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News from the National Academies
Date: Sept. 7, 2000
Contacts: Vanee Vines, Media Relations Associate
Mark Chesnek, Media Relations Assistant
(202) 334-2138; e-mail <news@nas.edu>

FOR IMMEDIATE RELEASE

Evidence Is Insufficient to Link Chronic Health Problems
To Specific Agents Associated With Gulf War

WASHINGTON -- A comprehensive assessment of the available scientific literature reveals that there is not enough evidence to link long-term health problems with exposures to certain drugs, chemicals, and vaccines known to be present during the Gulf War, says a new report by a committee of the National Academies' Institute of Medicine.

The committee evaluated the published, peer-reviewed research on the agents of greatest concern to representatives of Gulf War veterans' organizations for any evidence of a link between long-term health effects and exposure to sarin, pyridostigmine bromide (PB), depleted uranium, and the vaccines to prevent anthrax and botulism. Most of these studies involved exposures in occupational settings, terrorist attacks, and clinical trials. Only a small number studied veterans who may have been exposed to these agents while serving in the Gulf War theater.

Because little information exists on actual exposure levels -- a critical factor when assessing health effects -- the committee emphasized that it could not draw specific conclusions about the health problems of Gulf War veterans. At most, it found limited evidence from three studies that might suggest a link between long-term health effects and exposure to the nerve agent sarin at levels great enough to cause an immediate, intense reaction. But alternative explanations for this link could not be ruled out, and none of these three studies involved Gulf War veterans. On the other hand, the committee found limited, suggestive evidence of no link between exposure to uranium and kidney disease or -- at low exposure levels -- lung cancer.

"We'd like to give veterans and their families definitive answers, but the evidence simply is not strong enough," said committee chair Harold C. Sox Jr., professor and chair, department of medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H. "Without data on the levels of exposure in the Persian Gulf theater, answers will remain elusive."

Gulf War veterans who have experienced chronic health problems following their service are asking whether exposure to various chemical or biological agents might be responsible. Thousands of troops did come in contact with a number of agents before, during, and after the war. Because Iraq had used biological weapons in the past, troops were given vaccines to protect them in the event of an attack.

More than 150,000 U.S. troops are estimated to have received vaccines to protect them from either anthrax or botulism. As further preventive measures, some troops were given packets of the drug PB to be used in case of a chemical attack. If taken in advance, PB can blunt the effects of exposure to some chemical warfare agents. During the war, an estimated 250,000 troops took the drug. While the nerve agent sarin is not believed to have been used during hostilities, some troops may have been exposed to low levels of it during cleanup operations after the war. Also, as a result of friendly fire incidents, some troops were exposed to depleted uranium.

The U.S. Department of Veterans Affairs initially requested an Institute of Medicine study of potentially harmful chemical, biological, or environmental agents to which Gulf War veterans might have been exposed. Congress subsequently mandated a similar study listing 33 specific agents. This report is the first of a series; the next committee will review the scientific literature on pesticides and solvents.

Weighing the Evidence

The committee reviewed all relevant studies published in peer-reviewed journals. Because only a small number of studies directly involved Gulf War veterans, the committee extended its review to include research involving any human population that had contact with these agents at any dose. It carefully assessed the quality, limitations, and applicability of each study and used five categories to describe the strength of all the evidence.

Sufficient evidence of a causal relation, the strongest level of evidence, means that many studies have established a clear link between exposure to an agent and a health outcome. Among the other requirements, there must be a plausible biological explanation for the relationship. Evidence that establishes a link between exposures and symptoms with reasonable certainty, but fails to meet the higher standard of proof needed for causality, is characterized as sufficient evidence of an association. When a limited number of studies suggests that a link exists, but without reasonable certainty, the evidence is said to be limited or suggestive of an association. If several studies of adequate quality consistently fail to show a positive association at any level of exposure, the evidence is described as limited or suggestive of no association. Evidence that lacks sufficient quality, consistency, or statistical power to draw any conclusion is judged to be inadequate or insufficient to determine whether an association exists. Most of the evidence concerning long-term effects fell into this last category.

Sarin

The nerve agent sarin is so potent that as little as 100 milligrams -- the equivalent of about two drops -- penetrating the skin, eyes, or mucous membranes can cause convulsions and death. In its gaseous state, as little as 50 milligrams can be fatal. At lower levels, exposures can cause overstimulation of nerves and muscles within seconds or hours, creating symptoms such as severe cramping, difficulty breathing, twitching, pinpoint pupils, and heavy sweating. These widespread symptoms, called an acute cholinergic syndrome, clear up within days to months. After reviewing the accumulated science on short-term effects, the committee judged the evidence as sufficient to establish a causal relationship -- that exposure to a high-enough dose of sarin can cause an acute cholinergic syndrome.

But the evidence concerning long-term effects of sarin is much weaker, the committee said. Three studies -- two involving victims of terrorist attacks in Japan and one involving industrial accidents in the United States -- linked neurological and psychological symptoms that persisted for six months or longer following exposure to sarin. In one of the studies, some symptoms persisted for up to three years, the longest that any of the subjects were tracked. The doses of sarin in all three studies were high enough to trigger an intense, immediate reaction -- acute cholinergic signs and symptoms. Among the conditions that persisted over the long term were fatigue, headaches, blurred vision, and symptoms of post-traumatic stress disorder. Because of the limited number of studies, and because alternative explanations for the effects could not be ruled out, the committee described this evidence as "limited or suggestive of an association." The committee recommended further research to track the health of the victims of sarin attacks in Japan.

Available evidence does not permit any conclusion as to whether long-term health effects are associated with sarin exposures that were too low to produce any short-term signs or symptoms, the committee said. However, based on the findings of a study on nonhuman primates, it is reasonable to hypothesize that such an association could exist, and the committee recommended further research.

Pyridostigmine Bromide

PB is a drug routinely used in the treatment of myasthenia gravis -- a disease that causes weakening of the muscles. While effective, the drug can produce gastrointestinal and muscular symptoms that are transient, mild, and tolerable. Troops in the Gulf War were given packets of PB tablets to take in advance of a chemical-weapons attack, in the hope of moderating the effects of nerve agents. Recommended doses were lower than those commonly used by doctors to treat patients with myasthenia gravis.

After reviewing the evidence of PB's short-term effects, the committee characterized it as sufficiently strong to demonstrate an association between exposure and the immediate onset of mild, transient symptoms. But it said no conclusion could be drawn about its association with long-term health problems. One series of studies has suggested that PB, either alone or in combination with other chemicals, may be related to some chronic neurological changes or damage reported by Gulf War veterans. But the validity of this association is uncertain because of weaknesses in study design, and it requires further investigation, the committee said.

Depleted Uranium

During the Gulf War, some tanks and munitions containing depleted uranium caught fire or exploded. As a result, a number of military personnel inhaled or ingested depleted uranium. Flying fragments of the material injured others. In its depleted form, uranium is 40 percent less radioactive than in its natural state. The health effects of uranium have been widely investigated, mostly in occupational settings, but the committee found weaknesses in many of these studies. Based on this evidence, it said that no conclusion can be drawn about the effects of depleted uranium and the development of lymphatic or bone cancer; nonmalignant respiratory disease; diseases of the nervous system, gastrointestinal tract, and liver; and other health outcomes. Still, the committee did conclude that there is limited evidence of no association between exposure to uranium and kidney disease, nor between exposure to low levels of uranium and lung cancer. At high levels of exposure, however, the evidence about lung cancer was unclear. The committee recommended follow-up research on veterans with embedded fragments of depleted uranium, and other long-term studies.

Vaccines

The short-term local and systemic effects of the vaccines used to prevent anthrax and botulism have been documented, and the committee characterized the evidence as sufficient to demonstrate an association. Redness, swelling, and tenderness at the site of injection were typical side effects, lasting up to 48 hours. A small number of subjects in studies experienced systemic effects similar to those associated with any vaccination, such as fever that lasted for 24 to 48 hours.

Whether long-term adverse health effects are associated with vaccinations to prevent anthrax and botulism cannot be assessed, the committee concluded. No published, peer-reviewed studies have systematically used active surveillance to evaluate long-term health effects. But that situation is not unusual, as few vaccines have been monitored for adverse effects over long periods of time. The committee recommended that such studies be conducted to determine whether the vaccines produce chronic effects.

Some research has examined whether the cumulative effect of several vaccines in a short span of time can have long-term adverse consequences. However, the committee found shortcomings in these studies, and concluded that the evidence is inadequate or insufficient to determine whether an association exists.

The study was sponsored by the U.S. Department of Veterans Affairs. The Institute of Medicine is a private, nonprofit institution that provides health policy advice under a congressional charter granted to the National Academy of Sciences. A committee roster follows.

Read the full text of Gulf War and Health, Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines for free on the Web, as well as more than 1,800 other publications from the National Academies. Printed copies are available for purchase from the National Academy Press Web site or at the mailing address in the letterhead; tel. (202) 334-3313 or 1-800-624-6242. Reporters may obtain a pre-publication copy from the Office of News and Public Information at the letterhead address (contacts listed above).

INSTITUTE OF MEDICINE
Division of Health Promotion and Disease Prevention

Committee on Health Effects Associated with Exposures During the Gulf War

Harold C. Sox Jr., M.D.* (chair)
Joseph M. Huber Professor of Medicine
and Chair
Department of Medicine
Dartmouth-Hitchcock Medical Center
Lebanon, N.H.

Michael Aschner, Ph.D.
Professor
Department of Physiology and Pharmacology
School of Medicine
Wake Forest University
Winston-Salem, N.C.

Patricia A. Buffler, M.P.H., Ph.D.*
Dean Emerita and Professor of Epidemiology
School of Public Health
University of California
Berkeley

Lucio Guido Costa, Ph.D.
Professor and Director of Toxicology
Department of Environmental Health
University of Washington
Seattle

Firdaus Dhabhar, Ph.D.
Assistant Professor
College of Dentistry
Ohio State University
Columbus

Anthony L. Komaroff, M.D.
Professor of Medicine
Harvard Medical School;
Senior Physician
Brigham and Women's Hospital; and
Editor in Chief
Harvard Medical Publications
Boston

Janice L. Krupnick, Ph.D.
Clinical Professor of Psychiatry
Department of Psychiatry
Georgetown University, and
Clinical Psychologist
Washington, D.C.

Herbert E. Lowndes, Ph.D.
Professor
College of Pharmacy
Rutgers University
Piscataway, N.J.

Ernest L. Mazzaferri, M.D., M.A.C.P.
Emeritus Professor and Chair
Department of Internal Medicine
Ohio State University
Columbus

Demetrios J. Moschandreas, Ph.D.
Professor of Environmental Engineering and Associate Chair
Department of Chemical and
Environmental Engineering
Illinois Institute of Technology, and
Deputy Director
Institute for Science, Law, and Technology
Chicago

Charles E. Phelps, Ph.D.*
Provost
University of Rochester
Rochester, N.Y.

Samuel J. Potolicchio, M.D.
Professor
Department of Neurology
George Washington University Medical Center
Washington, D.C.

Jean F. Regal, Ph.D.
Professor of Pharmacology
Department of Pharmacology
School of Medicine
University of Minnesota
Duluth

Marc Schenker, M.D., M.P.H.
Professor of Medicine and Chair
Department of Epidemiology and
Preventive Medicine
School of Medicine
University of California
Davis

Peter H. Schur, M.D.
Professor of Medicine
Harvard University, and
Director
Clinical Immunology Lab
Brigham and Women's Hospital
Boston

Francoise Seillier-Moiseiwitsch, Ph.D.
Associate Professor
Department of Biostatistics
School of Public Health
University of North Carolina
Chapel Hill

Walter C. Willett, M.D., Dr.P.H.*
Professor of Epidemiology and Nutrition, and Chair
Department of Nutrition
Harvard School of Public Health
Boston

Scott L. Zeger, Ph.D.
Professor and Chair
Department of Biostatistics
School of Hygiene and Public Health
Johns Hopkins University
Baltimore

INSTITUTE STAFF

Carolyn Fulco, M.S.
Study Director

Cathy Liverman, M.L.S
Study Director

*Member, Institute of Medicine