical targets, including weapons manufacturing and storage sites, were 

destroyed during the war.66 A recent report from the U.S. General 

Accounting Office (GAO, renamed the Government Accountability Office 

in July, 2004) found that DOD’s Khamisiyah modeling efforts were 

seriously flawed and that available evidence indicates there were likely to 

have been multiple additional incidents during the war that potentially 

exposed Coalition troops to chemical weapons.343 As a result, GAO 

investigators concluded that the total number of Gulf War veterans who 

may have encountered low-level exposures to nerve agents in theater may 

exceed that currently identified in association with DOD’s Khamisiyah 

plume models.345 The GAO report also concluded that results of 

epidemiologic studies that have relied on DOD’s plume models to evaluate 

health effects related to the Khamisiyah exposures are likely to be 

unreliable. 

Does low-level exposure to chemical agents cause chronic 

illness? Letters sent by DOD advising Gulf War veterans that they might 

have been exposed to low-level nerve agents in association with 

Khamisiyah also indicated that there was little concern that such exposures 

would lead to adverse health consequences. Conventional wisdom had 

long held that low-dose exposure to nerve agents—that is, levels that do not 

cause acute signs and symptoms at the time of exposure—are not expected 

to cause delayed or chronic health problems. Until recent years, however, 

it appears that relatively little research had been done that specifically 

addressed this issue. Assumptions regarding low-dose exposures may have 

been based, to some extent, on early observations that individuals who 

became temporarily ill after exposure to less-than-lethal doses of nerve 

agents appeared, in general, to fully recover.289 It is unclear whether 

systematic evaluations were done in connection with wartime or accidental 

human exposure to nerve agents in order to determine if those affected 

experienced symptoms of ill health that were not immediately apparent or 

symptoms that persisted over an extended time period following exposure. 

A 1982 report from the National Academy of Sciences concluded that 

“although no evidence has been developed to date that any of the 

anticholinesterase test compounds surveyed carries long-term adverse 

human health effects in the doses used, the panel is unable to rule out the 

possibility that some anti-ChE agents produced long-term adverse health 

effects in some individuals.”213 

 An interesting report describes a “cerebro-organic delayed effect 

syndrome” affecting Germans in the 1950s who had worked as chemical 

weapons production and storage workers in the 1930s and 1940s in 

facilities that manufactured a variety of chemical agents, including 

sarin.282,283 Years after their employment, these workers reported 

experiencing persistent nonspecific symptoms (for example, fatigue, 

headache, gastrointestinal problems, chemical intolerances, memory 

deficits) as described in the following excerpt. 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 50

Although the exact types and combinations of exposures is not known for 

these German workers, this early report does provide an indication that the 

development of a delayed and chronic syndrome following low level 

exposure to chemical agents is, in the words of the investigator, 

“conceivable.” 

Sarin exposures in Japanese terrorist incidents. World events since 

the end of the Gulf War have mandated a closer look at the question of 

possible chronic effects resulting from low-dose exposure to nerve agents. 

Human experimental studies of nerve agent exposure are no longer 

conducted, of course, but observational studies of individuals exposed to 

sarin in two Japanese terrorist incidents in the 1990s have provided useful 

insights. In 1994, a terrorist incident in Matsumoto City, Japan, resulted in 

the exposure of over 600 individuals to sarin and seven deaths.208,227 The 

next year, over 5,000 people were exposed to sarin in a subway terrorist 

attack in Tokyo that resulted in 11 deaths. Many victims exhibited acute 

signs of toxicity following these incidents, including miosis (pupil 

constriction), seizures, tachycardia, respiratory distress, headache and 

nausea.208,228,295 Follow-up investigations have been conducted on survivors 

of both incidents, although no follow-up studies of individuals who 

A neuropsychiatric delayed-effect syndrome was found as a result of 

systematic investigations of former members of chemical weapons 

production and testing stations for the Wehrmacht. In terms of 

frequency, two groups of symptoms can be distinguished—each 

consisting of separate symptoms or signs. 

1. The great majority of persons examined show: 

• persistently lowered vitality accompanied by marked diminution 

in drive 

• defective autonomic regulation leading to cephalagia, 

gastrointestinal and cardiovascular symptoms, and premature 

decline in libido and potency 

• intolerance symptoms (alcohol, nicotine, medicines) 

• impression of premature aging 

2. Further, one or more symptoms of the second group were found: 

• depressive or subdepressive disorder of vital functions 

• cerebral vegetative (syncopal) attacks 

• slight or moderate amnestic and demential defects 

• slight organoneurological defects 

...On the basis of our studies of the etiologically different 

manifestations of intoxication, the possibility of a relatively uniform—

though equally unspecific—cerebro-organic delayed effect syndrome is 

conceivable. 

- U. Speigelberg, from a report on a group of 

German World War II chemical weapons workers 

who had filed a lawsuit in conjunction with their 

chronic ill health.282,289 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 51

reported no symptoms at the time of exposure have been reported.210,212

Studies have indicated that overt clinical signs of exposure generally 

resolved within 30 days.208 However, more than six months after the 

attacks, less overt, chronic abnormalities were observed in 

electroencephalography (EEG) measures of evoked potentials210 and 

postural sway measures of vestibulo-cerebellar function.366,369 The most 

extended follow up involving a large number of victims reported thus far 

found that, approximately three years after the Matsumoto attack, about 

one fourth of those exposed continued to experience a variety of symptoms, 

including weakness, fatigue, blurred vision, and sleep disturbances.211 

 Posttraumatic stress disorder also occurred among some victims of the 

Japanese terrorist attacks, requiring researchers to assess possible chronic 

effects of sarin exposure in the context of psychiatric symptoms resulting 

from traumatic stress. Investigators have generally concluded that 

psychiatric symptoms exhibited by survivors may be the result of the 

trauma of the experience, while other symptoms and neurobehavioral 

deficits are likely attributable to the long term effects of sarin 

exposure.210,223,298,367,368 

Animal studies of chronic effects of low-level sarin exposure.

Scientific understanding of the potential for low-level nerve agent 

exposures to produce chronic adverse health consequences has been 

dramatically advanced by a large number of animal studies published in 

rapid succession in recent years. These studies were sponsored, for the 

most part, by the U.S. Department of Defense and by the Purkeyne Military 

Medical Academy in the Czech Republic. Key findings from studies 

assessing chronic health effects of low-dose sarin exposure are summarized 

in Table 7. As shown, these studies investigated a variety of parameters 

measured after variable latency periods following sarin exposure at doses 

too low to produce immediate signs of toxicity. 

 These animal studies indicate, in general, that low-dose sarin exposure 

is associated with chronic indicators of both neurological and 

immunological impairment. A group of interrelated studies of particular 

interest comes from Lovelace Respiratory Research Institute in New 

Mexico. These studies, sponsored by DOD, were published together in 

2002. The first study reported that 30 days after rats were exposed to lowdose levels of inhaled sarin—that is, levels that did not induce immediate 

observable reactions—acetylcholinesterase levels and muscarinic 1 (M1) 

receptors were reduced, while muscarinic 3 (M3) receptors were increased 

in particular regions of the brain associated with memory and cognitive 

function (frontal cortex, basal ganglia, hippocampus, and olfactory bulb).113

A second study found no effect of low-level sarin exposure on rats’ body 

temperature or locomotor activity.57 However, the third study reported 

significant immunosuppressive effects of subclinical sarin exposure, as 

indicated by reductions in antibody formation and T-cell proliferation in 

response to mitogens and antigens. Investigators also determined that these 

effects appeared to be mediated by the autonomic nervous system, since 

immune suppression did not occur when an autonomic blocking agent was 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 52

administered to sarin-exposed rats.151 Also intriguing was a finding that 

low-level sarin exposure produced significantly reduced levels of 

corticosterone, an adrenal hormone generated in response to stressors.151,182 

TABLE 7 here 

 

 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 53

 Other research groups have also reported evidence of altered immune 

function, as well as physiological and behavioral indicators of neurological 

changes that result from low-level sarin exposure, as shown in Table 7. In 

addition, the Committee will follow with interest preliminary reports 

presented at the March, 2004, conference of the Society of Toxicology, 

from studies suggesting that low-dose sarin exposures may initiate 

persistent changes in the expression of genes involved in processes relevant 

to brain cell injury and inflammation.87,264 

 

 Given the probability that a significant number of Gulf War veterans 

may have been exposed to low levels of sarin and cyclosarin during and 

after the war, and recent research findings indicating that low-level sarin 

exposures can result in chronic health sequelae, the Committee concludes 

that low-level exposure to chemical agents must be thoroughly investigated 

as a potential contributing cause of the multisymptom illnesses affecting 

Gulf War veterans, and that it is important that the precise mechanisms of 

chronic adverse effects of low-dose exposures be identified. 

Exposure to acetylcholinesterase inhibitors during the Gulf 

War. As described, DOD estimates indicate that approximately 100,000 

Gulf War veterans may have been exposed to low levels of the nerve agents 

sarin and cyclosarin in association with the Khamisiyah incident. These 

nerve agents belong to a family of chemical compounds called 

acetylcholinesterase inhibitors (AChEi), which also includes many types of 

pesticides and pyridostigmine bromide (PB), the active ingredient in the 

NAPP pills still used to protect troops from the nerve agent soman. The 

known toxic effects of AChEi compounds are largely due to their inhibition 

of an enzyme that breaks down acetylcholine (ACh), one of the major 

signaling chemicals, or neurotransmitters, in the nervous system. In the 

presence of AChEi compounds, ACh accumulates in the synapses, or small 

spaces between nerves. This build-up produces an over stimulation of 

certain types of nerve cells that can lead to a broad range of immediate 

symptoms such as muscle contractions, pain, weakness and fatigue, slowed 

heart rate, tearing, runny nose, excess salivation, nausea, abdominal 

cramping and diarrhea, respiratory distress, cognitive impairment, and 

convulsions. Low-level exposures to AChEi compounds can produce 

relatively mild immediate symptoms, while higher-dose exposures can lead 

to respiratory failure and death. 

 While any exposure to nerve agents may be a potential cause for 

concern, exposure to less toxic types of AChEis such as pesticides are a 

routine part of life for many who use them in their homes or workplaces. 

In addition, studies have indicated that therapeutic use of the AChEi 

pyridostigmine bromide (PB) is generally safe under experimental 

conditions.35,58,88 What has not been conclusively determined is whether 

PB or pesticides, as used alone or in combination with other neurotoxic 

compounds during the Gulf War, could have contributed to the chronic 

illnesses affecting Gulf War veterans. 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 54

Long-term effects of pyridostigmine bromide use in the Gulf 

War are unknown. 

[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.” [SH] currently suffers from memory loss, 

fatigue, sore muscles and joints, insomnia, cough, some night 

sweats, diverticulitis, diarrhea, kidney stones, bloody stools, 

urinary urgency, growth on his eye, rashes, tingling and itching 

sensations, and depression and irritability. 

 - Report of the Senate Committee on Banking, 

Housing, and Urban Affairs, May 25, 1994347

 Pyridostigmine bromide (PB) is a carbamate drug that temporarily and 

reversibly inhibits AChE. It has been used since 1955 as a long-term 

treatment for myasthenia gravis, a chronic disease characterized by 

progressive muscle weakness. During the Gulf War, PB was classified as 

an investigational new drug for use as a preventive measure to protect 

troops from the acute and deadly effects of exposure to the nerve agent 

soman. Recommended usage was to take one 30-mg. tablet three times per 

day, at eight-hour intervals. Unit commanders had authority to order when 

and for how long PB was to be used, but no records are available that 

documented the actual extent of PB use during the war. In 2000, the 

RAND Corporation reported the results of a DOD-sponsored survey of 

pesticide and PB use among 2,005 veterans who had served on the ground 

during the Gulf War. Investigators estimated, based on survey results, that 

slightly more than half of in-theater Army, Navy, and Marine Corps 

personnel took PB pills at some time during the war, and just under one 

quarter of Air Force personnel. Among those who took PB, median use 

was about two pills per day for 10 days, although individual use varied, 

with some individuals reportedly taking considerably larger numbers of 

pills for extended periods of time.84 

 A detailed review of animal studies that provide information relevant to 

the efficacy and long-term safety of PB as an adjunctive pre-treatment for 

nerve agent exposure is beyond the scope of the present report. However, 

in 1999, the RAND Corporation published a comprehensive review of the 

scientific literature pertaining to these issues.93 This report, sponsored by 

DOD, provided detailed analysis of several hypothetical mechanisms that 

may have lead to heightened or altered PB effects during the Gulf War, as 

well as mechanisms through which PB might have produced chronic 

symptoms after the war. The report concluded that, based on available 

scientific information, PB could not be ruled out as a contributor to Gulf 

War veterans’ chronic unexplained illnesses. Further, the report pointed 

out that the many questions associated with both the safety and efficacy of 

PB use as a nerve agent pretreatment require further research and analysis, 

since decisions regarding this complex issue involve “trading off uncertain 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 55

health risks—but risks now shown to be biologically plausible—against 

uncertain gains from use of PB in the warfare setting.”93 

 An IOM review of the laboratory, clinical, and epidemiologic scientific 

literature related to PB, published in 2000, concluded that there was 

“inadequate/insufficient evidence to determine whether an association does 

or does not exist between PB and long-term adverse health effects.”134

The report pointed out that major areas of uncertainty regarding effects of 

PB use during the Gulf War include those regarding possible interactions 

with other agents present in theater that may have affected the 

pharmacological and toxicological properties of PB and genetic differences 

in susceptibility to PB. 

 As previously indicated, PB has been shown to be relatively nontoxic in 

short-term clinical studies of healthy human volunteers,35,88,90,142 although 

some, usually mild, side-effects of the drug have been noted.28,93,134 Higher 

rates of side-effects have been reported in association with higher PB 

dosages58 and when PB is taken under stressful conditions.265 In a survey 

of 148 Gulf War personnel conducted in April, 1991, about one third 

reported experiencing negative side-effects of PB.45 A survey of the 

medical officers who supported the XVIII Airborne Corps during the Gulf 

War indicated their impressions that about half of those taking PB 

experienced some type of adverse side-effects, predominantly 

gastrointestinal symptoms such as loose stools, abdominal cramps, and 

nausea.171 Several additional small, unpublished surveys of Gulf veterans in 

theater indicated that between 25 and 37 percent reported side-effects in 

association with PB use in theater, most commonly gastrointestinal 

difficulties.93 

 A number of epidemiologic studies have found that veterans who 

reported using PB during the war have higher rates of chronic ill health 

than veterans who did not use PB.52,107,138,222,259,349,361 A study of Ohio 

reservists suggested that a dose-response effect may exist for PB, since 

veterans who reported taking more PB pills during the war were found to 

have higher rates of ill health than veterans who reported taking fewer PB 

pills.260 Of particular interest are results from studies of Gulf veterans that 

have assessed possible associations between PB and illness using analytic 

techniques that control for the effects of multiple exposures in the same 

individuals. Such studies have consistently indicated that self-reported PB 

use during the war is associated with higher rates of multisymptom 

illness.52,107,222 Also of interest are the results of a 2003 study from the 

Boston VA Environmental Hazards Research Center, which compared 

neurocognitive measures between treatment-seeking Gulf War veterans and 

nondeployed veteran controls. As previously described, the study found 

that Gulf War veterans scored significantly worse than nondeployed 

veterans on tests of attention, visuospatial skills, visual memory, and mood. 

However, when Gulf War veterans were further assessed according to 

whether or not they had taken PB during the war, or were diagnosed with 

PTSD, investigators found that those who had used PB scored significantly 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 56

worse on tests of executive function, while no association was found 

between PTSD and cognitive function.294 

 

 In summary, the Committee concurs with previous scientific panels in 

concluding that additional research is needed to determine whether PB use 

during the Gulf War contributed to the development of the unexplained 

illnesses in Gulf War veterans. Existing epidemiologic and laboratory 

studies suggest that such a link is plausible, although little is currently 

known about the long-term health effects of PB use in wartime, particularly 

with respect to possible interactions between PB and exposure to other 

neurotoxic compounds and wartime stressors. 

Possible effects of pesticide use during the Gulf War. 

Evidence in the literature is suggestive, but not conclusive, 

that pesticides, specifically AChE inhibitors such as 

organophosphates and carbamates, could be among the 

potential contributing agents to some of the undiagnosed 

illnesses seen in Persian Gulf War veterans. 

- A Review of the Scientific Literature As It Pertains 

 to Gulf War Illnesses--Volume 8: Pesticides48 

 The deserts of Saudi Arabia, Iraq, and Kuwait were often extremely 

inhospitable environments for Coalition troops. In addition to temperature 

extremes and blinding sandstorms, the desert was home to an assortment of 

pests that included biting insects, ticks, and rodents. Protection of 

personnel from desert pests was an important concern for military health 

and sanitation operations during the Gulf War, charged with minimizing 

casualties due to pest-borne diseases. Earlier Middle East deployments had 

been associated with high rates of pest-borne infectious diseases, such as 

sand-fly fever in World War II.302 To prevent similar problems in the Gulf 

War, large supplies of insect repellants and pesticides were provided to 

military personnel. Service members in different branches and in different 

geographical areas used different types of compounds. Many used DEET 

cream or liquid on their skin and sprayed long-lasting pyrethroid 

compounds on their uniforms. Area fogs were regularly sprayed in camp 

areas to reduce flying insects, while pest strips or aerosols were used in 

tents. Prisoners of war were routinely sprayed with lindane for delousing 

purposes and some U.S. personnel reported wearing animal flea collars to 

ward off biting insects. 

 Organophosphate (OP) and carbamate pesticides, although not as potent 

as nerve agents, kill insects in much the same way as nerve agents kill 

people, by inhibition of AChE. It has long been known that OP pesticide 

poisoning can cause a chronic neuropathic syndrome.147 Scientific research 

regarding possible effects of low-level exposure to pesticides has focused 

almost exclusively on populations chronically exposed to pesticides by 

virtue of their occupations or where they live. For example, a 1999 study 

identified a similar pattern of neuropsychiatric symptoms (memory and 

attention deficits, impaired muscle strength, personality changes, chemical 

sensitivity) among farmers and community residents exposed to 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 57

organophosphate pesticides.63 Almost no research is available that 

provides information directly applicable to the possible consequences of 

subacute pesticide exposures over several months, often in combination 

with other pesticides and AChEi compounds, as experienced by military 

personnel stationed in the Gulf War theater. 

 In April, 2003, DOD issued its final Environmental Exposure Report on 

Pesticides. That report documented efforts of the Deployment Health 

Support Directorate to gather information on pesticide use in the Persian 

Gulf theater of operations, and its potential to have caused adverse health 

effects. The report determined that 37 individual pesticide ingredients were 

probably used during the Gulf War, and identified 15 pesticide products to 

be “pesticides of potential concern,” based on available information about 

the toxicity and use of the compounds in theater. The identified 

compounds of highest concern are listed in Table 8.321 

 In February, 2003, an IOM committee published an extensive report 

reviewing the scientific literature regarding the potential for specific types 

of insecticides and solvents used during the Gulf War to have contributed 

to the chronic health problems experienced by Gulf War veterans. The 

report focused on evidence regarding exposures to individual pesticides and 

defined health outcomes and concluded that there is limited/suggestive 

scientific evidence indicating that OP poisoning is associated with longterm neurobehavioral effects. However, the committee did not find there to 

be sufficient scientific evidence to determine whether or not OP exposures 

that do not produce acute symptoms of poisoning were likely to produce 

neurodegenerative disease such as Parkinson’s disease and ALS, cancer, or 

reproductive effects. The Committee also reviewed nine studies that 

evaluated chronic effects of OP exposures at levels not associated with 

acute signs of toxicity. These studies differed in design and quality, and 

identified varying degrees of neurobiological deficits in exposed cohorts. 

As a result, committee members did not reach consensus as to whether 

there was suggestive evidence or insufficient evidence to indicate that 

lower-level OP exposures were linked to chronic neurobehavioral 

effects.137 

 The RAND survey of pesticide and PB use during the Gulf War 

indicated that two-thirds of service members used some type of personaluse pesticides during deployment, with the proportion varying from 50 

percent who reported using DEET a median of 30 times per month to three 

percent who reported using flea collars while in theater. About half of 

surveyed Gulf War veterans reported using just one or two forms of 

personal-use pesticides in any one month, while about 10 percent used 

three or more forms. The survey also found that pesticide use varied in 

different veteran subgroups. For example, Army personnel reported the 

highest level of pesticide use and Air Force personnel the least. In 

addition, service members who lived in buildings during deployment used 

lesser amounts of pesticide spray and liquids than those living in the 

desert.84 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 58

TABLE 8 here 

 The RAND survey also identified a significant association between the 

amount of pesticide used and the number of PB pills taken in a given 

month. For example, six percent of veterans accounted for the highest 

level of personal pesticide use in theater, with an average of 120 pesticide 

applications in a 30-day period. This same group also consumed, on 

average, 19 PB pills in a 30-day period. In contrast, personnel who 

reported that they did not use personal pesticides while in theater took an 

average of only six PB pills per 30-day period.84 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 59

 Based on this and other information, the DOD Environmental Exposure 

Report on Pesticides concluded that at least 41,000 service members were 

likely to have been overexposed to pesticides during deployment to the 

Gulf. The report, the first from DOD to identify a possible contributing 

environmental cause for veterans’ illnesses, stated that “Overexposure to 

pesticides, particularly organophosphates and carbamates, may have 

contributed to the unexplained illnesses reported by some Gulf War 

veterans.”321 It recommended that further research be conducted regarding 

the effects of low-level pesticide exposures and interactions of pesticides 

with other chemicals, including PB and low-level exposure to nerve agents. 

Animal studies evaluating synergistic effects of combinations 

of Gulf War-related exposures. As previously described, multiple 

lines of evidence indicate that wartime exposures to different types of 

AChEi, including nerve agents, PB, and pesticides, may plausibly be linked 

to the development of chronic illnesses since the Gulf War. It is likely that 

when veterans encountered these exposures in the Persian Gulf theater, 

however, it was often in conjunction with other Gulf War-related exposures 

of potential concern. Studies have shown that different exposures during 

the war were highly correlated—that is, veterans who report some 

exposures in theater are also more likely to report other exposures.52,84,281

Correlations between multiple exposures are to be expected, since veterans 

in different locations at different times would likely have experienced 

similar combinations of exposures. Ground troops located in Iraq, Kuwait, 

and Northeastern Saudi Arabia during and after the period of active 

hostilities, for example, would have been most likely to be exposed to 

SCUD attacks, PB, oil well fires, depleted uranium, and airborne fallout 

from demolition of chemical targets. 

 Historically, in comparison to the extensively studied toxicological 

effects of thousands of individual chemical compounds, relatively little 

scientific research has been conducted to understand possible adverse 

health effects resulting from multiple concurrent exposures. In 1996, an 

important new area of Gulf War-related research was initiated through a 

collaborative effort between researchers at Duke University and the 

University of Texas Southwestern. The first published study from this 

group reported that chickens simultaneously exposed to three neurotoxic 

chemicals associated with Gulf War service—PB, the insect repellant 

DEET, and the insecticide permethrin—suffered significant adverse effects, 

while exposure to similar levels of the chemicals individually produced 

only minimal toxicity.9

 These findings were provocative, but also 

controversial, since the studies utilized exposure dosages higher than those 

typical of Gulf War service. In the years that followed, however, this 

research has been broadly extended to include lower-dose exposures to 

these and other chemical combinations, and in other animal models. 

 As a result, dozens of studies published by this and other research 

groups have now consistently demonstrated synergistic effects of different 

combinations of Gulf War-related exposures, as shown in Table 9. Such 

studies have identified significantly enhanced toxicities in different
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 60

 biological 

TABLE 9 here 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 61

TABLE 9 (cont) here 

biological systems and animal models that result from different 

combinations of Gulf War-related exposures. For example, combinations 

of DEET, PB, and permethrin have been shown to synergistically increase 

indicators of neurotoxicity, including changes in brain AChE levels and 

behavioral changes. Other studies have indicated that absorption of some 

topically-applied pesticides, such as DEET and permethrin, is increased by 

concurrent exposure to PB or JP-8 jet fuel. In addition, studies have 

demonstrated changes in immunological function that result from exposure 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 62

to chemical combinations. Taken as a whole, this body of evidence 

provides strong support for the contention that combinations of Gulf War 

exposures may have produced toxic effects that exceed those expected with 

individual exposures. It is important that research of this nature be 

continued to allow more precise determination of the mechanisms and 

pathways affected by multiple co-exposures to toxic agents in the Gulf 

War. It is also important that synergistic effects of multiple Gulf War 

exposures be considered in epidemiologic evaluations of risk factors 

associated with Gulf War veterans’ illnesses. 

Epidemiologic studies consistently link Gulf War illnesses to 

AChEi exposures. Veterans who served in the Gulf War experienced a 

unique environment characterized by a complex mix of wartime stressors, 

disease-bearing pests, and an amalgam of potentially toxic substances. 

Studies of human populations exposed to low-level AChEi, such as sarin or 

OP pesticides, are helpful in providing insights regarding potential longterm effects of these exposures individually, and animal studies provide 

essential information regarding possible synergistic effects of multiple 

exposures. There is, however, little clinical or epidemiologic research 

documenting possible long-term health effects of exposure to PB, nerve 

agents, and pesticide combinations. The only group that can be studied 

specifically to determine the effects of service in the 1990-1991 Gulf War 

are the veterans themselves. And, for the majority of Gulf War-related 

experiences and exposures, the only source of information currently 

available is to query veterans about characteristics of their wartime service. 

 Epidemiologic studies of Gulf veteran groups from different states and 

countries have provided generally consistent descriptions of the types of 

chronic symptoms reported by ill veterans. Among these studies, a number 

have evaluated rates of symptoms, symptom complexes, and other 

measures of ill health in relation to wartime exposures reported by 

veterans. Studies that have evaluated the risk of veterans’ ill health in 

relation to a long list of Gulf War-related exposures, without controlling for 

possible errors introduced by the effects of multiple concurrent exposures, 

typically find that most of the exposures about which veterans are asked 

seem to be linked with veterans’ chronic symptoms.138,349 However, 

studies that analyze risk factors for Gulf War illnesses more precisely by 

using techniques that control for confounding effects of multiple exposures, 

consistently find that a more limited number of wartime exposures are 

associated with higher rates of illness. 

 Epidemiologic studies have assessed both ill health and wartime 

exposures among Gulf War veterans in different ways. As shown in Table 

10, however, these studies have consistently identified AChEis to be 

significantly associated with higher rates of symptoms and illnesses in Gulf 

War veterans. The uniformity of these results contrasts with a lack of 

consistent findings in multivariable analyses for such wartime experiences 

as participation in combat, exposure to oil fire smoke, and exposure to 

depleted uranium. Limitations in epidemiologic studies that rely on selfreported exposures always require a cautious interpretation of findings. 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 63

However, the overall consistency of epidemiologic findings indicating 

higher rates of ill health in association with AChEi exposures, as reported 

by multiple studies using different methods and different populations, 

provides compelling support for a role of AChEis in the development of 

Gulf War veterans’ illnesses. 

Differences in enzymes that metabolize AChEi may predispose 

some individuals to greater vulnerability to neurotoxic 

exposures. As shown in Table 10, epidemiologic studies have 

consistently implicated exposure to AChEi compounds such as chemical 

nerve agents, PB, and pesticides as risk factors for Gulf War veterans’ 

illnesses. Additional research that strongly supports a causal role for 

AChEi exposures comes from a group of studies that have identified 

differences between ill and healthy Gulf War veterans in blood levels of 

enzymes used by the body to counteract the toxic effects of these 

compounds. 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 64

 An important question concerning wartime exposures and Gulf War 

veterans’ illnesses relates to the reasons why some veterans returned from 

theater with chronic symptoms, but others with similar exposures did not 

become ill. Answers to that question may relate to differences in individual 

susceptibility to the effects of some toxic exposures. Such differences 

could relate to different doses and combinations of exposures experienced 

by different individuals in theater. They might also arise from differences 

between individuals in their ability to clear the body of neurotoxic 

substances, due to biological differences in the enzymes that metabolize 

those compounds. 

 In 1999, investigators from the University of Texas Southwestern 

reported that ill Gulf War veterans had significantly reduced activity levels 

of paraoxonase (PON1), an enzyme that metabolizes, and thus inactivates, 

AChEi compounds.104 The most severely symptomatic Gulf veterans in the 

Texas study exhibited particularly low activity of PON1 type Q, the type 

most active in neutralizing the effects of the nerve agents sarin and 

soman.64 Veterans with low PON1 type Q activity were also more likely to 

have suffered acute adverse reactions to PB in theater. The following year, 

researchers from the United Kingdom reported that British veterans with 

Gulf War syndrome had significantly lower PON1 activity levels than 

matched healthy controls, independent of the specific PON1 genotype of 

the veteran. These investigators also concluded that veterans’ decreased 

capacity for metabolizing AChEis may have contributed to their 

development of Gulf War illnesses.193 However, a second study of British 

Gulf War veterans found that lower PON1 activity was not linked with ill 

health in Gulf War veterans, but was significantly lower, overall, among 

veterans who served in the Gulf War than in veterans who did not deploy to 

the Gulf.123 Taken together, these findings provide a consistent indication 

that differences in PON1 enzyme activity may be associated with Gulf War 

illnesses, or perhaps more generally with service in the Gulf War. 

However, the precise ways in which PON1 differences observed in Gulf 

War veterans may be linked to genetically-determined factors and/or Gulf 

War-related exposures remain unclear. 

 Putative roles for other metabolizing enzymes have also been suggested 

as possible explanations for why some veterans may have been more 

vulnerable to the effects of neurotoxic exposures than others. In 1995, 

investigators from Jerusalem described the case of an Israeli soldier who 

carried an atypical gene for the enzyme butyrylcholinesterase (BChE), 

known to be a scavenger for some cholinesterase-inhibiting compounds.190

Carriers of this gene are unable to metabolize a muscle relaxant commonly 

administered during surgery,187 and are also thought to be hypersensitive to 

some AChEi insecticides.81,189 This Israeli soldier suffered severe 

symptoms after receiving PB during the Gulf War. After conducting 

laboratory tests, investigators determined that his BChE was less able to 

bind with, and thus detoxify, PB and other AChEis, likely making him 

more susceptible to the toxic effects of these compounds. In a related 

unpublished report from a DOD-sponsored study, investigators from the 

University of Nebraska Medical Center found that relatively rare genetic 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 65

variations of BChE were identified disproportionately among Gulf veterans 

who reported being sick with Gulf War illness, compared to veterans who 

did not have these symptoms.188 The University of Texas Southwestern 

study also found that ill Gulf war veterans were more likely to have genetic 

variants and low activity levels of BChE, although these associations were 

based on small numbers and did not reach statistical significance.104

Findings from these reports are preliminary and should not be overinterpreted. But they do signal the need for further elaboration of possible 

linkages between BChE genotype and Gulf War veterans’ illnesses. 

 In related research sponsored by DOD, Israeli investigators have 

identified a mechanism though which exposure to AChEi or acute 

psychological stress leads to over-production of a normally rare variant of 

AChE, labeled AChE-R.168,169,280 Over-production of this enzyme has been 

associated with altered cognitive and behavioral function in animal 

studies,55 and with symptoms of fatigue in myasthenia gravis.38

Therapeutic interventions have been developed to counteract these effects, 

with preliminary promising results.38,271,279 The Committee looks forward 

to reviewing the results of a recently initiated VA study that will determine 

whether Gulf War veterans’ illnesses are associated with overproduction of 

AChE-R.278,364 

Summary of evidence regarding a probable link between 

exposures to neurotoxins and Gulf War veterans’ illnesses. 

Objective indicators of neurological impairment and disease, and excess 

neurological symptoms in Gulf War veterans require a thorough 

consideration of possible causes for these problems. Government reports 

have described the extent to which Gulf War veterans were exposed to a 

variety of potentially neurotoxic substances during their deployment to 

Southwest Asia. These include low-level exposures to sarin and 

cyclosarin, consumption of varying amounts of PB tablets, and use of 

varying amounts and combinations of insect repellants and insecticides. 

Many of these neurotoxic compounds exert their effects by inhibiting the 

action of a single enzyme that regulates acetylcholine, one of the most 

important signaling chemicals in the nervous system. Multiple lines of 

human and animal research indicate that these substances have the potential 

to cause long-term health effects similar to those experienced by Gulf War 

veterans. Animal research has also demonstrated that some combinations of 

Gulf War-related exposures can lead to adverse effects that significantly 

exceed those resulting from single exposures. Numerous epidemiologic 

studies of Gulf War veterans have consistently found higher rates of 

unexplained symptom complexes to be linked to self-reported use of PB 

and pesticides, and to possible exposure to chemical agents in theater. 

Several studies have also indicated that Gulf War illnesses occur 

disproportionately among veterans who might be more susceptible to the 

toxic effects of AChEi, due to biological differences in blood enzymes that 

inactivate these compounds. 

 Each area of research described, taken alone, provides an intriguing 

indication that exposure to AChEi compounds may have contributed to the 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 66

Finding 4 

Recommendations 

development of chronic symptoms during and after the Gulf War. Taken as 

a whole, however, this accumulated body of research provides compelling 

evidence of a probable link between neurotoxic exposures in the Gulf War 

and the development of Gulf War veterans’ illnesses. 

 The Committee recommends that the federal government expand 

research efforts to systematically investigate the chronic effects of exposure 

to neurotoxins encountered during the Gulf War, particularly 

acetylcholinesterase inhibitors such as sarin, pyridostigmine bromide, and 

carbamate and organophosphate pesticides. Studies that identify the 

specific pathways involved in adverse consequences of AChEi exposure 

and utilize objective biological markers of exposure sequelae are 

particularly important, as are studies that identify pathways amenable to 

therapeutic intervention. Specifically, the Committee recommends that 

VA: 

• Establish a comprehensive research program to investigate persistent 

and/or delayed effects of exposure to AChEi, including sarin and other 

nerve agents, at dosages comparable to those that may have been 

encountered in the Gulf War. Such research should focus on 

elaboration of the specific physiological pathways involved in possible 

adverse consequences of these exposures, including those involved in 

synergistic effects of combinations of neurotoxic exposures. 

• Work with scientists with appropriate expertise to comprehensively 

evaluate the role of differences in genotype and activity levels of 

enzymes such as paraoxonase, acetylcholinesterase, and 

butyrylcholinesterase, which are associated with the uptake and 

metabolism of neurotoxins, in susceptibility to wartime exposures and 

the development of Gulf War veterans’ illnesses. 

• Give priority to research studies designed to identify and utilize 

objective biological markers associated with the effects of exposure to 

AChEi. Such measures might pertain to effects in the brain or in 

peripheral areas influenced by acetylcholine such as the neuromuscular 

system, the gastrointestinal system, and the immune system. 

• Give priority to research studies capable of identifying pathways 

involved in chronic adverse effects of AChEi exposure that may be 

amenable to treatment interventions. 

• Expand VA and collaborative research efforts that capitalize on new 

technologies capable of identifying low-level residues of exposures, 

their metabolites, or persistent alterations in metabolism or genetic 

expression resulting from wartime exposures or associated with chronic 

unexplained illnesses in Gulf War veterans. 

 
Finding 4 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 67

• Analyze data from existing and future epidemiologic studies to 

reevaluate the association of combinations of neurotoxic exposures 

with chronic illness in Gulf War veterans. 

The Committee recommends that the Department of Defense (DOD): 

• Make available to researchers studying Gulf War veterans’ illnesses 

detailed information concerning the locations and dates of incidents 

involving destruction of chemical targets during and after the Gulf War. 

• Continue and expand research efforts that identify possible chronic 

effects of low-level exposure to sarin and other nerve agents, 

pesticides, and pyridostigmine bromide, individually and in 

combination. 
Finding 5 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 68

Finding 5 

Other wartime 

exposures may 

also have 

contributed to 

Gulf War veterans’ 

 illnesses.

 A variety of exposures potentially encountered by military personnel in 

the Persian Gulf theater have been suggested as possible causes or 

contributors to Gulf War veterans’ illnesses,130,132,215,221,240 as shown in 

Table 11. Because studies have consistently demonstrated that 

psychological factors do not adequately explain the symptoms experienced 

by the majority of ill veterans, the Committee concludes that other 

plausible causes for these conditions—that is, a broad range of Gulf Warrelated exposures—must be thoroughly evaluated as possible contributors 

to the development of veterans’ illnesses. 

Table 11. Exposures Suggested as Possible Contributors to 

Gulf War Veterans’ Illnesses 

Chemical weapons Depleted uranium 

Biological weapons Oil well fire smoke 

Pyridostigmine bromide Diesel fuel, jet fuel 

Pesticides Sand, dust 

Insect repellants Contaminated water, food 

Individual or multiple vaccines Infectious agents 

Antibiotics, antimalarials Chemical agent resistant coating 

 Committee deliberations have thus far focused primarily on the role of 

neurotoxicants and neurological pathology in Gulf War veterans’ illnesses. 

Additional studies and reports have suggested that other Gulf War-related 

exposures may be implicated in the etiology of these conditions. The most 

consistent epidemiologic findings come from studies linking multisymptom 

illnesses in Gulf War veterans to receipt of vaccines. The number and 

types of vaccines administered to Gulf veterans have been described in 

detail.132,134,311 Military personnel routinely receive a number of 

inoculations when they first enter service and prior to overseas 

deployments. Even under the best circumstances, a small proportion of 

individuals receiving vaccinations can be expected to experience adverse 

reactions. Such reactions are typically transient and mild, but can 

sometimes be chronic, serious, or even deadly.143 

 Information concerning a possible link between vaccines and chronic 

symptoms in Gulf veterans comes from multiple sources.22,23,256,342

Population-based studies have consistently found that immunizations 

reported to be received by Gulf veterans are associated with higher rates of 

multisymptom illness.24,52,94,120,195,261,349 These include findings of excess 

illness in Gulf War veterans associated with particular types of vaccines, 

the number of vaccines received, and the number of vaccines received after 

veterans’ arrival in theater. 
Finding 5 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 69

 Particular concern has focused on the anthrax vaccine administered to a 

reported 150,000 U.S. troops during the Gulf War, as well as to British, 

Canadian, and Australian personnel. Assessing possible associations 

between Gulf veterans’ illnesses and their receipt of anthrax and botulinum 

toxoid vaccines has been particularly challenging in studies of U.S. Gulf 

War veterans, since many units did not record information on these 

vaccines in the shot records of personnel. A number of potential problems 

with the anthrax vaccine have been suggested, including problems with 

quality control during the manufacturing process,335,339 changes in the 

manufacturing process that may have resulted in increased levels of active 

antigen,341 and the use of unapproved adjuvants to bolster the 

immunological reactivity of the vaccines.23,340 Reports have indicated that 

the anthrax vaccine administered during the Gulf War, commonly referred 

to as AVA (anthrax vaccine adsorbed) is associated with a relatively high 

rate of acute adverse reactions,342 and have pointed out that there is 

insufficient evidence to determine whether the AVA vaccine formulation 

may be associated with long-term health sequelae.134,339 

 Anecdotal reports have suggested that symptoms similar to those 

reported by Gulf veterans have also been reported by civilians who worked 

in the Persian Gulf theater and by Gulf War era veterans who received 

vaccines in preparation for deployment to Desert Storm but were never 

actually in theater.346 One epidemiologic study has reported an excess of 

symptoms among veterans who did not serve in theater but reported 

receiving shots from the military during the time of Desert Shield and 

Desert Storm.285 If chronic multisymptom illnesses were found to be 

associated with vaccines received by individuals who received the same 

shots as Gulf War veterans but experienced no other Gulf War-related 

exposures, a reasonable hypothesis would be that these vaccines also 

contributed to Gulf veterans’ illnesses. However, no studies have been 

published that have evaluated the rates of chronic multisymptom illnesses 

among civilians present in theater during the Gulf War, or among military 

populations who received AVA in the years following Desert Storm. In 

short, a number of important questions have been raised concerning the 

potential for vaccines to have contributed to Gulf War veterans’ illnesses. 

Many of these questions can be answered with relatively straightforward 

studies, but have not yet been addressed by government research.340 

 Unanswered questions relating to vaccines are just one example of the 

importance of further studying a variety of exposures for their potential role 

in Gulf War veterans’ illnesses. Scientific reviews commissioned by 

federal agencies have often indicated that there is insufficient scientific 

evidence to determine whether exposures encountered in the Persian Gulf 

theater are likely to be associated with chronic health problems such as 

those experienced by Gulf War veterans.48,93,134,137 The majority of 

exposures investigated thus far have been neither conclusively ruled in nor 

ruled out as having contributed to veterans’ chronic symptoms. 

 A major concern that has not been adequately addressed by studies of ill 

Gulf War veterans or by previous review panels is the potential for 
Finding 5 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 70

Finding 5 

Recommendations 

combinations of exposures to have produced adverse effects that do not 

typically occur when exposures are experienced individually. As 

previously described, animal studies have consistently shown that some 

Gulf War-related exposures can act synergistically, producing significantly 

enhanced levels of toxicity when combined (see Table 9). 

 Scientific questions regarding the nature and development of chronic 

symptoms after service in the Gulf War are extremely complex. It is 

important that research studies attempting to address these questions 

include hypotheses that recognize that the multiple overlapping symptom 

complexes observed in Gulf War veterans may have resulted from different 

individual exposures or different combinations of exposures in different 

veteran subgroups. Research studies that do not take into account these 

factors may be incapable of identifying associations that may exist between 

Gulf War–related exposures and veterans’ symptoms. 

 The Committee recognizes that the lack of specific exposure 

information for individual veterans presents a challenge to those charged 

with understanding the specific causes of Gulf War veterans’ illnesses. 

Yet, discerning the causes of Gulf War illnesses is of fundamental 

importance to understanding the pathophysiological underpinnings of these 

conditions, identifying effective treatments, and preventing similar 

problems from occurring in future deployments. The Committee believes 

that the use of multiple research approaches such as epidemiologic 

investigations of subgroups of Gulf veterans with known differences in 

deployment experiences and exposure histories,112,288 in conjunction with 

appropriate clinical and laboratory research, can shed considerable light on 

the likely relationships of Gulf War illnesses to exposures. 

 In the coming months, the Committee will investigate in greater detail 

evidence relating to the potential for a variety of exposures encountered 

during the Gulf War to have contributed to veterans’ illnesses. Future 

reports will include reviews of research related to exposures in theater such 

as infectious diseases, depleted uranium, oil well fire smoke and other 

petroleum products, and a more detailed consideration of evidence relating 

to vaccines. At this time, the Committee recommends that VA: 

• Support research efforts that investigate well-evidenced hypotheses 

concerning potential linkages between Gulf War veterans’ illnesses and 

wartime exposures, including possible chronic effects of combinations 

of Gulf War-related exposures. 

• Work with federal agencies (Centers for Disease Control and 

Prevention, National Institutes of Health, Department of Defense) 

involved in conducting vaccine trials that include administration of 

anthrax vaccine adsorbed (AVA) to ensure that these trials include 

follow-up assessments of study subjects a minimum of five years after 

inoculation. Such studies should utilize methods and instruments 
Finding 5 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 71

capable of capturing chronic symptoms and cognitive difficulties 

similar to those experienced by Gulf War veterans. 

• Conduct a retrospective cohort study that compares chronic symptoms 

and diagnosed conditions experienced by veterans who received AVA 

as part of the military’s mandatory anthrax vaccination program to 

those of a comparable group of veterans who did not receive this 

vaccine. 
Finding 6 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 72

Finding 6 

The health of Gulf 

War veterans must 

be carefully 

monitored to 

determine if Gulf 

War service is 

associated with 

excess rates of 

specific diseases, 

disease-specific 

deaths, or overall 

mortality. 

 Epidemiologic studies have provided preliminary indications that, in 

addition to excess rates of undiagnosed symptom-defined illnesses, Gulf 

veterans may also suffer from elevated rates of diagnosed medical 

conditions such as migraine headaches and respiratory and gastrointestinal 

conditions (see Table 2). However, definitive studies to determine whether 

Gulf veterans are at increased risk for clinically diagnosed conditions other 

than ALS have not been conducted. Also unknown is whether service in 

the Gulf War may eventually be linked to diseases that take many years to 

develop. 

 With diseases of long latency, particularly cancer but also some 

neurological diseases, any effect of exposure in the Gulf War is not likely 

to become apparent for at least 10 years after deployment. Therefore, the 

most critical period for monitoring rates of morbidity and mortality for 

such conditions is just beginning. The concern that service in war can be 

linked to specific diseases that do not become apparent for many years is 

not unprecedented. Studies of U.S. veterans of previous wars have found 

elevated rates of specific conditions not conclusively identified until 

decades after the war. For example, the IOM first determined in 2000 that 

there was evidence that Agent Orange exposure was linked to an increased 

rate of diabetes in Vietnam veterans, more than 25 years after the end of the 

war.135,327 Veterans exposed to ionizing radiation following the use of the 

atomic bomb during the occupation of Japan in 1945 and 1946 were first 

granted compensation for radiation-related cancers in 1988, over 40 years 

after those exposures.326 

 Epidemiologic studies of death rates among Gulf War veterans and 

nondeployed military personnel initially found that Gulf War service was 

associated with increased mortality due to accidental causes, but lower 

death rates from natural causes.153,192 Such findings suggested that the 

lower rate of disease-related mortality observed in Gulf veterans could be 

due to a “healthy warrior” effect of deployment, with those who deployed 

being generally healthier than those who had not.102 More recent U.S. 

mortality studies report death rates among Gulf War era veterans through 

1997, covering a period of seven years, and indicate that differences in 

death rates associated with Gulf War service have begun to moderate. That 

is, rates of disease-related deaths have become more similar in Gulf and 

nondeployed veterans, as have rates of accident-related deaths.154,301

Therefore, any “healthy warrior” effect that may have occurred in the early 

years after the Gulf War appears to have diminished over time. As a result, 

it may now be possible to more accurately identify any differences that 

may exist in disease-related mortality related to Gulf War service. For this 

reason, and because mortality due to diseases with long latency periods 

might just now be apparent, it is very important that frequent, detailed 

analyses of mortality data be carried out, and that results of these analyses 

be made public. 

 

 As previously described, existing studies comparing Gulf veterans to 

nondeployed era veterans have identified relatively few conditions for 

which Gulf veterans have been hospitalized at rates higher than those found 
Finding 6 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 73

in comparison populations. Hospitalization studies of Gulf veterans, 

however, must be interpreted with caution. In general, such studies were 

limited in their ability to detect excess rates of conditions affecting 

individuals no longer in the active component of the military.102

Hospitalization studies would also not be expected to identify excess rates 

of the types of conditions most commonly associated with Gulf War 

service, such as migraines, skin conditions, digestive disorders, 

neurocognitive impairment, and undiagnosed multisymptom illnesses, 

which are not generally associated with hospitalization. And, more 

obviously, these studies all have been conducted at a point in time too early 

to detect excess rates of illnesses such as cancer that can take many years to 

become clinically apparent. 

 Studies that found Gulf War service to be associated with a significantly 

elevated risk of ALS were first undertaken in response to veterans’ 

concerns regarding an apparently large number of ALS cases among 

relatively young Gulf War veterans.103,117 Similar concerns have been 

raised by veterans regarding other neurological conditions, such as multiple 

sclerosis (MS) and related demyelinating conditions, Parkinson’s Disease, 

and brain cancers.209 However, no formal studies investigating the 

prevalence of these conditions in Gulf War veterans have been conducted. 

 Epidemiologic studies have suggested that environmental exposures 

similar to those encountered during the Gulf War are associated with an 

increased risk of chronic neurological diseases with variable latency 

periods.40,71,74,203 Identification of any serious medical conditions that may 

occur disproportionately in Gulf War veterans is important for a number of 

reasons, most essentially for alerting veterans to possible health risks and 

available services. Veterans affected by any condition found to be 

associated with Gulf War service can, in turn, be further evaluated to 

provide additional information on etiologic factors that may have 

contributed to the development or progression of that condition. Gulf War 

veterans with ALS have reported anecdotally, for example, that a 

significant exposure to pesticides years after their return from Desert Storm 

seemed to be associated with the onset of the severe symptoms that 

ultimately led to their being diagnosed with ALS.146,346 

 A subset of the symptoms reported by Gulf veterans with unexplained 

illnesses are similar to those reported in the early stages of some 

neurodegenerative diseases. For example, early symptoms of MS can 

include numbness and tingling in the extremities, balance abnormalities, 

fatigue, mood and cognitive changes, vision problems, and muscle 

weakness—all symptoms commonly reported in studies of Gulf War 

veterans. Multiple studies have also reported that Gulf veterans report 

excess rates of tremors of the extremities,51,138,285,349 which can be an early 

presenting symptom of Parkinson’s disease. A number of preliminary 

findings suggest other possible similarities between Gulf War illnesses and 

Parkinson’s disease. For example, abnormal brain dopamine production, a 

defining feature of Parkinson’s disease, has also been found in a subset of 

highly symptomatic Gulf veterans.105 Two neuroimaging studies have 
Finding 6 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 74

found abnormalities in the basal ganglia region of the brains of 

symptomatic Gulf veterans,109,205 a region also affected in Parkinson’s 

disease.33,224 Further, variations in genotype and levels of the enzyme 

paraoxonase (PON1) have been reported in several studies of Gulf 

veterans.104,193 In particular, a predominance of the R variant at PON1 

position 192 has been identified both in symptomatic Gulf veterans,104 and 

in Parkinson’s disease patients.177 

 

 The occurrence of specific diseases among Gulf War veterans can be 

monitored in a number of ways. Clinical and hospitalization information 

on Gulf War veterans from allied countries where healthcare is primarily 

obtained through a single provider would be particularly helpful in this 

regard. However, general trends reflecting increases in specific conditions 

can be assessed through ongoing surveillance activities using databases 

maintained by the DOD, the Veterans Health Administration (VHA), the 

Veterans Benefits Administration (VBA), and the Social Security 

Administration (SSA). Such data can be used to identify “red flags” that 

signal whether rates of hospitalization, clinic visits, benefits claims, or 

deaths due to specific conditions appear to be occurring at abnormally high 

rates in this cohort, relative to veterans who did not deploy to the Gulf War. 

 Such an approach was utilized by clinical researchers at the Detroit VA 

Medical Center who, after noticing an excess of gallbladder disease among 

their young Gulf War veteran patients, obtained data maintained by VA’s 

National Surgical Quality Improvement Program (NFSQIP). Preliminary 

analyses indicated that the rate of gallbladder disease requiring 

cholecystectomy increased significantly between 1992 and 1997 among 

Gulf War veterans, while rates in other veteran groups declined.206

Researchers concluded that this increase could have resulted from 

abnormal bile emptying secondary to autonomic dysregulation in Gulf War 

veterans, although their preliminary findings were never formally pursued. 

These observations deserve further consideration, in light of recent findings 

indicative of autonomic dysfunction in Gulf War veterans. In addition, the 

approach used by these investigators provides a useful example of the 

potential utility of monitoring VHA data to identify conditions that may be 

occurring at elevated rates in Gulf War veterans. 

 Formal epidemiologic studies are required to conclusively determine 

whether or not Gulf War veterans are affected by excess rates of specific 

conditions, particularly when the conditions in question are relatively rare, 

difficult to diagnose, or not typically associated with service-connected 

benefits or premature death. Population-based studies that include 

appropriate comparison groups are needed to assess the incidence and 

prevalence of diseases and conditions of particular concern, such as those 

associated with neurological abnormalities. Such studies should assess 

disease rates in epidemiologically important veteran subgroups, such as 

veterans who served in specific areas or who have specific exposure 

histories. Similarly, if additional conditions of potential concern are 

identified through ongoing health data monitoring activities, formal studies
Finding 6 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 75

Finding 6 

Recommendations 

will be needed to assess the rates of those conditions in Gulf War veterans 

and appropriate comparison groups. 

 The possibility of links between Gulf War service and the development 

of serious neurological diseases increases the urgency of implementing 

research studies and surveillance activities necessary to address these 

concerns. It is important that priority epidemiologic studies and datamonitoring activities be implemented as soon as possible in order to 

optimize strategies for prevention, early intervention, and treatment of any 

Gulf War-associated conditions that may be identified through such 

activities. 

 The Committee recommends that rates of medical conditions and 

disease-specific mortality among Gulf War veterans be regularly assessed 

and reported, and that studies be undertaken to actively identify veterans 

with conditions of particular concern. Specifically, VA should: 

• Continue to identify ALS cases among Gulf War veterans, and 

evaluate the potential role of toxic exposures encountered in theater or 

after the war in the development or progression of this disease. 

Publish findings regarding any identified risk factors for ALS in Gulf 

War veterans, and provide this information to veterans. 

• Undertake epidemiologic studies to determine the prevalence of other 

serious neurological conditions, including multiple sclerosis (MS), 

Parkinson’s disease, and brain cancers, among Gulf War veterans in 

relation to appropriate comparison groups. Studies should include 

ascertainment of the number of cases of rare and difficult-to-diagnose 

neurological conditions that may have clinical similarities to 

recognized conditions such as ALS, MS, or Parkinson’s disease, but 

are difficult to precisely characterize. 

• Analyze and make available mortality data for U.S. Gulf War and 

nondeployed Gulf War era veterans every 18 months. Data should be 

analyzed for a wide range of ICD-9 categories and the results made 

publicly available, electronically and through published reports. Data 

already available, covering the period 1998 through 2003, should be 

analyzed and published immediately. 

• Utilize troop location information and data collected in VA’s National 

Health Survey of Gulf War-era Veterans and their Families to assess 

mortality among subcategories of Gulf War veterans grouped by 

exposure, location, and demographic and military characteristics. 

Analyses of mortality rates among Gulf War veterans that do not take 

into account differences in deployment experiences and exposures 

could mask even large mortality excesses associated with conditions 

encountered by a minority of those deployed. 
Finding 6 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 76

• Regularly monitor information contained in VA clinical and benefit 

claims data sources and provide annual reports of morbidity and 

mortality by available diagnostic categories. Age and sex-adjusted 

rates of hospitalization and benefits claims should be compared 

between Gulf War and nondeployed Gulf War era veterans, and 

across military subgroups identifiable through available data. 

• Recognizing that assessment of morbidity is difficult for U.S. 

veterans, for whom health care is not universally available from a 

single provider, explore the possibility of examining morbidity 

patterns in allied countries where such data are available. This 

information may help to identify excesses in chronic diseases before 

they become apparent using U.S. mortality data or the recommended 

surveillance activities. 

• Where surveillance of clinical or mortality data indicate a possible 

elevated rate of any condition in Gulf War veterans, undertake 

appropriate epidemiologic studies to determine the rate of occurrence 

of that condition among Gulf War veterans and an appropriate 

comparison group. 

• Where a possible excess of any condition is determined, make efforts 

to identify individuals with that condition among living veterans, 

especially in situations where early detection and treatment would be 

beneficial. 

 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 77

Finding 7

Important 

questions 

concerning the 

health of children 

and other family 

members of Gulf 

War veterans 

remain 

unanswered. 

 Media sources and veterans’ groups have reported for many years that 

children born to Gulf War veterans may have increased rates of birth 

defects in connection with their parents’ wartime service.14,30,39 In private 

and public comments to the Committee, Gulf veterans have continued to 

voice concerns about having children due to uncertainties about the risk of 

birth defects. Several studies conducted during the 1990s did not find 

significantly elevated birth defect rates in children of Gulf War veterans, 

and thus appeared to provide reassurance in this area. More recently, three 

large population-based studies have called these preliminary findings into 

question, indicating that several different types of birth defects may have 

occurred at higher rates in children of Gulf War veterans than in children of 

nondeployed Gulf War era veterans. Serious problems still appear, overall, 

to be very rare, but these studies demonstrate the need for further research 

in this area. 

 Questions also have been raised about whether veterans’ other family 

members, primarily their spouses and children, may have experienced 

higher rates of anomalous health problems since Desert Storm. Preliminary 

and anecdotal information suggesting this to be the case has been presented 

in media reports and government testimony.82,246,346,347 However, little 

scientific research has been conducted to determine whether Gulf veterans’ 

family members and other close contacts have experienced higher rates of 

unexplained symptoms or diagnosed medical conditions than comparison 

groups. As a result, questions about possible effects of Gulf War service 

on the health of veterans’ family members remain unanswered. 

Reproductive outcomes associated with wartime service. A 

1994 report prepared by the U.S. General Accounting Office for the U.S. 

Senate Committee on Veterans Affairs identified 21 “potential reproductive 

toxicants” that were present in theater during the 1990-1991 Gulf War 

deployment.336 Associations between birth defects and maternal toxic 

exposures have been described in a large number of research studies 

spanning decades.152,270 Paternal exposure to a variety of toxicants has also 

been linked to birth defects, although mechanisms for these effects are lesswell understood.53,65,299 In 1996, the IOM determined that there was 

limited/suggestive evidence that Agent Orange exposure and military 

service in Vietnam were associated with an increased risk of the 

development of spina bifida, a disabling birth defect involving failure of 

the spinal cord to close during the first month of gestation.133 A subsequent 

VA study determined that women veterans who had served in Vietnam 

reported a significantly higher number of children born with multiple 

different types of birth defects than women veterans who had not served in 

Vietnam. Investigators concluded that the identified excess was not likely 

due to selective recall or over-reporting of birth defects in this group.157

Consequently, VA now provides monthly disability allowances, vocational 

training, and healthcare benefits for children of women Vietnam veterans 

with a wide range of birth defects,325 and for children of both male and 

female Vietnam veterans born with spina bifida. 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 78

 In response to media reports of an apparently higher-than-normal 

number of children of Gulf veterans born with birth defects, research 

studies were undertaken in the 1990s to systematically evaluate birth defect 

rates in this population. Early studies did not identify significant 

connections between Gulf War service and children’s birth defects,17,19,59,234

but limitations in study designs left open the possibility that such a link 

might exist.336 

 The first published study in this area assessed the number of children 

with birth defects among those born to 52 members of two National Guard 

units in Mississippi.234 Three children with major birth defects and two 

with minor defects were identified, which investigators determined to be in 

the range of the number expected, based on national figures. Although 

these results suggested that the particular units studied had not experienced 

a dramatic excess in the overall rate of birth defects, the small size of the 

study and lack of a military comparison group prohibited statistical 

evaluation of rates of specific birth defects. A larger study of the birth 

records of over 75,000 live births at military hospitals between the years 

1991 and 1993 followed.59 Investigators concluded that there was no 

evidence of an increase in the rate of birth defects associated with Gulf War 

service. But again, these conclusions were questioned on the grounds of 

study limitations, including reliance on data obtained from birth records 

(which do not capture information on fetal deaths and infant abnormalities 

not detected at birth) and the absence of information on births in civilian 

hospitals.60,78,102 Children of veterans who separated from the military 

after the war, particularly children of veterans who were in poor health, 

would not be included in such studies. A related study of the same military 

hospital birth cohort identified a three-fold increase in the risk of 

Goldenhar syndrome among children born to Gulf War veterans, but the 

association was not statistically significant.19 Given the rarity of Goldenhar 

syndrome, the sample size of over 75,000 births was insufficient to 

determine whether the observed excess rate in children of Gulf veterans 

was due to chance. 

 In 2001, a report from VA’s large National Survey of Gulf War-era 

Veterans and their Families indicated that Gulf War veterans reported a 

significantly greater number of post-war pregnancies that ended in 

miscarriages or children born with birth defects than nondeployed era 

veterans. Among both male and female veterans, elevated rates were 

reported for all birth defects combined, and for subsets of reported 

problems considered to most likely represent actual birth defects (that is, 

excluding developmental disorders, perinatal conditions, and miscellaneous 

pediatric conditions).155 These results are summarized in Table 12. 

Stillbirths, pre-term deliveries, and infant mortality did not differ between 

deployed and nondeployed veterans in this study. 

 The primary concern regarding interpretation of these findings is that 

the apparent excess of birth defects might not represent an actual increase 

in risk, owing to the self-reported nature of the information. Estimates of 

an apparent association of birth defects with Gulf War service might have 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 79

 

been inflated if Gulf veterans had a greater tendency than nondeployed 

veterans to identify or report adverse birth outcomes. Recognizing this 

limitation, investigators sought to determine the accuracy of veteranreported birth defect information by reviewing medical records associated 

with the 206 “likely” birth defects reported in the study. Researchers were 

able to re-interview veterans and obtain medical records related to 139 (67 

percent) of those cases. In an October, 2003, presentation to the 

Committee, investigators reported that among birth defects for which 

medical records were reviewed, 88 percent were confirmed. This 

information was used to generate adjusted estimates of the association of 

Gulf War deployment with birth defects, based on the rates of confirmed 

cases. Adjusted estimates supported the study’s original findings that 

overall birth defect rates were significantly higher among both male and 

female Gulf War veterans than in nondeployed veterans.156 

 In 2003, investigators from the Naval Health Research Center published 

a study representing a massive effort that linked birth certificate data from 

1989 through 1993 from the six American states with active birth defect 

surveillance programs to military service records of Gulf War era 

veterans.20 Records for 11,961 infants born to Gulf War veterans and 

33,052 nondeployed era veterans were identified. Analyses indicated that 

for children born between 1989 and 1991, conceived prior to the war, birth 

defect rates were similar in Gulf War and nondeployed veterans. However, 

several types of birth defects were significantly more common among 

children born to Gulf War veterans in 1992 and 1993, conceived after the 

war. Children of male Gulf veterans had significantly higher rates of two 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 80

cardiovascular defects, tricuspid valve insufficiency and aortic valve 

stenosis. Female Gulf veterans were significantly more likely to have sons 

born with hypospadias, a defect of the male urinary tract opening. 

Researchers pointed out that their ability to detect these differences was 

made possible only by the comprehensive nature of their study design, 

which involved active surveillance of birth defects that extended beyond 

the neonatal period, and included births from both civilian and military 

hospitals. They also pointed out that the size of their study limited their 

ability to determine whether less common types of birth defects were 

associated with Gulf War service. 

 In 2004, British researchers reported the results of a survey targeting all 

personnel who had served in the Gulf War from the United Kingdom and a 

comparison group of veterans who had not served in the war.77,194 Results 

indicated that male Gulf War veterans reported a 50 percent higher rate of 

all congenital malformations combined, including significantly increased 

rates of malformations of the urinary and musculoskeletal systems. No 

significantly elevated rates were found among children of female Gulf War 

veterans, where analyses were limited by small numbers. Investigators 

were able to obtain clinical information for about half of the pregnancies 

identified and, similar to the U.S. survey, found that over 90 percent of 

veteran-reported conditions were confirmed by medical records. When 

analyses were limited to malformations for which investigators obtained 

medical confirmation, previously-identified associations between Gulf War 

service and birth defects were similar, but somewhat weakened in some 

instances. This suggests that although increased rates of birth defects in 

some categories are likely to reflect real differences between Gulf and 

nondeployed veterans, the magnitude of those differences may have been 

inflated to some extent by reporting bias. The British study also found that 

male Gulf War veterans reported a significantly higher rate of miscarriages 

resulting from pregnancies conceived after the war, compared to 

nondeployed veterans. No differences were observed in the number of 

stillbirths reported by the two veteran cohorts. 

 Additional concerns about reproductive health among Gulf War 

veterans comes from a recently published study that utilized a military 

hospital cohort to assess outcomes of pregnancies among women veterans 

between 1990 and 1992.18 Pregnancy outcomes for the 415 Gulf War 

veteran women who became pregnant during the time they served in theater 

did not differ from those of women who had not deployed to the Gulf. 

However, conceptions that occurred after Gulf veteran women returned 

from theater were significantly more likely to result in poor outcomes. 

Specifically, postwar conceptions included nearly a three-fold increase in 

the risk of spontaneous abortion and a seven-fold increase in the risk of 

ectopic pregnancy among Gulf veteran women, after controlling for other 

factors known to be associated with poor pregnancy outcomes. 

 Related information of interest comes from studies of pregnancy 

outcomes and births among local populations in Kuwait and Bahrain. In 

comparing hospital records from the years since the war to those from the 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 81

pre-war period, such studies have found post-war increases in the rates of 

spontaneous abortions, low birth weight babies, and congenital heart 

disease, particularly in the period immediately following the war.13,196,197,247

 Overall, the issue of birth defects and other adverse reproductive 

outcomes potentially associated with Gulf War service has been the subject 

of much concern and debate. Three broadly representative populationbased studies from different investigators and populations have now 

indicated that Gulf veterans may have experienced higher rates of some 

adverse reproductive outcomes than nondeployed veterans since the war. 

Yet fundamentally important questions remain. The specific types of birth 

defects linked to Gulf War service have varied in different studies, as have 

the magnitude of identified risks. Data from survey-based studies indicate 

that, overall, there appears to be grounds for concern that Gulf War service 

may be associated with elevated rates of miscarriages and for the total 

number of all types of birth defects combined. Increased risk both for 

miscarriages and for the overall number of birth defects since the war, 

while significant, are rather modest, with odds ratios in the range of 1.5 to 

2.0.77,155 However, relative risks for some specific types of birth defects 

identified in the six states with active birth defect surveillance are 

substantially higher.20 No studies in this area have had the capability to 

conclusively determine whether less common types of birth defects may be 

linked to Gulf War service. Also lacking is information on whether 

adverse reproductive outcomes are of greater concern in particular veteran 

subgroups, such as those who served in particular areas, experienced 

specific exposures, or have been chronically ill since the war. Further, 

existing research studies have focused primarily on birth defects occurring 

in the early years after the war, with relatively little information on 

outcomes in more recent years. 

 The Committee concludes, therefore, that currently available 

information is insufficient to provide a clear understanding of the extent to 

which Gulf War service may be associated with an increased rate of birth 

defects, nor of the specific types of birth defects that may be of concern. 

While substantial progress has been made in this area in recent years, 

additional research is needed to address pressing questions to which 

veterans and their families deserve answers. 

Health of other family members of Gulf War veterans. Children 

born since the war are not the only family members about which Gulf 

veterans have expressed concerns. Media and government reports have 

suggested that other family members and close contacts—primarily 

spouses and children living at home when veterans returned from 

Southwest Asia—have also experienced increased rates of anomalous 

health problems since the war.82,184,246,346 A 1994 report by the Banking 

Committee of the U.S. Senate described a survey of 1,200 ill veterans 

which indicated that 77 percent of veterans’ spouses and 68 percent of their 

children also had experienced unexplained health problems since the war, 

and that many had symptoms similar to those reported by veterans.347 Such 

health problems have been variously attributed to contagious infections,218
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 82

or family contact with contaminated clothing or equipment that veterans 

brought back from theater.184 Also perplexing are reports from veterans’ 

wives that they have suffered gynecological pain and other problems 

resulting from contact with the burning or acidic seminal fluid of their 

veteran husbands.31 

 While such reports are alarming, questions about the degree to which 

family members may have been affected by an excess of unexplained 

health problems can only be answered by research studies that 

systematically compare the health of Gulf veterans’ family members to 

family members of veterans who did not serve in the region. Surprisingly, 

despite the many claims and concerns expressed regarding this issue, very 

little research has been undertaken to evaluate the health of family 

members of Gulf veterans. For a number of years, VA invited family 

members of veterans who were on the Gulf War Registry to undergo a free 

medical examination. This program was reported to have been fraught 

with problems and inefficiencies,338 and no public report has ever been 

issued regarding family member participation or data collected through this 

effort. 

 The only federal research study targeting family members of Gulf 

veterans is part of VA’s large National Health Survey of Gulf War-era 

Veterans and their Families. This study was initiated in 1995 and 

conducted in three phases. Phase III of the project included comprehensive 

medical and psychiatric evaluations of a randomly selected group of Gulf 

War and nondeployed Gulf War era veterans, as well as spouses and 

children of Gulf War and nondeployed veterans. Exams were performed 

between 1998 and 2001 in 16 VA Medical Centers across the country. 

Findings from the study have not yet been published. However, in a 2003 

presentation to the Committee, VA investigators indicated that in 

comparisons between spouses of Gulf veterans and spouses of nondeployed 

veterans, no significant differences were found in either the primary or 

secondary health outcomes of interest. These outcomes included chronic 

fatigue syndrome and fibromyalgia, among other diagnosed conditions.365

Study results are not yet available on conditions other than birth defects in 

veterans’ children. 

 It is hoped that additional useful information regarding the health of 

veterans’ spouses and children will become available as results from Phase 

III of the National Health Survey of Gulf War-era Veterans and their 

Families are analyzed and published. It is important that detailed analyses 

be conducted that evaluate the health of family members of deployed and 

nondeployed veterans on a broad range of parameters. Comparisons should 

be made between family members of the two veteran cohorts overall, and 

between specific veteran subgroups of interest, including veterans with 

unexplained symptoms, veterans with other diagnoses, and veterans who 

had different experiences and exposures in theater. Results from this study 

will be the first reported in this area, so findings will help determine what, 

if any, additional studies are needed. Until that time, however, the 

Committee can only conclude that little systematically-collected 
Finding 7 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 83

Finding 7 

Recommendations 

information is currently available to determine whether or not veterans’ 

family members have been affected by an excess of unexplained health 

problems since veterans returned from the war. In contrast to the multiple 

large studies investigating birth defects and reproductive outcomes, almost 

no research has been conducted to evaluate the health of spouses, older 

children, and other close contacts of Gulf War veterans. 

 Important questions remain concerning the risk of birth defects and 

other health problems among family members of Gulf War veterans. The 

Committee therefore recommends that VA: 

• Accelerate efforts to complete analyses and publish results from Phase 

III of the National Health Survey of Gulf War-era Veterans and their 

Families. Reports should contain comprehensive information on the 

health of veterans’ spouses and children, including an accounting of 

specific diagnosed conditions, symptoms, and symptom complexes. 

Special effort should be made to assess childhood health problems or 

abnormalities not apparent at birth, including learning and behavior 

disorders. 

• Analyze data from existing VA studies to evaluate birth defects and 

other health measures for family members of important veteran 

subgroups. Analyses should include comparisons between the health of 

family members of veterans who are ill and veterans who are well, and 

comparisons among family members of veterans with different 

deployment, location, and exposure histories. 

• Develop studies with innovative designs to test for excess rates of 

specific birth defects, such as Goldenhar syndrome, that occur too 

rarely to address with the types of studies done in the past. 

• Continue to query veterans regarding reproductive outcomes and the 

health of family members in VA’s ongoing longitudinal study of Gulf 

War and nondeployed veterans, and follow up veteran-reported 

information on birth defects and other health conditions with medical 

record reviews. 

• Issue a public report detailing information and data collected in 

connection with VA’s medical evaluation program for family members 

of Gulf War veterans. 

• Provide clear information to veterans and clinicians concerning what is 

known about the risk of birth defects related to Gulf War service, and 

update that information as additional research becomes available.
Finding 8 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 84

Finding 8 

Progress in 

understanding Gulf 

War veterans’ 

illnesses has been 

hindered by lack of 

coordination and 

availability of data 

resources 

maintained by the 

Department of 

Defense and the 

Department of 

Veterans Affairs. 

 The locations, activities, and exposures experienced by individual 

veterans who served in the Gulf War were extremely diverse. Likewise, 

health problems experienced by veterans since the war have occurred in 

diverse patterns of symptoms and medical conditions. Progress in 

understanding these conditions requires the availability of an extensive 

amount of data that allows assessment of health parameters in a large 

number of Gulf War veterans collectively and in subgroups defined by 

characteristics of their health and deployment experiences. Scientists and 

government review panels have consistently pointed out that understanding 

Gulf War illnesses has been made more difficult by the lack of data on the 

types and levels of wartime exposures, including vaccines, experienced by 

individual veterans. But a substantial amount of data relevant to the health, 

military, and deployment experience of Gulf War veterans currently exists, 

collected and maintained by DOD and VA. Neither agency, however, has 

made full use of these data resources and their potential to provide 

important information regarding Gulf War veterans’ illnesses. 

 A clear understanding of the health of Gulf War veterans, as well as 

possible links between veterans’ health and aspects of their military 

service, has been hindered by the lack of availability, integration, and 

usability of data collected by various sectors within the federal government. 

A large number of datasets currently exist within both DOD and VA that, if 

properly coordinated and utilized, have the potential to shed considerable 

light on important questions related to Gulf War veterans’ illnesses. For 

DOD, relevant resources include data on military service dates and service 

occupations, troop locations and movements during Persian Gulf 

deployment, in-theater clinic and hospitalization records, locations and 

dates of Coalition destruction of chemical targets, various exposure 

measurement and modeling efforts conducted during and after the war, 

military clinic visits and hospitalizations after deployment, and health and 

exposure data collected in association with the Comprehensive Clinical 

Evaluation Program (CCEP). For VA these resources include data from 

VA’s large population-based national survey of Gulf War era veterans, data 

on medical conditions, laboratory assessments, and treatments associated 

with VA clinic visits and hospitalizations, diagnostic and treatment data for 

veterans seen in VA’s specialty Gulf War illness clinics, data on benefits 

claims filed by Gulf War era veterans, and data collected in conjunction 

with VA’s Gulf War Registry. 

 A pressing need exists for a centralized data resource that would bring 

together existing datasets relevant to the health of Gulf War veterans. 

Reconciling and integrating the various federal data resources and making 

this information available to qualified researchers would allow researchers 

to better identify meaningful veteran subgroups whose health and military 

experiences distinguish them from other ill veterans. This information is 

fundamentally required to sort out the complex illnesses and overlapping 

symptoms and etiologic factors that together constitute Gulf War veterans’ 

illnesses. Such a resource would also greatly facilitate efforts to monitor 

the health of Gulf War veterans over time. 
Finding 8 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 85

 Existing studies have indicated that the rates and characteristics of Gulf 

veterans’ conditions differ according to the locations and time periods in 

which they served in theater. As previously described, a population-based 

study of Kansas veterans found that Gulf War illness rates were 

significantly linked to where and when veterans served in theater.285

Other investigations, including a military study of Marines conducted in 

March, 1991,242 have also reported that symptom profiles and medical 

conditions among Gulf War veterans differ by the time and locations in 

which they served.72,107,138,198,245 Researchers have called for further 

refinement and clarification of these findings, pointing out the potential 

benefits to be gained from information that allows characterization of 

subgroups of veterans according to where and when they served, the type 

of units with which they served, and the occupations in which they engaged 

during the war.46,112,288 

 Other obvious benefits would be gained by compiling and integrating 

clinical, registry, and benefits information collected by different 

departments within DOD and VA, as well as by other federal agencies, 

such as the Social Security Administration (SSA), which collect data 

relevant to veterans’ health. The ideal scenario would involve complete 

integration of military, deployment, exposure, and health information from 

federal data sources to provide a seamless record of veterans’ deployment 

and health experiences during their military service and in the years since 

the Gulf War. 

 Currently, the only ongoing effort to compile and monitor data related to 

the health of Gulf War veterans comes from the Veterans Benefits 

Administration (VBA). The Gulf War Veterans Information System 

produces a quarterly report, commonly referred to as the GWVIS Report, 

which provides summary health and benefits data on all veterans who have 

served in the military since August of 1990, sub-grouped according to 

whether or not they served in the Persian Gulf War. This report is useful 

but limited in scope. It documents the disposition of benefits claims filed 

by Gulf War era veterans as well as the total number of hospitalizations and 

deaths identified in this cohort. The GWVIS Report does not provide 

analytic information, such as comparisons between the proportions of 

deployed and nondeployed veterans who have filed claims since the war. 

Nor does it provide information on specific medical conditions for which 

veterans have been hospitalized or filed claims. However, the GWVIS data 

team has been extraordinarily conscientious in refining DOD-provided data 

indicating whether Gulf War era veterans actually served in the Gulf War, 

and has, as a result, generated a valuable data resource that could be 

extremely valuable for research purposes and other federal uses. It 

provides a useful example of utilizing data supplied by DOD, and 

integrating it with benefits data maintained by VBA and clinical data 

maintained by the Veterans Health Administration (VHA). 

 There are other examples in which different data systems managed by 

VA and DOD have been merged and integrated to address defined research 

questions for specific projects. These include the prevalence study of 
Finding 8 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 86

Finding 8 

Recommendations 

ALS,117 and studies investigating rates of medical conditions, 

hospitalizations, and mortality in relation to troop locations and proximity 

to the Khamisiyah weapons demolition and oil well fires.61,100, 154,181,273,275, 

276 

 The integration of datasets in different formats generated by different 

departments within different agencies for different purposes is a complex 

and challenging task. The development and management of such a data 

resource would require a sustained commitment on the part of VA, and a 

significant level of intra- and inter-agency cooperation. It would also 

require the adoption of appropriate data management techniques and 

privacy restrictions to ensure that the data are truly useful and usable. 

 Progress in understanding Gulf War veterans’ illnesses would benefit 

significantly from researchers making full use of data collected and 

maintained by different departments and agencies within the federal 

government. The Committee therefore recommends that VA and DOD: 

• Cooperate fully in individual projects requiring linkages between 

specific Gulf War-associated databases, such as the unit location 

database and healthcare and benefits data, to facilitate the provision of 

integrated data resources for research purposes. 

• Develop a comprehensive data library that houses and integrates federal 

military, deployment, and health data resources relevant to service in 

the Gulf War and the health of Gulf War era veterans. This data library 

would serve as a central data resource capable of providing usable data 

for the purposes of conducting research on specific questions regarding 

Gulf War veterans’ illnesses and monitoring the health of Gulf War 

veterans. 

• Make federal data resources relevant to Gulf War veterans’ health and 

military experiences available to qualified government and nongovernment researchers, and adopt appropriate safeguards for the use 

of these data. 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 87

Finding 9

Research on Gulf 

War veterans’ 

illnesses has 

important 

implications for 

current and 

future military 

deployments and 

for homeland 

security. 

 Events associated with the Persian Gulf War and the chronic health 

problems experienced by veterans since the war have profound 

implications for military personnel currently serving in the Middle East and 

for those who will participate in future deployments. Equally important is 

the relevance of research on the nature and causes of Gulf War veterans’ 

illnesses to considerations related to homeland security and protection from 

terrorist attack. 

Applying the lessons of Gulf War veterans’ illnesses to current 

and future deployments. Many of the concerns related to Gulf War 

veterans’ illnesses are not unique to the Gulf War, but reflect challenges 

that are increasingly a part of modern warfare. In all times, in all wars, 

military personnel have faced life-threatening dangers and death from 

enemy attacks, deadly weapons, and diseases resulting from deployment to 

hostile areas. Over the years, military and veteran physicians and 

scientists have developed impressive expertise in addressing the visible 

wounds and injuries resulting from bullets and bombs, and in supporting 

veterans suffering from the long-term psychological effects of war. But 

little progress has been made in addressing another type of health challenge 

that has affected veterans serving in more recent wars. Such problems arise 

from exposure to hazardous chemical and biological substances that often 

do not cause visible wounds or immediate symptoms, but can work 

insidiously to produce long-term and poorly understood health problems. 

Military health professionals have been less successful in addressing these 

conditions, as evidenced by the chronic problems known to have persisted 

for many years among veterans exposed to chemical agents in World War 

I, nuclear bomb detonations in the 1940s and 1950s, chemical defoliants in 

Vietnam, and the complex mix of exposures encountered in Operation 

Desert Storm. 

 Although Desert Storm ended in 1991, military operations in the region 

have continued through the early years of the 21st century. American and 

allied forces have also served in other war zones around the world in the 

intervening years, and are now engaged in active hostilities in both Iraq and 

Afghanistan. Many of the risk factors potentially associated with Gulf War 

veterans’ illnesses continue to be a concern for those serving in these areas. 

They include the potential for exposure to chemical weapons, depleted 

uranium, multiple vaccines, infectious diseases and drugs taken to protect 

against local infections, the use of multiple types and combinations of 

pesticides, and the use of PB as a protective measure against the nerve 

agent soman. 

 

 Pyridostigmine bromide was classified as an investigational new drug 

for use in the 1990-1991 Gulf War. As previously described, little is 

known about the long-term health effects of the use of PB by healthy 

individuals, particularly under the circumstances in which it was taken 

during the Gulf War. Animal studies have indicated that PB may act 

synergistically with other neurotoxins to enhance the effects of those 

compounds, and scientific and government reports have not ruled out PB as 

a possible contributor to Gulf War veterans’ illnesses. Despite this 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 88

information, the U.S. Food and Drug Administration (FDA) approved the 

use of PB for military personnel as a chemical pretreatment against the 

nerve agent soman in February, 2003, just prior to the beginning of 

Operation Iraqi Freedom. As a result, the informed consent requirement 

and other restrictions that were in place when PB was classified as an 

investigational new drug are no longer applicable. 

 Many of the difficulties and delays in the government’s response to the 

chronic health problems affecting Gulf War veterans have resulted from 

information gaps and incomplete record-keeping related to veterans’ health 

and exposures during deployment. For example, substantial questions 

remain about the possible contribution of vaccines to Gulf War veterans’ 

illnesses. Evaluation of the contribution of vaccines to these conditions 

would have been greatly aided by the availability of properly maintained 

military vaccination records that included specific information on vaccine 

lots and dosage schedules. Should such problems and questions arise from 

current and future deployments, VA’s ability to identify and treat affected 

veterans would require access to comprehensive vaccine records 

maintained by DOD. The lack of such information would again confuse 

and delay efforts to address possible resulting health problems. 

 The conditions of war are challenging in innumerable ways, and 

military operations must emphasize measures that provide for the safety 

and survival of the soldier on the battlefield above all other health 

considerations. However, before deployment and after the soldier returns 

home, it is important that the federal government have in place programs 

that both minimize the risk of developing illnesses associated with 

hazardous exposures and address whatever unforeseen health problems 

may arise as a consequence of deployment. 

 These responsibilities have been recognized by both DOD and VA. In 

1999, the Department of Defense replaced its Office of the Special 

Assistant for Gulf War Veterans’ Illnesses with the Office of Force Health 

Protection and Readiness.174,322 This office has been responsible for 

programs designed to identify, minimize, and address medical and 

psychological risks due to occupational factors associated with deployment. 

VA has also taken a broader approach to understanding and addressing 

these issues, sponsoring both clinical and research programs that focus on 

deployment health. Since 2001, VA has sponsored two clinical and 

research centers that focus on the healthcare needs of veterans who return 

from wartime service with symptoms and conditions that are difficult to 

diagnose and treat. These War-Related Injury and Illness Study Centers 

are located at the VA Medical Centers in Washington, D.C. and East 

Orange, New Jersey.333 The Committee also understands that DOD and VA 

have worked cooperatively to develop a medical records system that will 

follow the health of individuals from military recruitment, through military 

service and deployments, and into the VA healthcare system after 

discharge.344 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 89

 The Committee commends these efforts, and urges both agencies to 

continue to move forward in the continued implementation of programs 

that minimize deployment-related health risks to military personnel, and 

more efficiently address unforeseen health consequences of hazardous 

deployments. It is clear, however, that some important deployment health 

initiatives with special relevance to the health problems affecting Gulf War 

veterans have not yet been fully implemented. As a result, there remains a 

concern that some of the same types of problems, particularly those related 

to the unavailability of health and exposure information, which delayed 

progress in the government’s response to Gulf War veterans’ illnesses, may 

again affect the government’s ability to respond to unforeseen medical 

consequences of current and future deployments. 

 To minimize these problems, the Committee concludes that it is 

extremely important that DOD implement several measures required to 

prevent and/or more efficiently address future deployment-related health 

problems. Prominent among these are medical examinations of military 

personnel before and after deployment that include collection and storage 

of blood samples. It is also imperative that VA and DOD continue to work 

together to share deployment information on military personnel, including 

known hazards encountered in theater, and to finalize implementation of an 

integrated medical records system that allows personnel to make a seamless 

transition between DOD and VA healthcare systems. 

Research on Gulf War illnesses has broad implications for 

homeland security and the war on terrorism. Alerts at home and 

military actions abroad provide constant reminders of the risk of terrorist 

attack. In the months since September 11, 2001, Americans have been 

keenly aware that the risk of exposure to chemical and biological weapons 

and the need for measures that provide protection from their effects is not 

limited to military populations. In the course of its deliberations on causes 

of and treatments for Gulf War veterans’ illnesses, the Committee has 

reviewed a large body of evidence related to the effects of chemical 

weapons, particularly nerve agents, and currently available medical 

countermeasures against those agents. 

 Exposures encountered during the Gulf War and research on Gulf War 

veterans’ illnesses provide important insights relevant to the risk of 

domestic exposure to nerve agents. As previously described, the 

Department of Defense has estimated that approximately 100,000 Gulf War 

veterans may have been exposed to nerve agents during the Khamisiyah 

demolitions in March, 1991, and a recent GAO investigation suggests that 

the total number of veterans exposed to nerve agents may be much 

higher.343 Recent research has called into question the long-held 

assumption that low-level exposures to nerve agents do not produce 

chronic adverse health effects. Additionally, the use of pyridostigmine 

bromide, the “nerve agent pre-treatment pill” taken to protect against nerve 

agents, may be implicated as a possible contributor to the chronic health 

problems experienced by Gulf War veterans. 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 90

 In the last several years, the federal government has made a major 

commitment to funding medical research programs aimed at defending the 

public from bioterrorism—that is, the use of biological agents to harm 

American civilians. The National Institutes of Health (NIH) invested 1.7 

billion dollars on research and development programs related to biodefense 

in fiscal year 2003, 1.6 billion in fiscal year 2004,323 and has requested an 

additional 1.7 billion dollars for biodefense research in fiscal year 2005.324

NIH has also begun taking steps to initiate research to develop medical 

responses to nuclear attack, requesting 47 million dollars in funding to 

develop treatments for nuclear or radiological injuries.324 

 Given the appropriate massive national effort to address the possible 

threat from terrorist use of biological agents, the Committee is concerned 

that no comparable large-scale program exists that is tasked with 

developing protection and treatment measures against the effects of 

chemical agents. No funding dedicated to research in this area has been 

requested by NIH, and funding for the U.S. Army Medical Research 

Institute of Chemical Defense, the scientific group historically tasked with 

sponsoring and conducting research in this area, has actually declined in 

recent years.269 

 As the country marshals its medical research resources to defend 

American citizens against the threat of weapons of mass destruction, it 

makes little sense to target biological and radiological threats, but leave 

chemical threats, the easiest and least costly for an adversary to acquire, 

undefended. This situation is particularly untenable now that recent 

scientific studies, such as those associated with Gulf War illnesses 

research, have begun to provide important breakthroughs in understanding 

the effects of chemical weapons, with significant implications for the 

development of prevention and treatment measures. In these dangerous 

times, it is critical that research to pursue these advances and other 

promising developments be aggressively encouraged and funded. 

 Some initial steps have been taken within the federal government to 

provide a preliminary framework for research efforts that address the threat 

of chemical weapons. In March, 2003, NIH convened a panel of experts 

“to identify gaps in scientific knowledge about chemical injury and repair, 

and to identify priorities for the research and development of medical 

countermeasures.”370 This meeting was followed, in April, 2004, by a 

workshop sponsored by the National Institute of Neurological Diseases and 

Stroke for federal government scientists and others “interested in research 

to develop medical countermeasures against chemical and biologic agents 

that affect the nervous system and could be used in a terrorist attack.”216

The workshop was organized to identify “research gaps of high priority in 

the area of counterterrorism and neuroscience research,” and attracted 

broad participation. In addition, the White House Office of Science and 

Technology Policy has convened a multiagency working group tasked with 

developing recommendations relating to critical needs in the area of 

domestic chemical defense. While these initial discussions are useful in 

laying the groundwork for future scientific and protective endeavors, at 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 91

Finding 9 

Recommendations 

present no programs have been developed and no funding allocated for 

government research that addresses critical gaps related to medical 

countermeasures against chemical agents. 

 As this report is being finalized, Congress has recently passed 

legislation establishing Project Bioshield, a program that will provide 

funding to private industry for development of medical countermeasures 

against biological, radiological, and chemical weapons. The inclusion of 

chemical threats in this program is a promising initial sign of progress in 

addressing this issue. It is important that Congress similarly extend NIH’s 

counterterrorism research program to include medical countermeasures 

against chemical threats. 

 With respect to the relevance of Gulf War illnesses research to current 

and future military deployments, the Committee applauds the efforts of the 

Secretary of Veterans Affairs in encouraging the Department of Defense to 

maintain comprehensive records of deployment-related health information, 

including receipt of vaccines, in connection with current military 

deployments. The Committee further recommends that: 

• DOD fully implement the military assessment programs mandated in 

1997 by Public Law 105-85, Section 765 (10 U.S.C. §1074f (1997)), 

which directs DOD to conduct detailed medical examinations of all 

military personnel before and immediately after deployment to hostile 

areas, including the collection and storage of blood samples taken 

before and after deployment. 

• DOD take steps to improve record keeping and exposure assessments 

related to military deployments. 

• DOD reassess policies regarding the use of pyridostigmine bromide as 

a prophylactic measure against the possible effects of nerve agents. 

This assessment should include a comprehensive review of scientific 

studies relating to adverse effects of pyridostigmine bromide in 

combination with other exposures, and revisiting policies concerning 

the circumstances and decisions that govern orders for the use of 

pyridostigmine bromide. 

• DOD and VA work cooperatively to immediately share information 

related to current military deployments, including health experiences 

and exposures in theater. 

• DOD and VA continue to work cooperatively to develop and 

implement a unified health data system that will include all health 

information of personnel through their military service and transition 

into the VA healthcare system. 
Finding 9 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 92

 With respect to the relevance of Gulf War illnesses research to 

preparations against chemical terrorism, the Committee recommends that 

Congress: 

• Establish a comprehensive medical chemical defense research program 

within the NIH counterterrorism research agenda, and provide adequate 

funding to field effective medical countermeasures. Enlist in this effort 

the capabilities of relevant agencies, including the Department of 

Defense and the Department of Veterans Affairs. 

• Expand funding for research programs sponsored by the Department of 

Defense relevant to chemical defense measures. In particular, continue 

and expand support for research programs that have provided important 

information regarding the chronic health effects of sarin and other 

chemical agents. 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 93

Finding 10 

Further progress in 

understanding and 

treating Gulf War 

veterans’ illnesses 

requires federal 

research programs 

that are properly 

focused, wellmanaged, and 

adequately funded. 

 

 Gulf War veterans’ illnesses pose a complex challenge—scientifically 

and administratively—for the federal agencies responsible for addressing 

them. The U.S. Departments of Veterans Affairs, Defense, and Health and 

Human Services have worked for over a decade on these problems, 

individually and collectively, spending hundreds of millions of dollars in 

research and untold additional funds on clinical care for ailing Gulf War 

veterans. Despite this massive effort and recent important scientific 

advances, much remains to be learned about the precise physiological 

characteristics of veterans’ illnesses and the particular exposures or 

combinations that caused veterans to become ill. Moreover, virtually 

nothing is known about treatments that can substantially improve the health 

of ill veterans. Why has so much effort resulted in such limited progress? 

The Committee believes there are a number of reasons, most having to do 

with the focus of the federal research effort and the lack of a clear and wellmanaged program to successfully complete research in areas most 

important to understanding and treating Gulf War veterans’ illnesses. 

 If progress in addressing Gulf War veterans’ illnesses research were to 

be measured in terms of the number of programs developed, the number of 

research projects funded, and the number of dollars spent, it might be 

argued that the federal government has made an admirable effort and 

considerable progress in undertaking activities to address these conditions. 

The most recent information compiled by the federal interagency 

Deployment Health Working Group Research Subcommittee indicates that, 

in fiscal years 1994 through 2002, federal agencies spent nearly 300 

million dollars for research on Gulf War veterans’ illnesses in support of 

239 individual research projects.73 Certainly, among the many research 

studies funded by federal agencies, a substantial number have provided 

valuable information on possible mechanisms of illness and long-term 

effects of exposures encountered in theater, as well as descriptive 

information on veterans’ symptoms and rates of mortality and 

hospitalization. As described throughout this report, the Committee 

commends both the researchers and the federal agencies whose efforts have 

resulted in important findings concerning the characteristics and 

physiological nature of Gulf War veterans’ illnesses and the long-term 

effects of exposures encountered in the Gulf War. Many of these scientific 

findings have only become available in the last few years, as research 

projects funded in the 1990s have been completed. 

 However, the Committee is committed to its charge of assessing the 

progress made in research on Gulf War veterans’ illnesses according to 

another standard—that is, the degree to which this research has improved 

the health of ill Gulf War veterans. If progress is measured by that central 

criterion, as well as by broader scientific standards, the Committee finds 

that the federal research program addressing Gulf War veterans’ illnesses 

has not succeeded in answering fundamental and essential questions 

regarding Gulf War veterans’ illnesses and, consequently, has not 

succeeded in providing information that has made a substantial difference 

in the health and lives of ill Gulf veterans. 

 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 94

Planning and coordination of federal research on Gulf War 

Veterans’ illnesses. 

A collaborative government-sponsored program has not been 

established. Evaluation of undiagnosed Persian Gulf illnesses 

has not followed a uniform protocol across military branches, 

VA facilities, and civilian physicians. This has led to imprecise 

description of disease and/or symptoms, uncertainties about 

underlying prevalence rates, and inconsistent treatments. 

Well-designed epidemiologic studies have not been conducted 

to link the illnesses of the military personnel with exposures in 

the Persian Gulf theater of operations. 

- NIH Technology Assessment Workshop Statement, 1994221

 Making scientific progress in areas that are poorly understood, as in any 

endeavor involving achievement of a complex objective, requires planning, 

coordination, execution, and ongoing evaluation of progress and priorities. 

Given the multifaceted nature of the exposures and illnesses associated 

with Gulf War service, it is especially important that the right research 

questions be asked and the best studies undertaken to answer those 

questions. In the early stages of addressing a complex research problem, it 

is important to pursue a broad range of potentially fruitful areas, often 

including many blind alleys, until scientific breakthroughs point 

investigators toward research areas most likely to provide significant 

insights, and away from areas least likely to yield progress. Such an 

undertaking is challenging in any circumstance, but especially so when it 

requires the coordinated efforts of several large federal agencies on 

complex scientific matters with potentially far-reaching political and 

economic implications. 

 The lack of scientific progress in addressing Gulf War veterans’ 

illnesses has not been due to a lack of federal initiatives aimed at 

identifying research priorities. Many of the recommendations provided by 

the Committee in this report parallel research priorities identified by earlier 

government review panels and committees. These include 

recommendations regarding the need to identify effective treatments for 

Gulf War veterans’ illnesses, coordinate federal data resources related to 

Gulf veterans, monitor the health of Gulf veterans over time, improve 

assessments of reproductive outcomes, and prospectively collect health and 

exposure data in association with future deployments.130,131,136,221,235,236, 

240,241,249,304 

 The Persian Gulf Veterans Coordinating Board (PGVCB), the federal 

interagency committee originally charged with coordinating research on 

Gulf War veterans’ illnesses, issued its first comprehensive research plan 

for addressing these conditions in 1995.235 The plan identified three central 

research priority areas: 

• Establish the nature and prevalence of symptoms, diagnosable 

illnesses, and unexplained conditions among Persian Gulf veterans. 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 95

• Identify the possible risk factors for any illnesses, beyond those 

expected to occur, among Persian Gulf veterans. 

• Identify appropriate diagnostic tools, treatment methods, and 

prevention strategies for any excess illness conditions found among 

Persian Gulf veterans. 

 Later PGVCB reports expanded on and revised these initial priorities in 

response to emerging information, such as the release of chemical nerve 

agents in the Khamisiyah incident. Short and long-term research objectives 

were established, and 21 priority research questions were identified in the 

board’s 1996 Working Plan for Research.236 The Board developed an 

additional set of research priorities in 1998, which included research on 

treatments for Gulf War veterans’ illnesses, longitudinal follow-up of ill 

Gulf War veterans, and research related to prevention of deploymentrelated health problems and improved assessment of risks and 

environmental hazards associated with deployment.249 

 As part of the federal research effort, DOD, VA, and to a lesser extent, 

the Department of Health and Human Services (HHS) have funded 

hundreds of studies that relate to many of the identified research objectives. 

Each year, PGVCB and its successor interagency coordinating committees 

(Research Working Group of the Military and Veterans Health 

Coordinating Board and the Deployment Health Working Group) have 

catalogued federal research projects and described research findings related 

to Gulf War veterans’ illnesses in annual reports to Congress. 

 Despite the long-established federal effort to identify research priorities, 

coordinate research, and fund specific studies, the priorities identified in 

the 1995 PGVCB report have yet to be satisfactorily addressed. For 

example, appropriate diagnostic tools and treatment methods for veterans’ 

unexplained illnesses have not yet been identified, specific risk factors for 

these conditions have not yet been clearly determined or acknowledged by 

government agencies, and the prevalence of diagnosed and undiagnosed 

conditions, while chronicled in multiple studies, have yet to be firmly 

established or recognized by any federal agency. The Deployment Health 

Working Group’s annual reports to Congress continue to identify multiple 

studies that relate in some way to the priority areas identified in its research 

plan. However, a demonstration of dollars spent or research that may relate 

to different aspects of Gulf War veterans’ illnesses is not the same as a 

demonstration of progress made in identified priority areas. 

 Perhaps the most obvious shortfall in the federal research effort to date 

has been the ongoing emphasis on studies focusing on psychological stress 

as the principal factor in the development of Gulf War veterans’ illnesses. 

As detailed in interagency committees’ annual reports to Congress between 

1994 and 2002, federal research efforts have included a large portfolio of 

studies focusing on deployment stress and psychiatric causes of Gulf War 

veterans’ illnesses. As scientific evidence has cumulatively demonstrated a 

relatively minor role for psychological stress as a primary factor in the 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 96

etiology of Gulf War veterans’ conditions, a shift in research focus has 

been needed to address the many other plausible explanations for veterans’ 

illnesses. Unfortunately, as will be discussed in more detail, this shift has 

not yet taken place. 

Gulf War-related research studies funded by the federal 

government. In its most recent annual report to Congress, published in 

April, 2004, the Deployment Health Working Group reported that federal 

agencies spent nearly 300 million dollars on Gulf War veterans’ illnesses 

research through fiscal year (FY) 2002,73 as shown in Table 13. As 

detailed in the report, direct federal costs for Gulf War illness-related 

research increased steadily after FY1994, reaching a peak level in FY2000. 

Thereafter, annual funding levels for Gulf War illnesses research declined 

steadily, and were projected to drop to just 19 million dollars in direct costs 

for FY2003, the lowest spending level since 1996. 

Table 13. Projected Federal Funding for Gulf War Veterans’ Illnesses 

Research through Fiscal Year 2003 

(reported in millions of dollars) 

Department 

Actual 

Funding* 

FY1994 – FY2002 

Projected 

Funding 

FY2003 

Projected 

Total 

FY1994 – FY2003 

DOD 219.1 13.5 232.6 

VA 64.5 4.8 69.3 

HHS 13.9 1.0 14.9 

Total 297.5 19.3 316.8 

* Total costs include both direct and indirect costs 

 Source: Annual Report to Congress: Federally Sponsored Research on Gulf War 

 Veterans’ Illnesses for 200273

 Over the years, DOD has provided the bulk of federal research funding 

directed at Gulf War veterans’ illnesses, and an extensive number of 

individual DOD-sponsored studies are chronicled in the 2002 Report to 

Congress. Of the DOD-sponsored projects identified as “Gulf War 

Research,” the majority of studies specifically related to unexplained 

multisymptom illnesses and the effects of Gulf War-associated exposures 

were funded prior to FY2000. As previously described, those DODsponsored research projects have produced important breakthroughs in 

such areas as the chronic effects of low-level sarin exposure and 

neurological impairment in Gulf War veterans. However, DOD funding 

for this type of research has been dramatically reduced in the last several 

years, in keeping with DOD’s shift from a focus on Gulf War veterans’ 

illnesses to more general “deployment health” research. DOD’s projected 

“Gulf War research” funding for FY2003 includes no new and just five 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 97

ongoing projects specifically related to Gulf War-related exposures and 

unexplained illnesses, and several projects related to prospective 

longitudinal assessment of post-Gulf War military personnel. Similarly, 

nearly all “Gulf War research” funding allocated by HHS since 2002 has 

been allocated for research on methods to improve the communication of 

health risks to personnel involved in post-Gulf War deployments.73

 As a result of DOD’s virtual withdrawal from the Gulf War-related 

health research effort, the Department of Veterans Affairs is the only 

federal agency currently sponsoring new research initiatives specifically 

targeting the unexplained health problems affecting Gulf War veterans. 

This change has had two major consequences. First, the overall amount of 

federal funding specifically focused on Gulf War-related research has 

declined considerably in recent years from an average of over 45 million 

dollars per year in direct and indirect costs between 1999 and 2001, to a 

projected total of just over 19 million dollars in direct costs in 2003. 

Second, the types of research undertaken and the scientists eligible to 

compete for available funding have dramatically changed. VA research 

funding is provided only to principal investigators employed as VA 

clinicians and scientists. Therefore, the range of research projects 

undertaken generally must fall within areas of expertise found “in house” at 

VA, with the exception of expertise provided by scientists outside of VA 

who collaborate in supporting roles with VA investigators. 

 As research relating to Gulf War veterans’ illnesses increasingly relies 

on VA support, it becomes ever more important that VA’s Gulf War 

research funding be well-focused and strategically allocated as part of a 

comprehensive plan designed to make significant progress on priority Gulf 

War illness research questions. However, it is clear from the research 

projects identified as comprising VA’s projected Gulf War Research 

portfolio for FY2003 that VA had not developed a strategic research plan 

aimed at addressing priority issues relating to the nature, causes, and 

treatments for Gulf War veterans’ illnesses. Of the nearly 4.8 million 

dollars projected by the Deployment Health Working Group to be allocated 

by VA in FY2003 for Gulf War Research, about 4.3 million was for 

research projects either initiated or continuing during FY2003.73 Those 

projects are identified in Table 14, with an indication of whether the funded 

research focused on Gulf War-related undiagnosed illnesses or exposures, 

other Gulf War-related medical issues, or stress and psychiatric illness. 

 As shown, over 2.4 million dollars, or 57 percent, of VA’s FY2003 Gulf 

War research funding was projected to be allocated for projects related to 

stress and psychological illness. In contrast, only about 741 thousand 

dollars (17 percent) was to be allocated for projects directly related to 

understanding Gulf veterans’ undiagnosed conditions or the effects of Gulf 

War-related exposures. A similar amount was to be spent on projects 

unrelated to either Gulf veterans’ conditions or stress, such as a program to 

educate VA clinicians on bioterror events. Moreover, the few funded Gulf 

War illness-related projects, while valuable individually, appear to 

represent a somewhat haphazard collection of studies. None of the funded 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 98
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 99

projects addresses treatments for veterans’ multisymptom illnesses, while 

the largest amount of projected funding for an individual study is provided 

for a behavioral therapy trial for PTSD. There is no evidence that VA has 

developed a comprehensive plan to fund studies of the highest priority and 

relevance to Gulf War veterans’ illnesses, including those that follow up 

and capitalize on earlier breakthrough research findings. In fact, the 

Committee was puzzled to find that the scientific advances made in Gulf 

War-related research during 2002 were scarcely mentioned by the 

Deployment Health Working Group in its 2002 report to Congress.73

 Given the growing importance of VA’s central role in sponsoring 

research on Gulf War veterans’ illnesses, the Committee was extremely 

concerned that the projects identified to Congress as constituting VA’s 

projected research program on Gulf War veterans’ illnesses for 2003 still 

focused overwhelmingly on stress-related conditions, with relatively little 

funding specifically targeted for research related to veterans’ 

multisymptom illnesses and the effects of Gulf War-related exposures. In 

light of the Committee’s previous conclusions regarding the nature and 

potential causes of Gulf War illnesses, the FY2003 research portfolio 

outlined in Table 14 makes little sense, and provides a strong indication of 

why VA has made little progress in addressing Gulf War veterans’ 

illnesses. 

 In October, 2002, VA announced that it would allocate up to 20 million 

dollars in FY2004 research funding for Gulf War veterans’ illnesses and 

other deployment health-related projects, and issued a broad announcement 

describing the types of research projects that would be supported under this 

new initiative.328 In February, 2004, nearly halfway through the fiscal year 

that was to have included this expanded research effort, the Committee 

learned that VA had funded only one Gulf War illness-related study in 

FY2004, for less than 500 thousand dollars. 

 The lack of success in identifying and funding promising studies was 

disappointing in light of VA’s FY2004 commitment, which had initially 

promised a fresh approach to research on Gulf War veterans’ illnesses. 

VA’s Office of Research and Development indicated to the Committee that 

Gulf War illness-related research proposals were not provided priority 

consideration under the deployment health initiative and were reviewed 

with other proposals by scientific panels that were not generally familiar 

with the issues and priorities associated with Gulf War illness-related 

research. Further, the funding commitment of “up to 20 million dollars” 

did not result in 20 million dollars being specifically set aside for 

deployment health or Gulf War illness research. In response to expressed 

concerns regarding the lack of progress made in association with the 

FY2004 funding initiative, VA has indicated to the Committee that it will 

redirect its research effort toward a more strategically designed and 

relevant Gulf War veterans’ illnesses research portfolio. The Committee 

welcomes this renewed commitment by VA and the expressed willingness 

of VA’s Office of Research and Development to utilize the Committee’s 

recommendations in this work. The Committee looks forward to reviewing 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 100

Finding 10 

Recommendations 

tangible evidence of a comprehensive and more appropriately directed 

research program that addresses priority research areas and implements 

specific management provisions to ensure that identified objectives are 

addressed. 

 Overall, the Committee finds that, although a number of federally 

sponsored research studies have provided important scientific advances 

related to Gulf War veterans’ illnesses, the federal research effort has yet to 

make the type of progress needed to improve the health of ill veterans. A 

large number of studies have been funded and a considerable amount of 

money spent, but federal agencies tasked with working together on Gulf 

War veterans’ illnesses have not succeeded in developing research 

programs that comprehensively and successfully address priority research 

objectives. The recent reduction of federal research funding to address 

Gulf War veterans’ illnesses is of particular concern now, as important 

advances relating to the nature of veterans’ illnesses and possible long-term 

effects of Gulf War-related exposures are beginning to emerge from 

previously funded federal research. Such advances should be aggressively 

pursued, since research investments now have the greatest potential to 

reduce the suffering of ill Gulf War veterans as well as future costs 

associated with their medical care. 

 Overall progress in addressing Gulf War veterans’ illnesses has been 

delayed by the lack of a well-coordinated federal research effort managed 

to successfully address key research priorities, and by an ongoing emphasis 

on studies that focus on psychological stress as the primary explanation for 

these conditions. The Department of Defense no longer supports new 

research on Gulf War veterans’ illnesses, resulting in a dramatic decrease 

in federal funding in this area in recent years. This is of particular concern 

now, as recent breakthroughs provide new progress in understanding 

veterans’ illnesses. The Committee therefore recommends that VA: 

• Develop a comprehensive federal research plan to address Gulf War 

veterans’ illnesses in conjunction with other participants in the 

Research Subcommittee of the Deployment Health Working Group and 

with the Research Advisory Committee on Gulf War Veterans’ 

Illnesses. The plan should address priority research topics identified in 

this and future Committee reports. It should also utilize scientific 

resources and funding mechanisms available at each federal agency in 

order to enlist government and non-government scientific experts most 

capable of undertaking research projects that best address priority 

topics. 

• In the context of the comprehensive federal research plan, adopt a 

strategic VA research program that identifies and addresses key 

research questions regarding the nature, causes, and treatments for Gulf 

War veterans’ illnesses, utilizing research solicitations that address 

specific priority Gulf War illnesses research topics. 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 101

• Maintain a substantial research funding commitment to address the 

health consequences of Gulf War deployment until specific treatments 

and causes for these conditions are identified. Specifically, VA should 

allocate not less than 15 million dollars in each of the next four years in 

support of a comprehensive and well-managed research portfolio. 

• Work with leading scientists—both those within VA and those not 

affiliated with VA—to develop comprehensive research protocols most 

capable of addressing priority Gulf War illnesses research questions. 

• Establish an effective management strategy for the VA Gulf War 

illnesses research portfolio to ensure that studies capable of addressing 

priority research questions are satisfactorily developed and completed. 

The program should be directed by a doctoral-level scientist with 

appropriate expertise in research directly relevant to Gulf War veterans’ 

illnesses. 

• Adopt a mechanism for reviewing and funding Gulf War illnesses 

research proposals that takes into account the relevance of proposed 

projects to identified Gulf War illnesses research priorities, in addition 

to the scientific merit of the proposed research. Merit review panels 

should include scientists familiar with current research on Gulf War 

veterans’ illnesses and established research priorities. 

• Allocate a significant proportion of Gulf War illnesses research funding 

to treatment research, including specific annual allocations for the 

recommended treatment development program and pilot studies, and 

additional funding for small and large clinical trials, as scientifically 

appropriate. 

• Give funding priority to studies that pursue significant research 

breakthroughs, such as those identified throughout this report. Do not

fund studies in areas that accumulated research has found not to be 

useful in understanding the unexplained illnesses affecting Gulf War 

veterans, unless such proposals can be justified by new evidence or 

innovative hypotheses. For example, although psychiatric conditions 

such as posttraumatic stress disorder are appropriate topics for 

deployment health research in general, research proposals on Gulf War 

veterans’ illnesses should not be funded if their principal focus is on 

psychological stress as the primary cause of these conditions. 

• In conjunction with the Committee, regularly review progress on the 

objectives established for the Gulf War illnesses research program, to 

determine which have been adequately addressed, which should be 

revised, and which require additional follow-through with new and/or 

more specific funding announcements. 
Finding 10 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 102

The Committee recommends that Congress: 

• Set a national goal to develop treatments for the chronic multisymptom illnesses affecting Gulf War veterans within five years. 

• Establish line-item funding within the appropriations budgets of the 

appropriate federal departments that provides a total annual federal 

Gulf War illnesses research commitment adequate to execute the 

comprehensive Gulf War illnesses research plan, and in no event less 

than 45 million dollars, consistent with the annual funding levels 

invested in Gulf War illnesses research between 1999 and 2001. 

• Designate that 15 million dollars of the annual federal Gulf War 

illnesses research funding be specifically added to VA’s current 

research and development budget in support of the recommended 

comprehensive Gulf War illnesses research program. The balance 

should be provided to the Departments of Defense and Health and 

Human Services, as appropriate for the specific projects to be funded 

and, in particular, for research conducted by non-government research 

scientists on a competitive basis. 
Conclusions 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 103

Conclusions Recent scientific progress in understanding Gulf War veterans’ illnesses 

has given new hope to ill veterans and provided a foundation for the 

important work that remains. These conditions have posed a difficult 

challenge for those whose health and lives have been affected by chronic 

and often debilitating symptoms for over a decade. Accumulated research 

evidence from studies conducted since the war clearly indicates that 

psychiatric illness and the effects of wartime stress cannot adequately 

explain Gulf War illnesses. In recent years, research studies have provided 

consistent evidence of linkages between exposure to neurotoxins during the 

war, particularly acetylcholinesterase-inhibiting compounds, and Gulf War 

veterans’ illnesses. Numerous animal studies have demonstrated both that 

low-dose exposure to chemical nerve agents can produce chronic adverse 

neurological and immunological effects and that combinations of Gulf 

War-related exposures often work synergistically to yield toxic effects that 

exceed those resulting from individual exposures. These studies parallel 

clinical research findings demonstrating neurological injury and 

impairment in Gulf War veterans and epidemiologic studies that have 

consistently identified significant associations between veteran-reported 

neurotoxin exposures and higher rates of multisymptom illnesses. Other 

Gulf War-related exposures also may be linked to veterans’ illnesses and 

will be more thoroughly addressed in future Committee reports. 

 While recent scientific advances in Gulf War illness-related research are 

encouraging, the most important work in effectively addressing these 

conditions lies ahead. The Committee judges research on Gulf War 

veterans’ illnesses according to one standard: the extent to which it can 

contribute to improvements in the health of ill veterans. Federal research 

efforts thus far have not identified treatments that provide marked 

improvement for a substantial number of ill veterans, and no efforts have 

been undertaken to systematically identify and develop treatments that may 

hold promise. The Committee considers the identification of treatments to 

be the highest priority for Gulf War illness research and strongly urges VA 

to aggressively pursue this objective. 

 A number of other key research initiatives regarding the health of Gulf 

War veterans also require immediate action. Additional work is needed to 

identify the precise physiological mechanisms underlying veterans’ 

multisymptom illnesses and the long-term effects of Gulf War-related 

exposures. The excess rate of amyotrophic lateral sclerosis among Gulf 

War veterans is particularly troubling and highlights the importance of 

determining whether Gulf War veterans are affected by excess rates of 

other neurological diseases such as Parkinson’s Disease and multiple 

sclerosis. It is imperative that VA undertakes well-designed studies to 

evaluate rates of illness and death due to these conditions and establish an 

ongoing program to monitor the health of Gulf War veterans over time, 

utilizing existing databases to identify other conditions of possible concern. 

This should include regular reports of mortality rates, including deaths due 

to specific conditions, among Gulf War veterans in comparison to 

nondeployed Gulf War era veterans. Gulf War veterans have been 

particularly concerned about possible effects of their wartime service on 
Conclusions 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 104

the health of their families, but clear information has not been available 

concerning the many unanswered questions in this area. Recent studies 

have suggested that children born to Gulf War veterans since the war may 

have higher-than-expected rates of some types of birth defects, although 

serious problems still appear, overall, to be rare. Systematic research is 

also needed to determine whether other family members of Gulf War 

veterans are affected by excess rates of illness, since no research findings in 

this area have yet been reported, including those from a large VA study of 

Gulf War era veterans’ family members. 

 Overall progress in addressing key questions about Gulf War veterans’ 

illnesses has been significantly delayed by the lack of a federal research 

strategy that effectively identifies key objectives and ensures that specific 

studies capable of satisfactorily meeting those objectives are carried out. 

Government-sponsored research on Gulf War veterans’ illnesses has 

historically focused disproportionately on stress as an explanation for these 

conditions. This emphasis has continued in VA’s Gulf War research 

portfolio to the present time, despite the lack of any indication that 

additional research in this area is likely to provide useful insights regarding 

the nature of or treatments for the multisymptom conditions affecting the 

majority of ill veterans. 

 In recent years, DOD has shifted its research emphasis and funding 

away from studies on Gulf War veterans’ illnesses. As a result, overall 

federal funding for this research has declined dramatically, and VA is 

currently the only federal agency funding new studies on these conditions. 

The reduced Gulf War illnesses research effort is of particular concern 

now, just as significant breakthroughs are pointing the way toward new 

research capable of making significant progress. Reducing the federal 

commitment to research on Gulf War veterans’ illnesses also makes little 

sense in light of its immediate relevance to current military deployments 

and domestic chemical defense. 

 

 The Committee applauds the important contributions of federally 

sponsored research studies that have provided important advances in 

understanding Gulf War veterans’ illnesses. However, the federal research 

effort has not succeeded, overall, in answering important questions 

regarding the specific physiological mechanisms, contributing causes, and 

treatments for these conditions and has consequently not made significant 

progress toward improving the health of ill Gulf War veterans. It is 

imperative that VA and other federal agencies not lose sight of this central 

goal, nor of their continued responsibility to address the health 

consequences of service in the Gulf War. 
Acknowledgements 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 105

Acknowledgments This report presents the major findings and recommendations of the 

Research Advisory Committee on Gulf War Veterans’ Illnesses during its 

first two years of deliberations. Committee members express sincere 

gratitude to the many individuals who have assisted in this work. The 

Committee thanks members of the Expert Advisory Panel and other 

scientists for their advice and insights in discussions regarding Gulf War 

veterans’ illnesses and related research. In particular, we are grateful to the 

following individuals who provided presentations at Committee meetings 

during 2002 and 2003: Dr. Maria Araneta, Dr. Carrolee Barlow, Dr. Tom 

Findley, Dr. Rogene Henderson, Dr. Denise Hynes, Dr. Han Kang, Dr. 

Michael Kilpatrick, Dr. Clare Mahan, Ms. Betty Mekdeci, Dr. Eugene 

Oddone, Ms. Susan Perez, Mr. Keith Rhodes, Dr. Antonio Sastre, Dr. 

Robert Sheridan, Dr. Hermona Soreq, Dr. Jennifer Vasterling, Dr. John 

Vogel, Dr. Roberta White, and Dr. Wilkie Wilson. The Committee also 

thanks the following members of the public and representatives of 

government agencies for insights provided during Committee meetings in 

2002 and 2003: Mr. Pat Eddington, Ms. Venus Hammack, Dr. Ronnie 

Horner, Ms. Alison Johnson, Dr. Rich Van Konynenburg, Mr. Kirt Love, 

Dr. Ruth McGill, Ms. Susan Nail, Dr. Meryl Nass, Ms. Denise Nichols, Dr. 

Francis O’Donnell, Dr. Dave Seipel, Dr. Sushil Sharma, Mr. Paul Sullivan, 

and Mr. Scott Walker. We are also grateful to many other individuals who 

have informally provided information and assistance to the Committee 

during this period, particularly Dr. Jeff Levin and Dr. James Moss. 

 The Committee would also like to express its appreciation to Secretary 

of Veterans Affairs Anthony J. Principi for his demonstrated commitment 

to Gulf War veterans in appointing a committee of scientists and veterans 

for the express purpose of taking a fresh look at scientific information 

related to Gulf War veterans’ illnesses and recommending research most 

capable of improving the health of ill veterans. The Committee also thanks 

the following individuals at the Department of Veterans Affairs who have 

provided information and assistance in support of this charge: Dr. Mindy 

Aisen, Dr. Steven Berkowitz, Dr. James Burris, Dr. John Feussner, Ms. 

Preeti Hans, Mr. Roger Kaplan, former Deputy Secretary Leo Mackay, Ms. 

Laura O’Shea, Ms. Janet Payton, Dr. Jonathan Perlin, Mr. Jeffrey Phillips, 

Mr. Phil Riggin, and Dr. Nelda Wray. The Committee particularly 

acknowledges the contributions of Drs. Aisen, Perlin, and Wray in charting 

a new direction in Gulf War illnesses research at VA’s Office of Research 

and Development. We also thank the following individuals at the 

Department of Defense who have provided information and assistance: 

Ms. Ellen Embrey, LTC Karl Friedl, Dr. Stephen Grate, LTC Brian Lukey, 

COL James Romano, and Dr. William Winkenwerder. Finally, the 

Committee gratefully acknowledges the work of those who have served on 

the Committee’s scientific staff: Ms. Amy Chadwick, Ms. Laura Palmer, 

and Dr. Diana Pickett. 

References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 107

References 

1. Abdel-Rahman AA, Abou-Donia MB, El-Masry EM, Shetty AK, Abou-Donia MB. Stress and 

combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce 

neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum. J 

Toxicol Environ Health A. 2004;67:163-192. 

2. Abdel-Rahman AA, Dechkovskaia AM, Goldstein LB, et al. Neurological deficits induced by 

malathion, DEET, and permethrin, alone or in combination in adult rats. J Toxicol Environ Health A. 

2004;67:331-356. 

3. Abdel-Rahman AA, Shetty AK, Abou-Donia MB. Disruption of the blood-brain barrier and neuronal 

cell death in cingulate cortex, dentate gyrus, thalamus, and hyptothalamus in a rat model of Gulf War 

syndrome. Neurobiol Dis. 2002;10:306-326. 

4. Abou-Donia MB, Dechkovskaia AM, Goldstein LB, Abdel-Rahman AA, Bullman SL, Khan WA. Coexposure to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and 

alterations in brain acetylcholinesterase activity. Pharmacol Biochem Behav. 2004;77:253-262. 

5. Abou-Donia MB, Goldstein LB, Dechkovskaia AM, et al. Effects of daily dermal application of DEET 

and permethrin, alone and in combination, on sensorimotor performance, blood-brain barrier, and 

blood-testis barrier in rats. J Toxicol Environ Health A. 2001;62:523-541. 

6. Abou-Donia MB, Goldstein LB, Jones KH, et al. Locomotor and sensorimotor performance deficit in 

rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination. 

Toxicol Sci. 2001;60:305-314. 

7. Abou-Donia MB, Suliman HB, Khan WA, Abdel-Rahman AA. Testicular germ-cell apoptosis in 

stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide 

(DEET), and permethrin. J Toxicol Environ Health A. 2003;66:57-73. 

8. Abou-Donia MB, Wilmarth KR, Abdel-Rahman AA, Jensen KF, Oehme FW, Kurt TL. Increased 

neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos. 

Fundam Appl Toxicol. 1996;34:201-222. 

9. Abou-Donia MB, Wilmarth KR, Jensen KF, Oehme FW, Kurt TL. Neurotoxicity resulting from 

coexposure to pyridostigmine bromide, DEET, and permethrin: implications of Gulf War chemical 

exposures. J Toxicol Environ Health. 1996;48:35-56. 

10. Abu-Qare AW, Abou-Donia MB. Combined exposure to sarin and pyridostigmine bromide increased 

levels of rat urinary 3-nitrotyrosine and 8-hydroxy-2'-deoxyguanosine, biomarkers of oxidative stress. 

Toxicol Lett. 2001;123:51-58. 

11. Abu-Qare AW, Abou-Donia MB. Combined exposure to DEET (N,N-diethyl-m-toluamide) and 

permethrin-induced release of rat brain mitochondrial cytochrome c. J Toxicol Environ Health A. 

2001;63:243-252. 

12. Abu-Qare AW, Suliman HB, Abou-Donia MB. Induction of urinary excretion of 3-nitrotyrosine, a 

marker of oxidative stress, following administration of pyridostigmine bromide, DEET (N,N-diethyl-mtoluamide) and permethrin, alone and in combination in rats. Toxicol Lett. 2001;2001:127-134. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 108

13. Abushaban L, Al-Hay A, Uthama B, Salama A, Selvan J. Impact of the Gulf War on congenital heart 

diseases in Kuwait. Int J Cardiol. 2004;93:157-162. 

14. American Legion. More Birth-Defect Studies Urged by Legion Commander (Press release). Jun 11, 

1997. 

15. Anger WK. Neurobehavioral tests and systems to assess neurotoxic exposures in the workplace and 

community. Occup Environ Med. 2003;60:531-538, 474. 

16. Anger WK, Storzbach D, Binder LM, et al. Neurobehavioral deficits in Persian Gulf veterans: evidence 

from a population-based study. J Int Neuropsychol Soc. 1999;5:203-212. 

17. Araneta MRG, Destiche DA, Schlangen KM, Merz RD, Forrester MB, Gray GC. Birth defects 

prevalence among infants of Persian Gulf War veterans born in Hawaii, 1989-1993. Teratology. 

2000;62:195-204. 

18. Araneta MRG, Kamens DR, Zau AC, et al. Conception and pregnancy during the Persian Gulf War: the 

risk to women veterans. Ann Epidemiol. 2004;14:109-116. 

19. Araneta MRG, Moore CA, Olney RS, et al. Goldenhar syndrome among infants born in military 

hospitals to Gulf War veterans. Teratology. 1997;56:244-251. 

20. Araneta MRG, Schlangen KM, Edmonds LD, et al. Prevalence of birth defects among infants of Gulf 

War veterans in Arkansas, Arizona, California, Georgia, Hawaii, and Iowa, 1989-1993. Birth Defects 

Res Part A Clin Mol Teratol. 2003;67:246-260. 

21. Armon C. Amyotrophic Lateral Sclerosis. In: Nelson LM, Tanner CM, Van Den Eeden SK, McGuire 

V, eds. Neuroepidemiology: From Principles to Practice. New York, NY: Oxford University Press; 

2004. 

22. Asa PB, Cao Y, Garry RF. Antibodies to squalene in Gulf War syndrome. Exp Mol Pathol. 2000;68:55-

64. 

23. Asa PB, Wilson RB, Garry RF. Antibodies to squalene in recipients of anthrax vaccine. Exp Mol 

Pathol. 2002;73:19-27. 

24. Australian Commonwealth Department of Veterans' Affairs. Australian Gulf War Veterans' Health 

Study Report. ACDVA. 2003. Available at: 

http://www.dva.gov.au/media/publicat/2003/gulfwarhs/pdf_table_of_contents.htm. 

25. Axelrod BN, Milner IB. Neuropsychological findings in a sample of Operation Desert Storm veterans. 

J Neuropsychiatry Clin Neurosci. 1997;9:23-28. 

26. Baynes RE, Halling KB, Riviere JE. The influence of diethyl-m-toluamide (DEET) on the percutaneous 

absorption of permethrin and carbaryl. Toxicol Appl Pharmacol. 1997;144:332-339. 

27. Baynes RE, Monteiro-Riviere NA, Riviere JE. Pyridostigmine bromide modulates the dermal 

disposition of [14C] permethrin. Toxicol Appl Pharmacol. 2002;181:164-173. 

28. Beekman R, Kuks JB, Oosterhuis HJ. Myasthenia gravis: diagnosis and follow-up of 100 consecutive 

patients. J Neurol. 1997;244:112-118. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 109

29. Bell NS, Amoroso PJ, Wegman DH, Seiner L. Proposed explanations for excess injury among veterans 

of the Persian Gulf War and a call for greater attention from policymakers and researchers. Inj Prev. 

2001;7:4-9. 

30. Bernstein D, Kelley T. The Gulf War comes home: sickness spreads, but the Pentagon denies all. The 

Progressive. Mar 1, 1995. 

31. Bernstein J, Perez A, Floyd R, Bernstein IL. Is burning semen syndrome a variant form of seminal 

plasma hypersensitivity? Obstet Gynecol. 2003;101:93-102. 

32. Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician-administered PTSD scale. J 

Trauma Stress. 1995;8:75-90. 

33. Blandini F, Nappi G, Tassorelli C, Martignoni E. Functional changes of the basal ganglia circuitry in 

Parkinson's disease. Prog Neurobiol. 2000;62:63-88. 

34. Blood CG, Aboumrad TL. A comparison of postdeployment hospitalization incidence between active 

duty Vietnam and Persian Gulf War Veterans. Mil Med. 2001;166:648-655. 

35. Borland RG, Brennan DH, Nicholson AN, Smith PA. Studies on the possible central and peripheral 

effects in man of a cholinesterase inhibitor (pyridostigmine). Hum Toxicol. 1985;4:293-300. 

36. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension 

and the chronic fatigue syndrome. JAMA. 1995;274:961-967. 

37. Bourdette DN, McCauley LA, Barkhuizen A, et al. Symptom factor analysis, clinical findings, and 

functional status in a population-based case control study of Gulf War unexplained illness. J Occup 

Environ Med. 2001;43:1026-1040. 

38. Brenner T, Hamra-Amitay Y, Evron T, Boneva N, Seidman S, Soreq H. The role of readthrough 

acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J. 2003;17:214-222. 

39. Briggs J, Miller K, Hudson D. The Tiny Victims of Desert Storm. Life. Nov 1995. 

40. Brooks BR. Risk factors in the early diagnosis of ALS: North American epidemiological studies. ALS 

CARE Study Group. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:S19-S26. 

41. Buchholz BA, Pawley N, Vogel J, Mauthe R. Pyrethroid decrease in central nervous system from nerve 

agent pretreatment. J Appl Toxicol. 1997;17:231-234. 

42. Buck OD, Walker JI. Posttraumatic stress disorder in Vietnam veterans: a review. South Med J. 

1982;75:704-706. 

43. Bunegin L, Mitzel HC, Miller CS, Gelineau JF, Tolstykh GP. Cognitive performance and 

cerebrohemodynamics associated with the Persian Gulf syndrome. Toxicol Ind Health. 2001;17:128-

137. 

44. Burchfiel JL, Duffy FH, Van Sim M. Persistent effects of sarin and dieldrin upon the primate 

electroencephalogram. Toxicol Appl Pharmacol. 1976;35:365-379. 

45. Caldwell JA, Jr. A brief survey of chemical defense, crew rest, and heat stress/physical training issues 

related to Operation Desert Storm. Mil Med. 1992;157:275-281. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 110

46. Campion EW. Disease and suspicion after the Persian Gulf War. N Engl J Med. 1996;335:1525-1527. 

47. Casacalenda N, Perry JC, Looper K. Remission in major depressive disorder: a comparison of 

pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry. 2002;159:1354-1360. 

48. Cecchine G, Golomb BA, Hilborne LH, Spektor DM, Anthony CR. A Review of Scientific Literature As 

It Pertains to Gulf War Illnesses - Volume 8: Pesticides. Washington, DC: National Defense Research 

Institute (RAND); 2000. 

49. Chaney LA, Rockhold RW, Mozingo JR, Hume AS. Potentiation of pyridostigmine bromide toxicity in 

mice by selected adrenergic agents and caffeine. Vet Hum Toxicol. 1997;39:214-219. 

50. Chaney LA, Wineman RW, Rockhold RW, Hume AS. Acute effects of an insect repellent, N,Ndiethyl-m-toluamide, on cholinesterase inhibition induced by pyridostigmine bromide in rats. Toxicol 

Appl Pharmacol. 2000;165:107-114. 

51. Cherry N, Creed F, Silman A, et al. Health and exposures of United Kingdom Gulf War veterans. Part 

I: The pattern and extent of ill health. Occup Environ Med. 2001;58:291-298. 

52. Cherry N, Creed F, Silman A, et al. Health and exposures of United Kingdom Gulf War veterans. Part 

II: The relation of health to exposure. Occup Environ Med. 2001;58:299-306. 

53. Chia SE, Shi LM. Review of recent epidemiological studies on paternal occupations and birth defects. 

Occup Environ Med. 2002;59:149-155. 

54. Clauw DJ, Engel CC, Jr, Aronowitz R, et al. Unexplained symptoms after terrorism and war: an expert 

consensus statement. J Occup Environ Med. 2003;45:1040-1048. 

55. Cohen O, Erb C, Ginzberg D, et al. Neuronal overexpression of "read through" acetylcholinesterase is 

associated with antisense-suppressible behavioral impairments. Mol Psychiatry. 2002;7:874-885. 

56. Collins JF, Donta ST, Engel CC, Jr, et al. The antibiotic treatment trial of Gulf War veterans' illnesses: 

issues, design, screening, and baseline characteristics. Control Clin Trials. 2002;23:333-353. 

57. Conn CA, Dokladny K, Menache MG, et al. Effects of sarin on temperature and activity of rats as 

model for Gulf War syndrome neuroregulatory functions. Toxicol Appl Pharmacol. 2002;184:77-81. 

58. Cook MR, Graham C, Sastre A, Gerkovich MM. Physiological and performance effects of 

pyridostigmine bromide in healthy volunteers: a dose-response study. Psychopharmacology (Berl). 

2002;162:186-192. 

59. Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. The risk of birth defects among 

children of Persian Gulf War veterans. N Engl J Med. 1997;336:1650-1656. 

60. Cowan DN, Gray GC, DeFraites RF. Counterpoint: responding to inadequate critique of birth defects 

paper. Am J Epidemiol. 1998;148:326-327. 

61. Cowan DN, Lange JL, Heller J, Kirkpatrick J, DeBakey S. A case-control study of asthma among U.S. 

Army Gulf War veterans and modeled exposure to oil well fire smoke. Mil Med. 2002;167:777-782. 

62. David AS, Farrin L, Hull L, Unwin C, Wessely S, Wykes T. Cognitive functioning and disturbances of 

mood in UK veterans of the Persian Gulf war: a comparative study. Psychol Med. 2002;32:1357-1370. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 111

63. Davies DR, Ahmed GM, Freer T. Chronic organophosphate induced neuropsychiatric disorder 

(COPIND): results of two postal questionnaire surveys. J Nutr Environ Med. 1999;9:123-134. 

64. Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CE. The effect of the human 

serum paraoxonase polymorphism is reversed with diazoxon, soman, and sarin. Nat Genet. 

1996;14:334-336. 

65. Davis DL, Friedler G, Mattison D, Morris R. Male-mediated teratogenesis and other reproductive 

effects: biologic and epidemiologic findings and a plea for clinical research. Reprod Toxicol. 

1992;6:289-292. 

66. Davis RG. Decisive Force: Strategic Bombing in the Gulf War: U.S. Air Force; 1996. 

67. Davis SD, Kator SF, Wonnett JA, Pappas BL, Sall JL. Neurally mediated hypotension in fatigued Gulf 

War veterans: a preliminary report. Am J Med Sci. 2000;319:89-95. 

68. Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy for chronic fatigue syndrome: a 

randomized controlled trial. Am J Psychiatry. 1997;154:408-414. 

69. DeFraites RF, Wanat ER, II, Norwood AE, Williams S, Cowan D, Callahan T. Investigation of a 

Suspected Outbreak of an Unknown Disease Among Veterans of Operation Desert Shield/Storm - 123rd 

Army Reserve Command, Fort Benjamin Harrison, Indiana. Washington, DC: Water Reed Army 

Institute of Research; Apr, 1992. 

70. del Aguila MA, Longstreth WT, Jr, McGuire V, Koepsell TD, van Belle G. Prognosis in amyotrophic 

lateral sclerosis: a population-based study. Neurology. 2003;60:813-819. 

71. Demers PA, Heyer NJ, Rosenstock L. Mortality among firefighters from three northwestern United 

States cities. Br J Ind Med. 1992;49:664-670. 

72. Democratic Staff of the US House of Representatives Committee on Veterans Affairs. VA Data Shows 

Increased Percentage of Undiagnosed Illness and Total Disability Among Certain Groups of Veterans 

Who Served in Southwest Asia Between August 2, 1990 and July 31, 1991. Democratic Staff Follow-up 

Report, October 25, 1999. Washington, DC: US House of Representatives; 1999. 

73. Deployment Health Working Group Subcommittee. Annual Report to Congress: Federally Sponsored 

Research on Gulf War Veterans' Illnesses for 2002. Washington, DC: U.S. Department of Veterans 

Affairs; 2004. 

74. Di Monte DA, Lavasani M, Manning-Bog AB. Environmental factors in Parkinsons' disease. 

Neurotoxicology. 2002;23:487-502. 

75. Donta ST, Clauw DJ, Engel CC, Jr, et al. Cognitive behavioral therapy and aerobic exercise for Gulf 

War veterans' illnesses: a randomized controlled trial. JAMA. 2003;289:1396-1404. 

76. Donta ST, Engel CC, Jr, Collins JF, et al. Benefits and harms of doxycycline treatment for Gulf War 

veterans illnesses: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2004;141:85-

94. 

77. Doyle P, Maconochie N, Davies G, et al. Miscarriage, stillbirth and congenital malformation in the 

offspring of UK veterans of the first Gulf War. Int J Epidemiol. 2004;33:74-86. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 112

78. Doyle P, Roman E, Maconochie N. Birth defects among children of Persian Gulf War veterans. N Engl 

J Med. 1997;337:1175-1176. 

79. Eddington PG. Gassed in the Gulf: The Inside Story of the Pentagon-CIA Cover-up of Gulf War 

Syndrome. Washington, DC: Insignia Publishing Company; 1997. 

80. Fiedler N. Neuropsychological approaches for the detection and evaluation of toxic symptoms. Environ 

Health Perspect. 1996;104:239-245. 

81. Fontoura-da-Silva SE, Chautard-Freire-Maia EA. Butyrylcholinesterase variants (BCHE and CHE2 

Loci) associated with erythrocyte acetylcholinesterease inhibition in farmers exposed to pesticides. 

Hum Hered. 1996;46:142-147. 

82. France D. The Families Who Are Dying for Our Country. Redbook. Sep 1994:117. 

83. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? 

Am J Med. 1997;102:357-364. 

84. Fricker RD, Jr. Pesticide Use During the Gulf War: A Survey of Gulf War Veterans. Washington, DC: 

National Defense Research Institute (RAND); 2000. 

85. Fukuda K, Nisenbaum R, Stewart GS, et al. Chronic multisymptom illness affecting Air Force veterans 

of the Gulf War. JAMA. 1998;280:981-988. 

86. Gabriel R, Bolton JPG, Bale AJ, Lee HA. Gulf war syndrome may be post-conflict dysfunction. BMJ. 

2002;324:914. 

87. Garrett CM, Paton SJ, Cool DR, Grubbs RD, Price WR, Morris M. Gene expression in mouse brain 

following subcutaneous injections of sarin. Presentation at: Annual Conference of the Society of 

Toxicology; Mar 25, 2004; Baltimore, MD. 

88. Gawron VJ, Schiflett SG, Miller JC, Slater T, Ball JF. Effects of pyridostigmine bromide on in-flight 

aircrew performance. Hum Factors. 1990;32:79-94. 

89. Given C, Given B, Rahbar M, et al. Effect of cognitive behavioral intervention on reducing symptom 

severity during chemotherapy. J Clin Oncol. 2004;22:507-516. 

90. Glikson M, Achiron A, Ram Z, et al. The influence of pyridostigmine administration on human 

neuromuscular functions - studies in healthy human subjects. Fundam Appl Toxicol. 1991;16:288-298. 

91. Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G. Dysautonomias: clinical disorders of the 

autonomic nervous system. Ann Intern Med. 2002;137:753-763. 

92. Goldstein G, Beers SR, Morrow LA, Shemansky WJ, Steinhauer SR. A preliminary neuropsychological 

study of Persian Gulf veterans. J Int Neuropsychol Soc. 1996;2:368-371. 

93. Golomb BA. A Review of the Scientific Literature As It Pertains to Gulf War Illnesses - Volume 2: 

Pyridostigmine Bromide. Washington, DC: National Defense Research Institute (RAND); 1999. 

94. Goss Gilroy Inc. Health study of Canadian forces personnel involved in the 1991 conflict in the Persian 

Gulf: Volume I. Gulf War Illness Advisory Committee - Department of National Defence. Apr 20, 1998. 

Available at: http://www.forces.gc.ca/site/reports/Health/vol1_TOC_e.htm. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 113

95. Gowans SE, deHueck A, Voss S, Silaj A, Abbey SE, Reynolds WJ. Effect of a randomized, controlled 

trial of exercise on mood and physical function in individuals with fibromyalgia. Arthritis Rheum. 

2001;45:519-529. 

96. Gray GC, Coate BD, Anderson CM, et al. The postwar hospitalization experience of U.S. veterans of 

the Persian Gulf War. N Engl J Med. 1996;335:1505-1513. 

97. Gray GC, Kaiser KS, Hawksworth AW, Hall FW, Barrett-Connor E. Increased postwar symptoms and 

psychological morbidity among U.S. Navy Gulf War veterans. Am J Trop Med Hyg. 1999;60:758-766. 

98. Gray GC, Reed RJ, Kaiser KS, Smith TC, Gastanaga VM. Self-reported symptoms and medical 

conditions among 11,868 Gulf War-era veterans: The Seabee health study. Am J Epidemiol. 

2002;155:1033-1044. 

99. Gray GC, Smith TC, Kang HK, Knoke JD. Are Gulf War veterans suffering war-related illnesses? 

Federal and civilian hospitalizations examined, June 1991 to December 1994. Am J Epidemiol. 

2000;151:63-71. 

100. Gray GC, Smith TC, Knoke JD, Heller JM. The postwar hospitalization experience of Gulf War 

veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq. Am J Epidemiol. 

1999;150:532-540. 

101. Haley RW. Is Gulf War syndrome due to stress? The evidence reexamined. Am J Epidemiol. 

1997;146:695-703. 

102. Haley RW. Point: bias from the "healthy-warrior effect" and unequal follow-up in three government 

studies of health effects of the Gulf War. Am J Epidemiol. 1998;148:315-323. 

103. Haley RW. Excess incidence of ALS in young Gulf War veterans. Neurology. 2003;61:750-756. 

104. Haley RW, Billecke S, La Du BN. Association of low PON1 type Q (type A) arylesterase activity with 

neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol. 1999;157:227-233. 

105. Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. Effect of basal 

ganglia injury on central dopamine activity in Gulf War syndrome: correlation of proton magnetic 

resonance spectroscopy and plasma homovanillic acid levels. Arch Neurol. 2000;57:1280-1285. 

106. Haley RW, Hom J, Roland PS, et al. Evaluation of neurologic function in Gulf War veterans. A blinded 

case-control study. JAMA. 1997;277:223-230. 

107. Haley RW, Kurt TL. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A 

cross-sectional epidemiologic study. JAMA. 1997;277:231-237. 

108. Haley RW, Kurt TL, Hom J. Is there a Gulf War syndrome? Searching for syndromes by factor 

analysis of symptoms. JAMA. 1997;277:215-222. 

109. Haley RW, Marshall WW, McDonald GG, Daugherty MA, Petty F, Fleckenstein JL. Brain 

abnormalities in Gulf War syndrome: evaluation with 1H MR spectroscopy. Radiology. 2000;215:807-

817. 

110. Haley RW, Vongpatanasin W, Wolfe GI, et al. Blunted circadian variation in autonomic regulation of 

sinus node function in veterans with Gulf War syndrome. Am J Med. 2004 [In press]. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 114

111. Hamilton KE, Dobson KS. Cognitive therapy of depression: pretreatment patient predictors of outcome. 

Clin Psychol Rev. 2002;22:875-893. 

112. Hatch MC. Health symptoms in Persian Gulf veterans: where do we go from here? Am J Ind Med. 

1998;33:103. 

113. Henderson RF, Barr EB, Blackwell WB, et al. Response of rats to low levels of sarin. Toxicol Appl 

Pharmacol. 2002;184:67-76. 

114. Hersh SM. Against All Enemies: Gulf War Syndrome - The War Between America's Ailing Veterans 

and Their Government. New York, NY: Ballantine Publishing; 1998. 

115. Hierholzer R, Munson J, Peabody C, Rosenberg J. Clinical presentation of PTSD in World War II 

combat veterans. Hosp Community Psychiatry. 1992;43:816-820. 

116. Hom J, Haley RW, Kurt TL. Neuropsychological correlates of Gulf War syndrome. Arch Clin 

Neuropsychol. 1997;12:531-544. 

117. Horner RD, Kamins KG, Feussner JR, et al. Occurrence of amyotrophic lateral sclerosis among Gulf 

War veterans. Neurology. 2003;61:742-749. 

118. Hotopf M. Treating Gulf War veterans' illnesses: are more focused studies needed? JAMA. 

2003;289:1436-1437. 

119. Hotopf M, Chidgey J, Addington-Hall J, Ly KL. Depression in advanced disease: a systematic review 

Part 1. Prevalence and case finding. Palliat Med. 2002;16:81-97. 

120. Hotopf M, David AS, Hull L, Ismail K, Unwin C, Wessely S. Role of vaccinations as risk factors for ill 

health in veterans of the Gulf War: cross sectional study. BMJ. 2000;320:1363-1367. 

121. Hotopf M, David AS, Hull L, Ismail K, Unwin C, Wessely S. The health effects of peacekeeping 

(Bosnia, 1992-1996): a cross-sectional study - comparison with nondeployed military personnel. Mil 

Med. 2003;168:408-413. 

122. Hotopf M, David AS, Hull L, Nikalaou V, Unwin C, Wessely S. Gulf war illness - better, worse, or just 

the same? A cohort study. BMJ. 2003;327:1370-1374. 

123. Hotopf M, Mackness MI, Nikalaou V, et al. Paraoxonase in Persian Gulf War veterans. J Occup 

Environ Med. 2003;45:668-675. 

124. Hoy JB, Cornell JA, Karlix JL, Schmidt CJ, Tebbett IR, van Haaren F. Interactions of pyridostigmine 

bromide, DEET and permethrin alter locomotor behavior of rats. Vet Hum Toxicol. 2000;42:65-71. 

125. Hoy JB, Cornell JA, Karlix JL, Tebbett IR, van Haaren F. Repeated coadministration of pyridostigmine 

bromide, DEET, and permethrin alter locomotor behavior of rats. Vet Hum Toxicol. 2000;42:72-76. 

126. Hulet SW, McDonough JH, Shih T-M. The dose-response effects of repeated subacute sarin exposure 

on guinea pigs. Pharmacol Biochem Behav. 2002;72:835-845. 

127. Husain K, Somani S. Delayed toxic effects of nerve gas sarin and pyridostigmine under physical stress 

in mice. Journal of Burns & Surgical Wound Care (online journal). Jan 18, 2003. Available at: 

http://www.journalofburns.com/read.php?articlerow=39. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 115

128. Husain K, Vijayaraghavan R, Pant SC, Raza SK, Pandey KS. Delayed neurotoxic effect of sarin in 

mice after repeated inhalation exposure. J Appl Toxicol. 1993;13:143-145. 

129. Hyams KC, Wignall FS, Roswell R. War syndromes and their evaluation: from the U .S. Civil War to 

the Persian Gulf War. Ann Intern Med. 1996;125:398-405. 

130. Institute of Medicine. Health Consequences of Service During the Persian Gulf War: Initial Findings 

and Recommendations for Immediate Action. Washington, DC: National Academy Press; 1995. 

131. Institute of Medicine. Health Consequences of Service During the Persian Gulf War: 

Recommendations for Research and Information Systems. Washington, DC: National Academy Press; 

1996. 

132. Institute of Medicine. Interactions of Drugs, Biologics, and Chemical in U.S. Military Forces. 

Washington, DC: National Academy Press; 1996. 

133. Institute of Medicine. Veterans and Agent Orange - Update 1996. Washington, DC: National Academy 

Press; 1996. 

134. Institute of Medicine. Gulf War and Health: Volume 1 - Depleted Uranium, Pyridostigmine Bromide, 

Sarin, Vaccines. Washington, DC: National Academy Press; 2000. 

135. Institute of Medicine. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. 

Washington, DC: National Academy Press; 2000. 

136. Institute of Medicine. Gulf War Veterans - Treating Symptoms and Syndromes. Washington, DC: 

National Academy Press; 2001. 

137. Institute of Medicine. Gulf War and Health: Volume 2 - Insecticides and Solvents. Washington, DC: 

National Acadmey Press; 2003. 

138. Iowa Persian Gulf Study Group. Self-reported illness and health status among Gulf War veterans: a 

population-based study. JAMA. 1997;277:238-245. 

139. Ishoy T, Suadicani P, Guldager B, Appleyard M, Hein HO, Gyntelberg F. State of health after 

deployment in the Persian Gulf: The Danish Gulf War Study. Dan Med Bull. 1999;46:416-419. 

140. Ismail K, Everitt B, Blatchley N, et al. Is there a Gulf War syndrome? Lancet. 1999;353:179-182. 

141. Ismail K, Kent K, Brugha T, et al. The mental health of UK Gulf war veterans: phase 2 of a two-phase 

cohort study. BMJ. 2002;325:576-579. 

142. Izraeli S, Avgar D, Almog S, et al. The effect of repeated doses of 30 mg pyridostigmine bromide on 

pilot performance in an A-4 flight simulator. Aviat Space Environ Med. 1990;61:430-432. 

143. Jacobson RM. Vaccine safety. Immunol Allergy Clin North Am. 2003;23:589-603. 

144. Jamal GA, Hansen S, Apartopoulos F, Peden A. The "Gulf War syndrome". Is there evidence of 

dysfunction in the nervous system? J Neurol Neurosurg Psychiatry. 1996;60:449-451. 

145. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. 

Arch Intern Med. 1999;159:2129-2137. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 116

146. Johnson A. Gulf War Syndrome: Legacy of a Perfect War. Brunswick, ME: MCS Information 

Exchange; 2001. 

147. Johnson MK. The delayed neuropathy caused by some organophosphorus esters: mechanism and 

challenge. CRC Crit Rev Toxicol. 1975;3:289-316. 

148. Jones E, Hodgins-Vermaas R, McCartney H, et al. Post-combat syndromes from the Boer war to the 

Gulf war: a cluster analysis of their nature and attribution. BMJ. 2002;324:321-324. 

149. Jones KH, Dechkovskaia AM, Herrick EA, Abdel-Rahman AA, Khan WA, Abou-Donia MB. 

Subchronic effects following a single sarin experience exposure on blood-brain and blood-testes barrier 

permeability, acetylcholinesterase, and acetylcholine receptors in the central nervous system of rat: a 

dose-response study. J Toxicol Environ Health A. 2000;61:695-707. 

150. Joseph SC. A comprehensive clincial evaluation of 20,000 Persian Gulf War veterans. Mil Med. 

1997;162:149-155. 

151. Kalra R, Singh SP, Razani-Boroujerdi S, et al. Subclinical doses of the nerve gas sarin impair T cell 

responses through the autonomic nervous system. Toxicol Appl Pharmacol. 2002;184:82-87. 

152. Kalter H. Teratology in the 20th century: environmental causes of congenital malformations in humans 

and how they were established. Neurotoxicol Teratol. 2003;25:131-282. 

153. Kang HK, Bullman TA. Mortality among U.S. veterans of the Persian Gulf War. N Engl J Med. 

1996;335:1498-1504. 

154. Kang HK, Bullman TA. Mortality among US veterans of the Persian Gulf War: 7-year follow-up. Am J 

Epidemiol. 2001;154:399-405. 

155. Kang HK, Magee CA, Mahan CM, et al. Pregnancy outcomes among U.S. Gulf War veterans: a 

population-based survey of 30,000 veterans. Ann Epidemiol. 2001;11:504-511. 

156. Kang HK, Mahan CM. A review of medical records for 206 children with birth defects reported by 

Gulf War era veteran parents. Presentation at: Meeting of the Research Advisory Committee on Gulf 

War Veterans' Illnesses; Oct 27, 2003; Washington, DC. 

157. Kang HK, Mahan CM, Lee KY, Magee CA. Women Vietnam Veterans Reproductive Outcomes Health 

Study. Washington, DC: Department of Veterans Affairs; Oct 1998. 

158. Kang HK, Mahan CM, Lee KY, Magee CA, Murphy FM. Illnesses among United States veterans of the 

Gulf War: a population-based survey of 30,000 veterans. J Occup Environ Med. 2000;42:491-501. 

159. Kang HK, Mahan CM, Lee KY, et al. Evidence for a deployment-related Gulf War syndrome by factor 

analysis. Arch Environ Health. 2002;57:61-68. 

160. Kang HK, Natelson BH, Mahan CM, Lee KY, Murphy FM. Post-traumatic stress disorder and chronic 

fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. 

Am J Epidemiol. 2003;157:141-148. 

161. Kassa J, Koupilova M, Vachek J. Long-term effects of low-level sarin inhalation exposure on the 

spatial memory of rats in a T-maze. Acta Medica (Hradec Kralove). 2001;44:93-96. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 117

162. Kassa J, Krocova Z, Sevelova L, Sheshko V, Kasalova I, Neubauerova V. Low-level sarin-induced 

alteration of immune system reaction in inbred BALB/c mice. Toxicology. 2003;187:195-203. 

163. Kassa J, Krocova Z, Sevelova L, Sheshko V, Kasalova I, Neubauerova V. The influence of single or 

repeated low-level sarin exposure on immune functions of inbred BALB/c mice. Basic Clin Pharmacol 

Toxicol. 2004;94:139-143. 

164. Kassa J, Krocova Z, Sevelova L, Sheshko V, Pavlis O. The influence of low-level sarin inhalation 

exposure on the host resistance and immune reaction of inbred BALB/c mice after their infection with 

Francisella tularensis LVS. Cent Eur J Public Health. 2004;12:S36-S38. 

165. Kassa J, Krocova Z, Vachek J. Long-term alteration of immune functions following low level exposure 

to sarin in rats. Acta Medica (Hradec Kralove). 2000;43:91-94. 

166. Kassa J, Pecka M, Tichy M, et al. Toxic effects of sarin in rats at three months following single or 

repeated low-level inhalation exposure. Pharmacol Toxicol. 2001;88:209-212. 

167. Kassa J, Skopec F, Vachek J. The long-term changes in liver DNA and total protein contents following 

low level sarin exposure in rats. Acta Medica (Hradec Kralove). 2000;43:19-22. 

168. Kaufer D, Friedman A, Seidman S, Soreq H. Actue stress facilitates long-lasting changes in cholinergic 

gene expression. Nature. 1998;393:373-377. 

169. Kaufer D, Friedman A, Seidman S, Soreq H. Anticholinesterases induce multigenic transcriptional 

feedback response suppressing cholinergic neurotransmission. Chem Biol Interact. 1999;119-120:349-

360. 

170. Kazis LE, Miller DR, Skinner KM, et al. Patient-reported measures of health: The Veterans Health 

Study. J Ambulatory Care Manage. 2004;27:70-83. 

171. Keeler JR, Hurst CG, Dunn MG. Pyridostigmine used as a nerve agent pretreatment under wartime 

conditions. JAMA. 1991;266:693-695. 

172. Kemp BJ, Kahan JS, Krause JS, Adkins RH, Nava G. Treatment of major depression in individuals 

with spinal cord injury. J Spinal Cord Med. 2004;27:22-28. 

173. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the 

National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048-1060. 

174. Kilpatrick M. Medical Research in Department of Defense. Presentation at: Meeting of the Research 

Advisory Committee on Gulf War Veterans' Illnesses; Oct 28, 2003; Washington, DC. 

175. Kimerling R, Clum GA, Wolfe J. Relationships among trauma exposure, chronic posttraumatic stress 

disorder symptoms, and self-reported health in women: replication and extension. J Trauma Stress. 

2000;13:115-128. 

176. Knoke JD, Gray GC. Hospitalizations for unexplained illnesses among U.S. veterans of the Persian 

Gulf War. Emerg Infect Dis. 1998;4:211-219. 

177. Kondo I, Yamamoto M. Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to 

Parkinson's disease. Brain Res. 1998;806:271-273. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 118

178. Kroenke K, Price RK. Symptoms in the community. Prevalence, classification, and psychiatric 

comorbidiy. Arch Intern Med. 1993;153:2474-2480. 

179. Landrigan PJ. Illness in Gulf War veterans. Causes and consequences. JAMA. 1997;277:259-261. 

180. Lange G, Tiersky LA, DeLuca J, et al. Psychiatric diagnoses in Gulf War veterans with fatiguing 

illness. Psychiatry Res. 1999;89:39-48. 

181. Lange JL, Schwartz DA, Doebbeling BN, Heller JM, Thorne PS. Exposures to the Kuwait oil fires and 

their association with asthma and bronchitis among Gulf War veterans. Environ Health Perspect. 

2002;110:1141-1146. 

182. Langley RJ, Kalra R, Mishra NC, Sopori ML. Central but not the peripheral action of cholinergic 

compounds suppresses the immune system. Neuroimmunol. 2004;148:140-145. 

183. Lauterbach EC, Cummings JL, Duffy J, et al. Neuropsychiatric correlates and treatment of 

lenticulostriatal diseases: a review of the literature and overview of research opportunities in 

Huntington's, Wilson's, and Fahr's diseases. A report of the ANPA Committee on Research. American 

Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 1998;10:249-266. 

184. Levine J. Gulf War vets accuse Pentagon of chemical weapons cover-up. CNN Health. Sep 19, 1996. 

Available at: http://www.cnn.com/HEALTH/9609/20/nfm/gulf.war/. 

185. Lindem K, Heeren T, White RF, et al. Neuropsychological performance in Gulf War era veterans: 

traumatic stress symptomatology and exposure to chemical-biological warfare agents. J Psychopathol 

Behav Assess. 2003;25:105-119. 

186. Lo SC, Tsai S, Benish JR, Shih JW, Wear DJ, Wong DM. Enhancement of HIV-1 cytocidal effects in 

CD4+ lymphocytes by the AIDS-associated mycoplasma. Science. 1991;251:1074-1076. 

187. Lockridge O. Genetic variants of human serum cholinesterase influence metabolism of the muscle 

relaxant succinylcholine. Pharmacol Ther. 1990;47:35-60. 

188. Lockridge O. Project Summary: Butyrylcholinesterase genetic variants in persons with Gulf War 

illness. 1999. Available at: http://www.gulflink.osd.mil/medsearch/GeneticStudies/DoD60.shtml. 

189. Lockridge O, Masson P. Pesticides and susceptible populations: people with butyrylcholinesterase 

genetic variants may be at risk. Neurotoxicology. 2000;21:113-126. 

190. Loewenstein-Lichtenstein Y, Schwarz M, Glick D, Norgaard-Pedersen B, Zakut H, Soreq H. Genetic 

predisposition to adverse consequences of anti-cholinesterases in 'atypical' BCHE carriers. Nat Med. 

1995;1:1082-1085. 

191. Macfarlane GJ, Biggs A-M, Maconochie N, Hotopf M, Doyle P, Lunt M. Incidence of cancer among 

UK Gulf War veterans: cohort study. BMJ. 2003;327:1373-1377. 

192. Macfarlane GJ, Thomas E, Cherry N. Mortality among UK Gulf War veterans. Lancet. 2000;356:17-

21. 

193. Mackness B, Durrington PN, Mackness MI. Low paraoxonase in Persian Gulf War veterans selfreporting Gulf War syndrome. Biochem Biophys Res Commun. 2000;276:729-733. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 119

194. Maconochie N, Doyle P, Davies G, et al. The study of reproductive outcome and the health of offspring 

of UK veterans of the Gulf war: methods and description of the study population. BMC Public Health. 

2003;3:4. 

195. Mahan CM, Kang HK, Dalager NA, Heller JM. Anthrax vaccination and self-reported symptoms, 

functional status, and medical conditions in the National Health Survey of Gulf War Era Veterans and 

Their Families. Ann Epidemiol. 2004;14:81-88. 

196. Makhseed M, el-Tomi N, Moussa MA, Musini VM. Post-war changes in the outcome of pregnancy in 

Maternity Hospital, Kuwait. Med Confl Surviv. 1996;12:154-167. 

197. Makhseed M, Musini VM, Hassan NA, Saker E. Post-invasion change in the trend of complications and 

outcome of pregnancy in Maternity Hospital Kuwait from 1981 to 1995. Med Confl Surviv. 

1999;15:161-170. 

198. Marshall F, Gass A. Gulf War diseases: a critical review of 400 examinations. Presentation at: 

Conference on Federally Sponsored Gulf War Veterans' Illnesses Research; June 1998; Arlington, VA. 

199. Marshall GM, Davis LM, Sherbourne CD. A Review of the Scientific Literature As It Pertains to Gulf 

War Illnesses - Volume 4: Stress. Washington, DC: National Defense Research Institute (RAND); 

1999. 

200. McCain WC, Lee R, Johnson MS, et al. Acute oral toxicity study of pyridostigmine bromide, 

permethrin, and DEET in the laboratory rat. J Toxicol Environ Health. 1997;50:113-124. 

201. McGregor BA, Antoni MH, Boyers A, Alferi SM, Blomberg BB, Carver CS. Cognitive-behavioral 

stress management increases benefit finding and immune function among women with early-stage 

breast cancer. J Psychosom Res. 2004;56:1-8. 

202. McGuire V, Longstreth WT, Jr, Koepsell TD, van Belle G. Incidence of amyotrophic lateral sclerosis in 

three counties in western Washington state. Neurology. 1996;47:571-573. 

203. McGuire V, Longstreth WT, Jr, Nelson LM, et al. Occupational exposures and amyotrophic lateral 

sclerosis. A population-based case-control study. Am J Epidemiol. 1997;145:1076-1088. 

204. Menon PM, Nasrallah HA, Reeves RR, Ali JA. Hippocampal dysfunction in Gulf War syndrome. A 

proton MR spectroscopy study. Brain Res. 2004;1009:189-194. 

205. Meyerhoff DJ, Lindgren J, Hardin D, Griffis JM, Weiner MW. Reduced N-acetylaspartate in the right 

basal ganglia of ill Gulf War veterans by magnetic resonance spectroscopy. Proceedings of the 

International Society of Magnetic Resonance Medicine. Vol 9; 2001:994. 

206. Milner BI, Kozol R, Khuri S, Hur Q, Fligiel SEG. Gallbladder disease in Gulf War veterans. 

Presentation at: Conference on Federally Sponsored Gulf War Veterans' Illnesses Research; Jun 17-19, 

1998; Washington, DC. 

207. Milner IB, Axelrod BN, Pasquantonio J, Sillanpaa M. Is there a Gulf War syndrome? JAMA. 

1994;271:661. 

208. Morita H, Yanagisawa N, Nakajima T, et al. Sarin poisoning in Matsumoto, Japan. Lancet. 

1995;346:290-293. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 120

209. MSVETS: Veterans with Multiple Sclerosis. Online Discussion Group. 2004. Available at: 

http://healthgroups.yahoo.com/group/MSVETS/. 

210. Murata K, Araki S, Yokoyama K, et al. Asymptomatic sequelae to actue sarin poisoning in the central 

and autonomic nervous system 6 months after the Tokyo subway attack. J Neurol. 1997;244:601-606. 

211. Nakajima T, Ohta S, Fukushima Y, Yanagisawa N. Sequelae of sarin toxicity at one and three years 

after exposure in Matsumoto, Japan. J Epidemiol. 1999;9:337-343. 

212. Nakajima T, Sato S, Morita H, Yanagisawa N. Sarin poisoning of a rescue team in the Matsumoto sarin 

incident in Japan. Occup Environ Med. 1997;54:697-701. 

213. National Academy of Sciences. Possible Long-Term Health Effects of Short-Term Exposure to 

Chemical Agents: Volume 1 - Anticholinesterases and Anticholinergics. National Academy Press; 1982. 

214. National Cancer Institute - Office of Cancer Complementary & Alternative Medicine. The Preparation 

of Best Case Series and the Conduct of Pilot Clinical Trials using CAM Modalities. 2004. Available at: 

http://www3.cancer.gov/occam/bcs_preparation.html. 

215. National Gulf War Resource Center. National Gulf War Resource Center 2003 Self Help Guide. 2003. 

Available at: http://www.ngwrc.org/Documents/NGWRCSelfHelpGuideNov2003.pdf. 

216. National Institute of Neurological Diseases. NINDS Counterterrorism and Neuroscience Research 

Workshop: Apr 7-8, 2004. Available at: http://www.masimax.com/counterterrorism/. 

217. Nicolson GL, Hyman E, Korenyi-Both A, et al. Progress on Persian Gulf War illnesses - reality and 

hypothesis. Int J Occup Med Toxicol. 1995;4:365-370. 

218. Nicolson GL, Nasralla MY, Nicolson NL, Haier J. High prevalence of mycoplasmal infections in 

symptomatic (chronic fatigue syndrome) family members of Mycoplasma-positive Gulf War illness 

patients. J Chronic Fatigue Syndr. 2003;11:21-36. 

219. Nicolson GL, Nicolson NL. Diagnosis and treatment of mycoplasmal infections in Persian Gulf War 

Illness-CFIDS patients. Int J Occup Med Immunol Toxicol. 1996;5:69-78. 

220. Nicolson GL, Rosenberg-Nicolson NL. Doxycycline treatment and Desert Storm. JAMA. 

1995;273:618-619. 

221. NIH Technology Assessment Workshop Panel. The Persian Gulf Experience and Health: NIH 

Technology Assessment Workshop Statement. National Institutes of Health; Apr 27-29, 1994. 

222. Nisenbaum R, Barrett DH, Reyes M, Reeves WC. Deployment stressors and a chronic multisymptom 

illness among Gulf War veterans. J Nerv Ment Dis. 2000;188:259-266. 

223. Nishiwaki Y, Maekawa K, Ogawa Y, et al. Effects of sarin on the nervous system in rescue team staff 

members and police officers 3 years after the Tokyo subway sarin attack. Environ Health Perspect. 

2001;109:1169-1173. 

224. Obeso JA, Rodriguez-Oroz M, Marin C, et al. The origin of motor fluctuations in Parkinson's disease. 

Neurology. 2004;62:S17-S30. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 121

225. O'Brien MM, Shroyer AL, Moritz TE, et al. Relationship between processes of care and coronary 

bypass operative mortality and morbidity. Med Care. 2004;42:59-70. 

226. Oddone E, Horner RD. Occurence of Amyotrophic Lateral Sclerosis (ALS) among Gulf War Veterans 

(CSP#500). Presentation at: Meeting of the Research Advisory Committee on Gulf War Veterans' 

Illnesses; Oct 27, 2003; Washington, DC. 

227. Okudera H. Clinical features of nerve gas sarin terrorism in Matsumoto. J Clin Neurosci. 2002;9:17-21. 

228. Okumura T, Takasu N, Ishimatsu S, et al. Report on 640 victims of the Tokyo subway sarin attack. Ann 

Emerg Med. 1996;28:129-135. 

229. Olgun S, Gogal RM, Jr., Adeshina F, Choudhury H, Misra HP. Pesticide mixtures potentiate the 

toxicity in murine thymocytes. Toxicology. 2004;196:181-195. 

230. Patten SB, Beck CA, Williams JVA, Barbui C, Metz LM. Major depression in multiple sclerosis: a 

population-based perspective. Neurology. 2003;61:1524-1527. 

231. Peckerman A, LaManca JJ, Smith SL, et al. Cardiovascular stress responses and their relation to 

symptoms in Gulf War veterans with fatiguing illness. Psychosom Med. 2000;62:509-516. 

232. Peckerman A, Natelson BH, Kipen HM, et al. Quantitative sensory testing in Gulf War veterans with 

chronic fatigue syndrome. J Environ Med. 1999;1:235-240. 

233. Peden-Adams MM, Eudaly J, Eudaly E, et al. Evaluation of immunotoxicity induced by single or 

concurrent exposure to N,N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet 

fuel. Toxicol Ind Health. 2001;17:192-209. 

234. Penman AD, Tarver RS. No evidence of increase in birth defects and health problems among children 

born to Persian Gulf War veterans in Mississippi. Mil Med. 1996;161:1-6. 

235. Persian Gulf Veterans Coordinating Board. A Working Plan for Research on Persian Gulf Veterans' 

Illnesses. Washington, DC: U.S. Department of Veterans Affairs; 1995. 

236. Persian Gulf Veterans Coordinating Board. A Working Plan for Research on Persian Gulf Veterans' 

Illnesses. Washington, DC: U.S. Department of Veterans Affairs; 1996. 

237. Pierce PF. Physical and emotional health of Gulf War veterans women. Aviat Space Environ Med. 

1997;68:317-321. 

238. Powell P, Bentall RP, Nye FJ, Edwards RHT. Randomised controlled trial of patient education to 

encourage graded exercise in chronic fatigue syndrome. Br Med J. 2001;322:1-5. 

239. Powell P, Bentall RP, Nye FJ, Edwards RHT. Patient education to encourage graded exercise in chronic 

fatigue syndrome: 2-year follow-up of randomised controlled trial. Br J Psychiatry. 2004;184:142-146. 

240. Presidential Advisory Committee on Gulf War Veterans' Illness. Final Report. Washington, DC: U.S. 

Government Printing Office; 1996. 

241. Presidential Special Oversight Board for Department of Defense Investigations of Gulf War Chemical 

and Biological Incidents. Final Report. Washington, DC. Dec 20, 2000. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 122

242. Preventive medicine augmentation team after action report. Final report: illness and injury among US 

Marines during Operation Desert Storm. 1993. Available at: 

http://www.gulflink.osd.mil/declassimages/bumed/19961230/123096_sep96_decls1_0001.html. 

243. Proctor SP, Heaton KJ, White RF, Wolfe J. Chemical sensitivity and chronic fatigue in Gulf War 

veterans: a brief report. J Occup Environ Med. 2001;43:259-264. 

244. Proctor SP, Heeren T, White RF, et al. Health status of Persian Gulf War veterans: self-reported 

symptoms, environmental exposures and the effect of stress. Int J Epidemiol. 1998;27:1000-1010. 

245. Proctor SP, Imai A, Gopal S, White RF, Wolfe J, Ozonoff D. Spatial analysis (using GIS techniques) of 

reported health symptoms and exposures in Gulf War troop location data in relationship with symptom 

reports veterans in the Gulf region. Presentation at: Conference on Illnesses among Gulf War Veterans: 

A Decade of Scientific Research; Jan 24-26, 2001; Washington, DC. 

246. Radetsky P. The Gulf War within. Discover. Aug 1997:69-71, 73-75. 

247. Rajab KE, Mohammad AM, Mustafa F. Incidence of spontaneous abortion in Bahrain before and after 

the Gulf War of 1991. Int J Gynaecol Obstet. 2000;68:139-144. 

248. Reid S, Hotopf M, Hull L, Ismail K, Unwin C, Wessely S. Multiple chemical sensitivity and chronic 

fatigue syndrome in British Gulf War veterans. Am J Epidemiol. 2001;153:604-609. 

249. Research Working Group of the Persian Gulf Veterans Coordinating Board. Annual Report to 

Congress: Federally Sponsored Research on Gulf War Veterans' Illnesses for 1998. Washington, DC: 

U.S. Department of Veterans Affairs; 1999. 

250. Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in 

Wichita, Kansas. Arch Intern Med. 2003;163:1530-1536. 

251. Richardson MA. Research of complementary/alternative medicine therapies in oncology: promising but 

challenging. Journal of Clinical Oncology. 1999;17:38-43. 

252. Riviere JE, Baynes RE, Brooks JD, Yeatts JL, Monteiro-Riviere NA. Percutaneous absorption of 

topical N,N-diethyl-m-toluamide (DEET): effects of exposure variables and coadministered toxicants. J 

Toxicol Environ Health A. 2003;66:133-151. 

253. Riviere JE, Monteiro-Riviere NA, Baynes RE. Gulf War related exposure factors influencing topical 

absorption of 14C-permethrin. Toxicol Lett. 2002;135:61-71. 

254. Roberson MR, Schmidt MB, Gonzales MD, McAvoy KM, Francisco CP, McDonough JH. Depression 

of cholinesterase activity by low-dose sarin exposure may lead to persistent changes that influence 

behavior. Presentation at: Annual Meeting of the Society for Neuroscience; Nov 3, 2002; Orlando, FL. 

255. Roland PS, Haley RW, Yellin W, Owens K, Shoup AG. Vestibular dysfunction in Gulf War syndrome. 

Otolaryngol Head Neck Surg. 2000;122:319-329. 

256. Rook GAW, Zumla A. Gulf War syndrome: is it due to a systemic shift in the cytokine balance towards 

a Th2 profile. Lancet. 1997;349:1831-1833. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 123

257. Rubins HB, Nelson DB, Noorbaloochi S, Nugent S. Effectiveness of lipid-lowering medications in 

outpatients with coronary heart disease in the Department of Veterans Affairs System. Am J Cardiol. 

2003;92:1177-1182. 

258. Sastre A. Physiological and genetic aspects of autonomic dysfunction in Gulf War veterans. 

Presentation at: Meeting of the Research Advisory Committee on Gulf War Veterans' Illness; Jun 16, 

2003; Washington, DC. 

259. Schumm WR, Reppert EJ, Jurich AP, et al. Pyridostigmine bromide and the long-term subjective health 

status of a sample of female reserve component Gulf War veterans: a brief report. Psychol Rep. 

2001;88:306-308. 

260. Schumm WR, Reppert EJ, Jurich AP, et al. Pyridostigmine bromide and the long-term subjective health 

status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychol Rep. 

2002;90:707-721. 

261. Schumm WR, Reppert EJ, Jurich AP, et al. Self-reported changes in subjective health and anthrax 

vaccination as reported by over 900 Persian Gulf War era veterans. Psychol Rep. 2002;90:639-653. 

262. Scremin OU, Shih T-M, Huynh L, Roch M, Booth R, Jenden DJ. Delayed neurologic and behavioral 

effects of subtoxic doses of cholinesterase inhibitors. J Pharmacol Exp Ther. 2003;304:1111-1119. 

263. Scremin OU, Shih T-M, Huynh L, et al. Effects of chronic exposure to low levels of cholinesterase 

inhibitors on cerebral blood flow. Presentation at: Annual Meeting of the Society for Neuroscience; 

Nov 5, 2002; Orlando, FL. 

264. Sekowski JW, Bucher J, Orehek M, et al. Low-level inhalation exposure to sarin and cyclosarin leads to 

enhanced expression of neuronal cell death and regeneration related genes. Presentation at: Annual 

Conference of the Society of Toxicology; Mar 25, 2004; Baltimore, MD. 

265. Sharabi Y, Danon Y, Berkenstadt H, et al. Survey of symptoms following intake of pyridostigmine 

during the Persian Gulf war. Isr J Med Sci. 1991;27:656-658. 

266. Sharief MK, Priddin J, Delamont RS, et al. Neurophysiologic analysis of neuromuscular symptoms in 

UK Gulf War veterans: a controlled study. Neurology. 2002;59:1518-1525. 

267. Sharpe L, Sensky T, Timberlake N, Ryan B, Allard S. Long-term efficacy of a cognitive behavioural 

treatment from a randomized controlled trial for patients recently diagnosed with rheumatoid arthritis. 

Rheumatology (Oxford). 2003;42:435-441. 

268. Sharpe M, Hawton K, Surawy C, et al. Cognitive behaviour therapy for the chronic fatigue syndrome: a 

randomised controlled trial. Br Med J. 1996;312:22-26. 

269. Sheridan RE. Health Effects of Low-dose Chemical Agent Exposure. Presentation at: Meeting of the 

Research Advisory Committee on Gulf War Veterans' Illnesses; Oct 28, 2003; Washington, DC. 

270. Shi L, Chia SE. A review of studies on maternal occupational exposures and birth defects, and the 

limitations associated with these studies. Occup Med (Lond). 2001;51:230-244. 

271. Shohami F, Kaufer D, Chen Y, et al. Antisense prevention of neuronal damages following head injury 

in mice. J Mol Med. 2000;78:228-236. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 124

272. Sillanpaa MC, Agar LM, Milner IB, Podany EC, Axelrod BN, Brown GG. Gulf War veterans: a 

neuropsychological examination. J Clin Exp Neuropsychol. 1997;19:211-219. 

273. Smith TC, Corbeil TE, Ryan MAK, Heller JM. In-theater hospitalization of US and allied personnel 

during the 1991 Gulf War. Am J Epidemiol. 2004;159:1064-1076. 

274. Smith TC, Gray GC, Knoke JD. Is systemic lupus erythematosus, amyotrophic lateral sclerosis, or 

fibromyalgia associated with Persian Gulf War service? An examination of Department of Defense 

hospitalization data. Am J Epidemiol. 2000;151:1053-1059. 

275. Smith TC, Gray GC, Weir JC, Heller JM, Ryan MAK. Gulf War veterans and Iraqi nerve agents at 

Khamisiyah: postwar hospitalization data revisited. Am J Epidemiol. 2003;158:457-467. 

276. Smith TC, Heller JM, Hooper TI, Gackstetter GD, Gray GC. Are Gulf War veterans experiencing 

illness due to exposure to smoke from Kuwaiti oil well fires? Examination of Department of Defense 

hospitalization data. Am J Epidemiol. 2002;155:908-917. 

277. Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ. Amyotrophic lateral sclerosis in Olmsted 

County, Minnesota, 1925 to 1998. Neurology. 2002;59:280-282. 

278. Soreq H. Relationship between serum enzyme activities in Gulf War-era deployed veterans and 

demographic parameters. Presentation at: Meeting of the Research Advisory Committee on Gulf War 

Veterans' Illnesses; Oct 27, 2003; Washington, DC. 

279. Soreq H, Seidman S. Anti-sense approach to anticholinesterase therapeutics. Isr Med Assoc J. 

2000;2:81-85. 

280. Soreq H, Seidman S. Acetylcholinesterase - new roles for an old actor. Nat Rev Neurosci. 2001;2:294-

302. 

281. Spencer PS, McCauley LA, Lapidus JA, Lasarev MR, Joos SK, Storzbach D. Self-reported exposures 

and their association with unexplained illness in a population-based case-control study of Gulf War 

veterans. J Occup Environ Med. 2001;43:1041-1056. 

282. Spiegelberg U. Psychopathologisch-neurologische Schilden nach Einwirkung synthetischer Gifte. Vol 

III. Darmstadt: Wehr und Wissen Verlagsgesellschaft mbH; 1961. 

283. Spiegelberg U. Psychopathologish-neurologisheche spat und dauershaden nach gewerblicher 

intoxikation durch phosphorsaureester (alkylphosphate). In: Excerpta Medica, ed. 14th International 

Congress on Occupational Health. Vol 62; 1963:1778-1780. 

284. Stark D, Kiely M, Smith A, Velikova G, House A, Selby P. Anxiety disorders in cancer patients: their 

nature, associations, and relation to quality of life. J Clin Oncol. 2002;20:3137-3148. 

285. Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with 

characteristics of person, place, and time of military service. Am J Epidemiol. 2000;152:992-1002. 

286. Steele L. Chronic fatigue and Gulf War illness: is the case definition of CFS useful in describing the 

health problems associated with service in the Persian Gulf War. Presentation at: Fifth International 

Conference of the American Association for Chronic Fatigue Syndrome; Jan 26-29, 2001; Seattle, WA. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 125

287. Steele L. Defining Gulf War illness as the pattern of symptoms that distinguishes Gulf War veterans 

from a referent population. Proceedings of the Conference on Illnesses among Gulf War Veterans: A 

Decade of Scientific Research. Washington, DC: The Research Working Group: Military and Veterans 

Health Coordinating Board; 2001:133. 

288. Steele L. Invited commentary: unexplained health problems after Gulf War service - finding answers to 

complex questions. Am J Epidemiol. 2001;154:406-409. 

289. Stockholm Interational Peace Research Institute. Delayed Toxic Effects of Chemical Warfare Agents. 

Stockholm: Almquist & Wiksell International; 1975. 

290. Storzbach D, Campbell KA, Binder LM, et al. Psychological differences between veterans with and 

without Gulf War unexplained symptoms. Portland Environmental Hazards Research Center. 

Psychosom Med. 2000;62:726-735. 

291. Storzbach D, Rohlman DS, Anger WK, Binder LM, Campbell KA. Neurobehavioral deficits in Persian 

Gulf veterans: additional evidence from a population-based study. Environ Res. 2001;85:1-13. 

292. Straus SE. Bridging the gulf in war syndromes. Lancet. 1999;353:162-163. 

293. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH. Physical health 

symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Mil 

Med. 1995;160:131-136. 

294. Sullivan K, Krengel M, Proctor SP, Devine S, Heeren T, White RF. Cognitive functioning in treatmentseeking Gulf War veterans: pyridostigmine bromide use and PTSD. J Psychopathol Behav Assess. 

2003;25:95-103. 

295. Suzuki J, Kohno T, Tsukagosi M, Furuhata T, Yamazaki K. Eighteen cases exposed to sarin in 

Matsumoto, Japan. Intern Med. 1997;36:466-470. 

296. Thanvi BR, Munshi SK, Vijaykumar N, Lo TC. Neuropsychiatric non-motor aspects of Parkinson's 

disease. Postgrad Med J. 2003;79:561-565. 

297. Tiersky LA, Natelson BH, Ottenweller J, Lange G, Fiedler N, DeLuca J. Functional status and mood in 

Persian Gulf veterans with unexplained fatiguing illness. Mil Psychol. 2000;12:233-248. 

298. Tochigi M, Umekage T, Otani T, et al. Serum cholesterol, uric acid and cholinesterase in victims of the 

Tokyo subway sarin poisoning: a relation with post-traumatic stress disorder. Neurosci Res (NY). 

2002;44:267-272. 

299. Trasler JM, Doerksen T. Teratogen update: paternal exposures - reproductive risks. Teratology. 

1999;60:161-172. 

300. Tucker JB. Evidence Iraq used chemical weapons during the 1991 Persian Gulf War. The 

Nonproliferation Review. 1997:114-122. 

301. U.K. Ministry of Defence. 1990/1991 Gulf Conflict - UK Gulf Veterans Mortality Data. 2004. 

Available at: http://www.dasa.mod.uk/natstats/gulf/intro.html. 

302. U.S. Army - Office of the Surgeon General. Infectious Diseases. Vol II. Washington, DC: 1963. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 126

303. U.S. Centers for Disease Control and Prevention. Unexplained illness among Persian Gulf War 

veterans in an Air National Guard unit: preliminary report - August 1990-March 1995. MMWR Morb 

Mortal Wkly Rep. 1995;44:443-447. 

304. U.S. Centers for Disease Control and Prevention. The Health Impact of Chemical Exposures During the 

Gulf War: A Research Planning Conference. Atlanta, GA; 2000. 

305. U.S. Department of Defense. Final Report of the Defense Science Board Task Force on Persian Gulf 

War Health Effects. Jun 1994. 

306. U.S. Department of Defense - Office of the Inspector General. Report of Investigation Concerning The 

Missing U.S. Central Command Nuclear, Biological and Chemical Desk Logs. Oct 20, 1997. 

307. U.S. Department of Defense - Office of the Special Assistant for Gulf War Illnesses. Case Narrative: 

Czech and French Reports of Possible Chemical Agent Detections. Jul 29, 1998. 

308. U.S. Department of Defense - Office of the Special Assistant for Gulf War Illnesses. Case Narrative: 

Reported Detection of Chemical Agent, Camp Monterey, Kuwait - Final Report. Dec 8, 1999. 

309. U.S. Department of Defense - Office of the Special Assistant for Gulf War Illnesses. Case Narrative: 

An Nasiriyah Southwest Ammunition Storage Point - Final Report. Sep 26, 2000. 

310. U.S. Department of Defense - Office of the Special Assistant for Gulf War Illnesses. Case Narrative: 

The Cement Factory - Final Report. Aug 4, 2000. 

311. U.S. Department of Defense - Office of the Special Assistant for Gulf War Illnesses. Information 

Paper: Vaccine Use During the Gulf War. Dec 7, 2000. 

312. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: 11th Marines - Final Report. May 25, 2001. 

313. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: Al Jubayl, Saudi Arabia - Final Report. Oct 25, 2001. 

314. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: Possible Chemical Warfare Agent Incident Involving a United States Marine - Final Report. 

Jan 25, 2001. 

315. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: Possible Mustard Release at Ukhaydir Ammunition Storage Depot - Final Report. Feb 16, 

2001. 

316. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: Reported Mustard Exposure - Operation Desert Storm - Final Report. Jun 22, 2001. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 127

317. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: The Gulf WarAir Campaign - Possible Chemical Warfare Agent Release at Al Muthanna, 

February 8, 1991 - Final Report. Nov 15, 2001. 

318. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: U.S. Marine Corps Minefield Breaching - Final Report. Jan 31, 2001. 

319. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: Chemical Warfare Agent Release at Muhammadiyat Ammunition Storage Site - Final 

Report. Apr 4, 2002. 

320. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. Case 

Narrative: U.S. Demolition Operations at Khamisiyah - Final Report. Apr 16, 2002. 

321. U.S. Department of Defense - Office of the Special Assistant to the Under Secretary of Defense 

(Personnel and Readiness) for Gulf War Illnesses, Medical Readiness, and Military Deployments. 

Environmental Exposure Report: Pesticides - Final Report. Apr 17, 2003. 

322. U.S. Department of Defense Office of Force Health Protection & Readiness. Force Health Protection. 

2004. Available at: http://www.ha.osd.mil/fhpr/fhp_pillars.cfm. 

323. U.S. Department of Health and Human Services. FY 2004 Budget in Brief. 2004. Available at: 

http://www.hhs.gov/budget/04budget/fy2004bib.pdf. 

324. U.S. Department of Health and Human Services. FY 2005 Budget in Brief - National Institutes of 

Health. 2004. Available at: http://hhs.gov/budget/05budget/nih.html. 

325. U.S. Department of Veterans Affairs. Benefits for Women Vietnam Veterans' Children with Birth 

Defects. 2004. Available at: http://www.vba.gov/bln/21/Topics/Women/Birth.htm. 

326. U.S. Department of Veterans Affairs. VA Fact Sheet: VA Programs for Veterans Exposed to Radiation. 

Jan 1997. Available at: http://www.va.gov/oaa/pocketcard/NRpg11.asp. 

327. U.S. Department of Veterans Affairs. VA links Agent Orange and Diabetes (Press release). Nov 9, 

2000. Available at: http://www1.va.gov/opa/pressrel/PressArtInternet.cfm?id=227. 

328. U.S. Department of Veterans Affairs. VA doubles Gulf War research funding (Press release). Oct 30, 

2002. Available at: http://www1.va.gov/OPA/pressrel/PressArtInternet.cfm?id=531. 

329. U.S. Department of Veterans Affairs. Gulf War Veterans Information System (GWVIS) May 2004 

Report. Washington, DC. Jun 22, 2004. 

330. U.S. Department of Veterans Affairs and Department of Defense Development Work Group. Post 

Deployment Health Evaluation and Management. Washington, DC: Office of Quality and Performance 

and the Veterans Affairs and Department of Defense Development Work Group, Veterans Health 

Administration, Department of Veterans Affairs; Sep 2001. OQP publication 10Q-CPG/PDH-01. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 128

331. U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline 

Working Group. Medically Unexplained Symptoms: Chronic Fatigue and Pain. Washington, DC: 

VA/DOD Clinical Practice Guideline Working Group, Veterans Health Administration, Department of 

Veterans Affairs, and Health Affairs, Department of Defense; Aug 2002. OQP publication 10QCPG/CF&P-01. 

332. U.S. Department of Veterans Affairs Cooperative Studies Program. Clinical trials of cognitive 

behavioral treatment for posttraumatic stress disorder in women veterans. 2004. Available at: 

http://www.clinicaltrials.gov/ct/show/NCT00032617?order=30. 

333. U.S. Department of Veterans Affairs Office of Public Health and Environmental Hazards. War-Related 

Illness and Injury Study Centers (WRIISCs). Available at: 

http://www.vethealth.cio.med.va.gov/WRIISC.htm. 

334. U.S. Department of Veterans Affairs VHA, U.S. Department of Defense. Combined Analysis of the VA 

and DOD Gulf War Clinical Evaluation Programs: A Study of the Clinical Findings from Systematic 

Medical Examinations of 100,339 U.S. Gulf War Veterans. Washington, DC. Sep 2002. 

335. U.S. Food and Drug Administration. Inspection Report of Bioport's Anthrax Vaccine Manufacturing 

Process. Nov 1999. Available at: http://www.avip2001.net/DOCS/FDA_1999.pdf. 

336. U.S. General Accounting Office. Operation Desert Storm: Questions Remain on Possible Exposure to 

Reproductive Toxicants. Washington, DC. Aug 1994. GAO/PEMD-94-30. 

337. U.S. General Accounting Office. Gulf War Illnesses: Public and Private Efforts Relating to Exposures 

of U.S. Personnel to Chemical Agents. Washington, DC. Oct 1997. GAO/NSIAD-98-27. 

338. U.S. General Accounting Office. VA Health Care: Persian Gulf Dependents' Medical Exam Program 

Ineffectively Carried Out. Washington, DC. Mar 1998. GAO/HEHS-98-108. 

339. U.S. General Accounting Office. Anthrax Vaccine: Safety and Efficacy Issues. Washington, DC. Oct 

12, 1999. GAO/T-NSIAD-00-48. 

340. U.S. General Accounting Office. Gulf War Illnesses: Questions About the Presence of Squalene 

Antibodies in Veterans Can Be Resolved. Washington, DC. Mar 1999. GAO/NSIAD-99-5. 

341. U.S. General Accounting Office. Anthrax Vaccine: Changes to the Manufacturing Process. 

Washington, DC. Oct 23, 2001. GAO-02-181T. 

342. U.S. General Accounting Office. Anthrax Vaccine: GAO's Survey of Guard and Reserve Pilots and 

Aircrew. Washington, DC. Sep 2002. GAO-02-445. 

343. U.S. General Accounting Office. Gulf War illnesses: Preliminary Assessment of DOD Plume Modeling 

for U.S. Troops Exposure to Chemical Agents. Washington, DC. Jun 2003. GAO-03-833T. 

344. U.S. General Accounting Office. Computer-Based Patient Records: Improved Planning and Project 

Management Are Critical to Achieving Two-Way VA-DOD Health Data Exchange. Washington, DC. 

May 19, 2004. GAO-04-811T. 

345. U.S. General Accounting Office. Gulf War Illnesses: DOD's Conclusions About U.S. Troops' Exposure 

Cannot Be Adequately Supported. Washington, DC. Jun 2004. GAO-04-159. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 129

346. U.S. House Committee on Goverment Reform and Oversight. Gulf War Veterans' Illnesses: VA, DOD 

Continue to Resist Strong Evidence Linking Toxic Causes to Chronic Health Effects (Second Report). 

Washington, DC. Nov 7, 1997. HR 105-338. 

347. U.S. Senate Committee on Banking, Housing, and Urban Affairs. U.S. Chemical and Biological 

Warfare-related Dual Use Exports To Iraq and Their Possible Impact on the Health Consequences of 

the Persian Gulf War. Washington, DC. May 25, 1994. 

348. U.S. Senate Committee on Veterans' Affairs. Report of the Special Investigation Unit on Gulf War 

Illnesses. U.S. Government Printing Office S. PRT. 105-39. Washington, DC. 1998. 

349. Unwin C, Blatchley N, Coker W, et al. Health of UK servicemen who served in Persian Gulf War. 

Lancet. 1999;353:167-178. 

350. van Haaren F, Cody B, Hoy JB, et al. The effects of pyridostigmine bromide and permethrin, alone or 

in combination, on response acquisition in male and female rats. Pharmacol Biochem Behav. 

2000;66:739-746. 

351. van Haaren F, Haworth SC, Bennett SM, et al. The effects of pyridostigmine bromide, permethrin, and 

DEET alone, or in combination, on fixed-ratio and fixed-interval behavior in male and female rats. 

Pharmacol Biochem Behav. 2001;69:23-33. 

352. Verbrugge LM, Ascione FJ. Exploring the iceberg. Common symptoms and how people care for them. 

Med Care. 1987;25:539-569. 

353. Vogel JS, Keating GA, Buchholz BA. Protein binding of isofluorophate in vivo after coexposure to 

multiple chemicals. Environ Health Perspect. 2002;110:1031-1036. 

354. Wagner AW, Wolfe J, Rotnitsky A, Proctor SP, Erickson DJ. An investigation of the impact of 

posttraumatic stress disorder on physical health. J Trauma Stress. 2000;13:41-55. 

355. Ware JE, Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 

framework and item selection. Med Care. 1992;30:473-483. 

356. White J, McCabe M, Hawkins M. The NCI best case series process. Presentation at: Conference on 

Comprehensive Cancer Care II: Integrating Complementary & Alternative Therapies; Jun 11, 1999; 

Arlington, VA. 

357. White RF. Service in the Gulf War and significant health problems: focus on the central nervous 

system. J Psychopathol Behav Assess. 2003;25:77-83. 

358. White RF, Proctor SP, Heeren T, et al. Neuropsychological function in Gulf War veterans: relationship 

to self-reported toxicant exposures. Am J Ind Med. 2001;40:42-54. 

359. Whiting P, Bagnall A-M, Sowden AJ, Cornell JE, Mulrow CD, Ramirez G. Interventions for the 

treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001;286:1360-

1368. 

360. Wolfe J, Proctor SP, Erickson DJ, et al. Relationship of psychiatric status to Gulf War veterans' health 

problems. Psychosom Med. 1999;61:532-540. 
References 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 130

361. Wolfe J, Proctor SP, Erickson DJ, Hu H. Risk factors for multisymptom illness of US Army veterans of 

the Gulf War. J Occup Environ Med. 2002;44:271-281. 

362. Wolfe J, Proctor SP, White RF, Friedman MJ. Re: "Is Gulf War syndrome due to stress? The evidence 

reexamined". Am J Epidemiol. 1998;148:402. 

363. Wray NP. Doxycycline Treatment of Gulf War Veterans' Illnesses: A Veterans Affairs Cooperative 

Study. Presentation at: Meeting of the Research Advisory Committee on Gulf War Veterans' Illnesses; 

Feb 3, 2003; Washington, DC. 

364. Wray NP. Gulf War Illness Research Initiatives. Presentation at: Meeting of the Research Advisory 

Committee on Gulf War Veterans' Illnesses; Oct 27, 2003; Washington, DC. 

365. Wray NP. National Health Survey of Gulf War Era Veterans and Their Families Phase III: Medical 

Evaluations. Presentation at: Meeting of the Research Advisory Committee on Gulf War Veterans' 

Illnesses; Feb 3, 2003; Washington, DC. 

366. Yokoyama K, Araki S, Murata K, et al. A preliminary study on delayed vestibulo-cerebellar effects of 

Tokyo subway sarin poisoning in relation to gender difference: frequency analysis of postural sway. J 

Occup Environ Med. 1998;40:17-21. 

367. Yokoyama K, Araki S, Murata K, et al. Chronic neurobehavioral and central and autonomic nervous 

system effects of Tokyo subway sarin poisoning. J Physiol (Paris). 1998;92:317-323. 

368. Yokoyama K, Araki S, Murata K, et al. Chronic neurobehavioral effects of Tokyo subway sarin 

poisoning in relation to posttraumatic stress disorder. Arch Environ Health. 1998;53:249-256. 

369. Yokoyama K, Araki S, Nishikitani M, Sato H. Computerized posturography with sway frequence 

analysis: application in occupational and environmental health. Ind Health. 2002;40:14-22. 

370. Zerhouni EA. Testimony before the U.S. Senate Committee on Health, Education, Labor & Pensions. 

Jul 24, 2003. Available at: http://labor.senate.gov/testimony/074_tes.html. 
Appendices 

 

Appendix A 

Committee Members 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 133

Appendix A 

Members of the 

Research Advisory 

Committee on Gulf 

War Veterans’ 

Illnesses

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. 

Nicola Cherry, M.D., Ph.D.

 Dr. Cherry is Chair of the Department of Public Health Sciences at the 

University of Alberta. She is an occupational physician and epidemiologist 

with a particular interest in the effect of environmental chemicals on the 

nervous and reproductive systems. She was principal investigator on the 

U.K. study of Gulf War veterans conducted at the University of 

Manchester. 

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

 Dr. Golomb is Assistant 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. 

Joel C. Graves 

 Mr. Graves was enlisted for nine years and an armor officer for nine 

years. He is a Persian Gulf War veteran, and retired from the U.S. Army in 

1997 as a captain. 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 syndrome. 

Robert W. Haley, M.D. 

 Dr. Haley is Professor and Chief of the Epidemiology Division in the 

Department of Internal Medicine at the University of Texas Southwestern 

Medical Center in Dallas, where he hold the U.S. Armed Forces Veterans 

Distinguished Chair for Medical Research, Honoring America’s Gulf War 

Veterans. Dr. Haley performed epidemiologic research at the U.S. Centers 

for Disease Control and Prevention from 1973-1983 before joining the 

medical school faculty in Dallas. His research includes national studies of 

hospital-acquired infections and other infectious diseases as well as studies 

on the neurophysiologic basis of Gulf War syndrome. He received the 

Commendation Medal of the U.S. Public Health Service for his research 

and is a member of the Association of American Physicians. 
Appendix A 

Committee Members 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 134

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

 Ms. Knox served with the 251st Evacuation Hospital at King Khalid 

Military City, Saudi Arabia, during Desert Shield/Desert Storm. During 

her tenure as a Clinical Assistant Professor at the University of South 

Carolina College of Nursing, she was appointed by President Clinton to 

serve on the Presidential Advisory Committee on Gulf War Veterans' 

Illnesses from 1995-1998. Currently, LTC Knox serves as the 91W 

Healthcare Specialist Coordinator within the Medical Command of 

the South Carolina Army National Guard and works as Senior Sales 

Representative in the Neuroscience Division of Eli Lilly and Company. 

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

 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. 

Pierre J. Pellier, M.D.

 Dr. Pellier is Vice President for the Clinical Department of the 

Neurosciences Medicine Development Centre, GlaxoSmithKline 

Pharmaceuticals, where he oversees the development of new drugs for 

neurological and psychiatric diseases. He holds a Doctorate of Medicine 

and a Specialist Diploma in hepato-gastroenterology from the Paris 

Medical Universities. 

Stephen L. Robinson 

 Mr. Robinson is a former Airborne Ranger and Ranger instructor. His 

last assignment in the military was in the Office of the Secretary of 

Defense, working in the Preliminary Analysis Directorate for the Special 

Assistant on Gulf War Illnesses. Mr. Robinson has been the Executive 

Director of the National Gulf War Resource Center since 2001. He is a 

Gulf War veteran and a recognized expert on Gulf War illnesses and 

chemical and biological weapons exposures. 

Steve Smithson 

 Mr. Smithson is an assistant director for the American Legion, with 

responsibility for Gulf War and deployment-related issues. 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. 
Appendix A 

Committee Members 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 135

Lea Steele, Ph.D. (Scientific Director)

 Dr. Steele is Research Associate Professor in the College of Human 

Ecology at Kansas State University. She is an epidemiologist and human 

ecologist with a special research interest in the study of complex medical 

conditions that are difficult to diagnose and treat. Dr. Steele 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. 

Consultant to the Committee

Jack Melling, Ph.D.

 Dr. Melling is former Chief Executive of the U.K. Microbiological 

Research Authority and was previously Director of the Salk Institute of 

Biologicals Development Center and Director of the Karl Landsteiner 

Institute for Vaccine Development. He is currently a consultant to the 

United States Government Accountability Office and a Senior Program 

Manager at the Battelle Memorial Institute. 

Appendix B 

Advisory Panel 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 137

Appendix B

2002-2004 

Members of the 

Expert Advisory 

Panel for the 

Research Advisory 

Committee on Gulf 

War Veterans’ 

Illnesses

Ira B. Black, M.D. 

Chair, Department of Neurosciences and Cell Biology 

University of Medicine and Dentistry-Robert Wood Johnson Medical 

School 

Floyd E. Bloom, M.D. 

Chair, Department of Neuropharmacology 

TSRI Scripps Research Institute 

Joseph T. Coyle, M.D. 

Eben S. Draper Professor of Psychiatry and Neuroscience 

Harvard Medical School 

Eugene Johnson, M.D. 

Professor, Department of Neurology 

Washington University 

Marcel Mesulam, M.D. 

Director, The Cognitive Neurology and Alzheimer’s Disease Center 

Northwestern University Medical School 

James J. Tuite III 

President, enviroSec, Inc. 

Bailus Walker, Jr., M.D. 

Professor of Environmental and Occupational Medicine 

Howard University College of Medicine 
 
Appendix C 

Committee Charter 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 139

Appendix C 

Charter of the 

Research Advisory 

Committee on Gulf 

War Veterans’ 

 Illnesses

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 (RACGWVI). 

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 studies, research plans, 

and research strategies relating to the health consequences of military 

service in the Southwest Asia theater of operations during the Persian Gulf 

War. The Committee shall not conduct scientific research. 

The guiding principle for the work of the Committee shall be the premise 

that the fundamental goal of Gulf War-related 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 of Gulf War-associated illnesses. 

The Committee shall review all relevant 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 Gulf War-associated 

illnesses. 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(S): The Committee was established in 

compliance with statutory instructions contained in Section 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 Department of Veterans Affairs 

will provide support for the Committee. A VA employee selected by the 

Secretary of Veterans Affairs shall be the Designated Federal Officer, 

under the direction of the Committee chair. 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. 
Appendix C 

Committee Charter 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 140

DUTIES FOR WHICH THE COMMITTEE IS RESPONSIBLE: 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 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. 

To augment the expertise of the Committee, the Secretary may authorize 

the Committee to contract 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 Persian 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. The Secretary of Veterans Affairs may appoint non-US 

citizens as Committee members. 

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 may establish subcommittees to carry out specific projects 

or assignments. The Committee chair shall notify the Secretary upon the 

establishment of any subcommittee, including its function, members 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. 

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 Regulations for any travel made in connection with their duties as 

members of the Committee. 
Appendix C 

Committee Charter 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 141

ESTIMATED NUMBER AND FREQUENCY OF MEETINGS: Meetings 

of the Committee shall occur not less than twice annually at the call of the 

chair. Meetings of the subcommittee(s) shall be convened as necessary. A 

federal government official shall be present at all meetings. 

COMMITTEE TERMINATION DATE: None. 

DATE CHARTER IS FILED: 

 -- Signed -- 4/19/04 

APPROVED: ________________________ _______________ 

 Secretary of Veterans Affairs Date 

 
Abbreviations 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 142

ABT Antibiotic Treatment Trial 

ACh Acetylcholine 

AChE Acetylcholinesterase 

AChEi Acetylcholinesterase inhibitor 

ALS Amyotrophic lateral sclerosis 

AVA Anthrax vaccine adsorbed 

BChE Butyrylcholinesterase 

CCEP Comprehensive Clinical Evaluation Program 

CDC U.S. Centers for Disease Control and Prevention 

CFS Chronic fatigue syndrome 

ChE Cholinesterase 

CI Confidence interval 

CMI Chronic multisymptom illness 

DEET N,N-diethyl-meta-toluamide or N,N-diethly-3-

methylbenamide (an insect repellant)

DFP Diiosopropylfluorophosphate, used to simulate 

nerve agents in laboratory research 

DOD U.S. Department of Defense 

EBT Exercise/Behavioral Therapy Trial 

EEG Electroencephalogram 

FY Fiscal year 

GAO U.S. General Accounting Office, renamed the U.S. 

Government Accountability Office in July, 2004 

GWVIS Gulf War Veterans Information System 

HHS U.S. Department of Health and Human Services 

ICD-9 International Classification of Diseases, 9th

Revision 

IOM Institute of Medicine 

MEG Magnetoencephalography 

MRI Magnetic resonance imagining 

MRS Magnetic resonance spectroscopy 

MS Multiple sclerosis 

NAA/Cr N-acetyl-aspartate/creatine ratio 

NIH National Institutes of Health 

Abbreviations

NK Natural killer cells 

NTE Neuropathy target esterase 
Abbreviations 

Research Advisory Committee on Gulf War Veterans’ Illnesses 

2004 Report and Recommendations • 143

OP Organophosphate 

PB Pyridostigmine bromide 

PET Positron-emission tomography 

PGVCB Persian Gulf Veterans Coordinating Board 

PON1 Paraoxonase 

PTSD Posttraumatic stress disorder 

SF-36 Medical Outcomes Study Survey Form 36 

SPECT Single photon emission tomography 

SSA U.S. Social Security Administration 

VA U.S. Department of Veterans Affairs 

VAMC VA Medical Center 

VBA Veterans Benefits Administration, U.S. 

Department of Veterans Affairs 

VHA Veterans Health Administration, U.S. Department 

of Veterans Affairs 

WRIISC War-Related Injury and Illness Study Center