RESEARCH

Finding 16: Federal research strategy has been blind to
promising hypotheses due to reliance on unfounded DOD conclusions regarding chemical exposures.

In 1996, the DOD admitted for the first time that 300 to 400 PGW troops had likely been exposed to chemical weapons. The number of affected troops continued to be raised upward until July 1997, when DOD estimated that the number of exposed troops was estimated at 98,900.⁽³⁶³⁾
VA's Dr. Kenneth Kizer testified on January 21, 1997 that "the issue of chemical warfare agents ... and the investigation into that arena, was delayed, and that investigative focus was given a lower priority because of the information that had been provided by DOD." ⁽³⁶⁴⁾ As a result, the PGW registry didn't require VA physicians to ask sick veterans detailed questions about potential chemical and biological weapons exposure until 1995.⁽³⁶⁵⁾ In fact, the VA diagnostic screening protocol failed to identify even one veteran exposed to chemical weapons agents or other toxins.
VA continues to assert that acute symptoms following exposure to chemical weapons must be present in veterans exposed to these agents. In the absence of acute symptoms, the veteran is presumed by the VA not to be exposed.
Many scientific and medical witnesses have testified that chemical exposures result in injury to the limbic system at the brain stem. This injury, in turn, causes neuro-immunological disorders which are often characterized as chronic fatigue syndrome, fibromyalgia or multiple chemical sensitivity. These disorders are thought by many experts to be a spectrum of neuro-immunological illnesses with a variety of causes and symptoms.
Dr. William Baumzweiger, a neurologist and psychiatrist, who was at the time a VA physician in Los Angeles, testified that organophosphate chemical exposure resulted in "a syndrome which has been known since the late 1800's, was very clearly documented by 1930, and which there have been a number of accidental exposures, tragedies in the 1930's, 1970's, 1980's... . The signs and symptoms of acute neurotoxicity do not have to be so dramatic as seizures and death. They can be very mild and they can consist of headaches, nausea, vomiting, episodes of psychosis, personality change ..." ⁽³⁶⁶⁾
However, the January 15, 1997 issue of the Journal of the American Medical Association was devoted to PGW research. A study conducted by Dr. Robert Haley and colleagues at the University of Texas Southwestern Medical Center at Dallas concluded that PGW veterans illnesses were attributable to "subtle brain, spinal cord and nerve damage-but not stress. The damage was caused by exposure to combinations of low-level chemical nerve agents and other chemicals, including pyridostigmine bromide in anti-nerve-gas tablets, DEET in a highly concentrated insect repellant, and pesticides in flea collars that some troops wore. Different combinations of the chemicals appear to have caused the 3 different syndromes." To arrive at this conclusion, Dr. Haley and his colleagues conducted three studies in a group of 249 members of a U.S. Navy reserve unit. This study could have been just as easily conducted by DOD or VA.
The Departments also failed to consider historical research which supported consideration of possible toxic exposures with delayed onset as the cause of PGW syndrome. Furthermore, DOD and VA did not consider the possibility that PB could mask the effects of chemical exposure. If this were the case, delayed neurotoxicity would not appear for perhaps several
years. ⁽³⁶⁷⁾

Finding 17: Institutional and methodological constraints make it unlikely the current research structure will find the causes and effective treatments for Gulf War veterans' illnesses in the short term.

Military institutional biases are adversely affecting the identification of causes and treatments for PGW illnesses. Exposure to genotoxic materials was not quantatively monitored and records of chemical exposures were not maintained. As a result, data on these subjects will never be available and a direct proof of a causative relationship between chemical exposures and PGW illnesses may be unattainable. However, the circumstantial evidence is overwhelming.
There is also strong existing medical bias against the spectrum of illnesses described as neuro-immunological central nervous system disorders. Dr. Clauw said "it appears that there is a group of closely related systemic conditions, such as fibromyalgia and chronic fatigue syndrome, as well as a group of closely related organ-specific conditions, such as migraine headaches and irritable bowel syndrome, that form one large spectrum of illness with common demographics, inciting factors and treatment."⁽³⁶⁸⁾
Many of the disease conditions of which Gulf War veterans complain, such as chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity are poorly understood and only recently characterized by standardized diagnostic criteria. Dr. Clauw testified, "The countless individuals who were previously healthy, who returned from the war with severe symptoms, are compelling evidence that these individuals developed these illnesses as a result of their military service." ⁽³⁶⁹⁾
He added:

much more funding is needed for research into this whole spectrum of conditions. The problems regarding the diagnosis and treatment of Persian Gulf veterans are a symptom of a much bigger problem that we have in this country. Amazingly enough, despite the very high prevalence of these illnesses in the population, the aggregate amount of yearly funding for these conditions, through all of the institutes at the NIH, and through other sources such as the DOD, may perhaps reach $20 million. This spectrum of illnesses cost the government alone billions of dollars in lost productivity disability and health care costs. The costs to the private sector are much larger.⁽³⁷⁰⁾

GAO testified, "We found that the bulk of ongoing Federal research on Gulf War veterans' illnesses focuses on the epidemiological study of the prevalence and the cause of the illnesses." ⁽³⁷¹⁾
GAO concluded, "the ongoing epidemiological research will not be able to provide precise, accurate, and conclusive answers regarding the causes of veterans' illnesses because of these formidable methodological problems."⁽³⁷²⁾ GAO recommended that "the Secretaries of Defense and Veterans Affairs (1) set up a plan for monitoring the clinical progress of Gulf War veterans to help promote effective treatment and better direct the research agenda and (2) give greater priority to research on effective treatment for ill veterans and on low-level exposures to chemicals and their interactive effects and less priority to further epidemiological studies."⁽³⁷³⁾
VA has not sought a case definition for PGW illness and this has hampered development of a set of diagnostic criteria which would enable treating physicians to identify and correctly diagnose sick veterans.
In 1994, the Center for Disease Control and Prevention's [CDC] Dr. William C. Reeves, began developing a working case definition of PGW symptoms. CDC utilized this case definition to determine epidemiologically that Gulf-related illnesses are more frequent in PGW veterans than non-deployed troops. VA did not initiate action to determine a case definition when it began receiving reports of PGW illnesses in 1991. As a result, 3 valuable years were lost.

Finding 18: The FDA was passive in granting and failing to enforce the conditions of a waiver to permit use of PB by DOD.

Immediately prior to Operation Desert Shield, the Assistant Secretary of Defense for Health Affairs requested that HHS waive the requirement to obtain informed consent from military personnel for use of non-approved drugs and biologics because under military combat exigencies it was not feasible. The Pentagon argued that the policy of individual informed consent is not feasible in battlefield conditions and runs counter to the needs of the unit as a whole. If the military gave soldiers the choice of accepting or refusing to take an Investigational New Drug [IND], those who chose not to take the drugs would violate their overriding obligation both to their unit and to the military, and the military would violate its obligation to protect the soldiers. Soldiers who refused to take an Investigational New Drug would place themselves at risk and expose others in their unit to harm as well.
On December 21, 1990, FDA issued an interim regulation to amend its current informed consent regulations to permit the Commissioner of Food and Drugs to make the determination that obtaining informed consent from military personnel for the use of an investigational drug or biologic is not feasible in certain battlefield or combat-related situations.
The regulation had an immediate effective date because of the urgency created by Operation Desert Shield.
DOD requested waivers from FDA to administer three drugs to protect troops from biological or chemical attack. FDA denied one of the requests, but granted waivers for an unlicensed polyvalent vaccine against botulism and for pyridostigmine bromide [PB] as a wartime contingency pretreatment for nerve gas exposure. PB was approved by FDA for the treatment of myasthenia gravis, a neuromuscular disorder, but not as a prophylactic against nerve gas.
In such situations where informed consent was not feasible, FDA's interim regulation required that, "DOD collect data on any use of these products without informed consent. FDA will review these data and will revoke or modify the determination if the review indicates that the determination is no longer appropriate."
However, HHS staff members have informed subcommittee staff that DOD did not collect the required data and FDA has not aggressively pursued DOD's violation of the FDA-DOD agreement.
DOD has admitted that the information sheets which FDA required as a condition of the waiver, were never provided to military personnel ordered to take the vaccines and PB. As a result, Gulf War veterans did not know to include this information in their medical records or to mention the exposures when seeking medical care for PGW illnesses.
FDA's Interim Final Rule permitting waiver of informed consent for use of unapproved products in a military exigency is still in effect. The Presidential Advisory Committee on Gulf War Veterans' Illnesses' [PAC] expressed concern in its December 1996 report "about the amount of time FDA is taking to move forward with opening up the Interim Final Rule_which was issued almost 6 years ago for public comment."⁽³⁷⁴⁾
The PAC recommended, "If FDA decides to reissue the Interim Final Rule as final, it should first issue a Notice of Proposed Rulemaking. Among the areas that specifically should be revisited are: Adequacy of disclosure to service personnel; adequacy of recordkeeping; long-term follow up of individuals who receive investigational products; review by an institutional review board outside of DOD; and additional procedures to enhance understanding, oversight, and accountability." ⁽³⁷⁵⁾
On July 29, 1997, more than 7 years after FDA issued the waiver, the agency published a request for comments in the Federal Register, soliciting public comments on the following issues: whether FDA should revoke or maned the interim rule of December 1990 and if the latter, whether and how it should be amended; when is it ethical to expose volunteers to toxic chemical and biological agents to test the effectiveness of products that may be used to provide potential protection against those agents; and if the products that may be used for protection against toxic substances cannot be ethically tested in humans, what evidence would be needed to adequately demonstrate their safety and effectiveness.
The comment period closed October 30, 1997. After evaluating the responses, FDA will publish a proposal for action.

IV. RECOMMENDATIONS

DIAGNOSIS

Recommendation 1: Congress should enact a Gulf War toxic exposure act establishing the presumption, as a matter of law, that veterans were exposed to hazardous materials known to have been present in the war theater.

The premise of both VA and DOD approaches to Gulf War veterans illnesses has been that toxic exposures played no role in causing the mysterious range of maladies known as "Gulf War Syndrome." That presumption is no longer warranted.
The widespread presence of a host of hazardous substances throughout the war theater, including low levels of chemical warfare agents in some areas, has been well established. ⁽³⁷⁶⁾ In sufficient doses, each of those substances has been cited as a public health threat.⁽³⁷⁷⁾ That U.S. troops were widely and frequently exposed to one or more of these substances, i.e., smoke from oil well fires, PB tablets or "tabs," organophosphate pesticides, has never been denied.
What has been so long denied is that the admitted exposures were of any long term clinical significance. Yet it is only in the long term that a causal link between exposures and subsequent health effects in those exposed will be demonstrable using standard epidemiological analysis.
In the meantime, sick veterans and their families bear the burden of trying to prove not only that exposures took place, but in what quantity and in what combination(s). But in attempting to reconstruct their medical histories for this purpose, veterans find key records missing or unavailable. Inoculation records were not maintained for many. Information on the use of PB tabs was not recorded. Troop location data is not available below the unit level, making it impossible to place individuals in areas known to have been contaminated. NBC logs are missing.
Establishing a presumption of exposure to the hazardous substances known to have permeated the war area would lift that impossible burden. It would place the onus properly on Federal officials to rebut the presumption with peer reviewed research and clinical findings. Such a presumption would free the VA and DOD of the unworthy task of defending an improbable version of what did not happen in the Gulf War, and allow them to support veterans in proving what did happen there. It would also serve U.S. military doctrine by assuring future combatants that the wounds of war, however delayed or difficult to diagnose, will be acknowledged and treated.
In the absence of definitive scientific information, reasonable presumptions must be made. Citing just such an absence of scientific consensus, the Pentagon and the VA continue to presume toxic exposures play no significant role in the etiology of Gulf War illnesses. However, given the weight of evidence regarding toxic exposures and probable health effects, that presumption may never have been, but is certainly no longer, reasonable.

Recommendation 2: The VA should contract with an independent scientific body composed of non-Government scientific experts representing, at a minimum, the disciplines of toxicology, immunology, microbiology, molecular biology, genetics, biochemistry, chemistry, epidemiology, medicine and public health for the purpose of identifying those diseases and illnesses associated in peer-reviewed literature with singular, sustained, or combined exposures to the hazardous materials to which Gulf War veterans are presumed to have been exposed.

Despite subsequent recommendations in this report to divest VA and DOD of control over the Gulf War research agenda, this proposal is made so the departments have access to the objective expertise necessary to implement Recommendation 1. While it may have been enough in the past to say the Department, "has always remained open to the possibility that PGW veterans were potentially exposed to a wide variety of hazardous agents while serving in the Southwest Asia theater of operations, including chemical warfare agents,"⁽³⁷⁸⁾ this recommendation would transform that passive posture into a more active pursuit of information on exposures and health effects.
Particularly in view of the many variables and innumerable combinations of likely Gulf War exposures, the VA must be in a position to pursue complex, interdisciplinary hypotheses regarding toxic stressors.⁽³⁷⁹⁾ The list of presumed exposures will need to be updated and refined. This recommendation seeks to ensure VA maintains adequate scientific breadth in that process, and does not fall prey to a static view of exposure health effects.

Recommendation 3: The VA Gulf War Registry and the DOD Comprehensive Clinical Evaluation Program should be re-evaluated by an independent scientific body which shall make specific recommendations to change both programs from crude research tools into effective clinical diagnosis and outcomes monitoring efforts.

The subcommittee found serious weaknesses in the structure and implementation of the Gulf War health registry programs.⁽³⁸⁰⁾ VA officials characterized their Registry as "a very crude health surveillance tool,"⁽³⁸¹⁾ and a primary source of promising hypotheses for subsequent research. However, in practice, promising but inconvenient hypotheses about the role of chemical exposures were not pursued. Instead, they were dismissed as biased by the self-selected nature of the Registry cohort. Dr. Murphy told the subcommittee, "It should be remembered that the Registry and other examination program data are provided through medical records of self-selected health care-seeking individuals and is not likely to be reflective of the entire population of Persian Gulf War veterans." ⁽³⁸²⁾
Not even near unanimity could overcome VA's resistance to drawing conclusions from their own Registry data. "In 1992 Physician Registry staff documented that 93 percent of Persian Gulf War veterans reported they had been exposed to 1 or more of the 12 contaminants. This percentage declined to a low of 87 percent in 1993, and increased to a high of 98 percent by 1996." ⁽³⁸³⁾ Yet the effects of low level chemical exposures did not become a research priority for the VA until after the announcement of probable exposures at Khamisiyah.⁽³⁸⁴⁾
VA was far less constrained about drawing favorable inferences, however subtly, from Registry data. After appropriate disclaimers about the limitations of Registry data as epidemiological tools, Former VA Secretary Jesse Brown nevertheless concluded, "If there were a neurotoxic exposure that could cause serious neurologic disease in a high proportion of Persian Gulf veterans, it would probably have been identified in the 60,000 Registry exams completed to date." ⁽³⁸⁵⁾
The VA can't continue to have it both ways in the use of Registry information_disclaiming unwelcome propositions while embracing favorable conclusions grounded in the same data. To be of value to veterans, participation in the Registry should demonstrably improve his or her health as well as advance what can be known about the health of all Gulf War veterans. That will require greater use of the VA Referral Centers and the addition of outcomes monitoring as an integral part of the Registry program.⁽³⁸⁶⁾
The Institute of Medicine [IOM] is about to complete studies of the VA and DOD Registry programs. Perhaps that work could be continued to arrive at recommendations for more fundamental changes in the design and implementation of the programs to address the serious weaknesses noted by the subcommittee, GAO and others, and to suggest safeguards against the selective use of health registry data.

Recommendation 4: The VA should refer all Phase II Registry examinations to Gulf War Referral Centers.

Only 2.6 percent of veterans' cases VA reported as having undiagnosable illnesses were evaluated at Gulf War Referral Centers.⁽³⁸⁷⁾ It appears the Uniform Case Assessment Protocol used by both the VA and DOD is not being consistently followed, and often permits a description of symptoms to serve as a diagnosis.⁽³⁸⁸⁾
This lack of aggressive inquiry leaves the VA without the body of detailed test results and clinical assessments needed to discern the subtle manifestations of delayed neuropathies. Absent more effective use of the Referral Centers, the Registry will remain a mere inventory of inconsistently gathered case histories.

Recommendation 5:

[NOTES]

363. Statement of Bernard Rostker to the PAC meeting, Buffalo, NY, July 29 and 30, 1997 (in subcommittee files).
364. Testimony of Kenneth Kizer, Human Resources Subcommittee hearings, No. 1, pp. 50-60.
365. Ibid.
366. Testimony of William Baumzweiger, Human Resources Subcommittee hearings, No. 1-4, p. 480.
367. See supra note 148 and accompanying text.
368. Testimony of Daniel Clauw, Human Resources Subcommittee hearings, Nos. 1-4, p. 178.
369. Ibid., p. 179.
370. Ibid., p. 180.
371. See supra note 196, p. 51.
372. Ibid., p. 54.
373. Ibid., p. 59.
374. PAC Report, p. 27.
375. PAC Report, p. 52.
376. See supra text accompanying note 7.
377. Report to Congress 1993, 1994, 1995, p. 55, U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA (1997).
378. Statement of Frances Murphy, Human Resources and Intergovernmental Relations Subcommittee hearings, Nos. 1-4, p. 414.
379. See also Recommendations 5, 16 and 17, infra.
380. See findings 5, 6, 7, 10 and 12, supra.
381. Testimony of Frances Murphy, Human Resources and Intergovernmental Relations Subcommittee hearings No. 1-4, p. 435.
382. Ibid., p. 412.
383. See supra note 227, p. 5.
384. See supra note 381, p. 414.
385. See supra text of letter from Jesse Brown to Chairman Shays in Background section. See also, attachments to chairman's opening statement, Human Resources and Intergovernmental Relations Subcommittee hearings, Nos. 5-6, p. 14.
386. See infra Recommendations 4 and 9.
387. See supra note 227, p. 5.
388. Ibid., p. 4.