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Dangerous Chemical Combination Presents Possible Scenario for Gulf War Illnesses

Published April 17, 1996 | Updated January 20, 2016

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Duke Health News919-660-1306

WASHINGTON, D.C. -- Animal experiments at Duke University
Medical Center show that harmless doses of three chemicals used
to protect Gulf War soldiers from insect-borne diseases and
nerve-gas poisoning are highly toxic when used in combination,
researchers reported Wednesday. They said the findings may
explain the wide array of symptoms reported by an estimated
30,000 Gulf War veterans.

In studies using chickens, the researchers specifically
found that two pesticides, DEET and permethrin, and the
anti-nerve gas agent pyridostigmine bromide (PB) were harmless
when used alone, even at three times the doses soldiers likely
received. But when used in combination, the chemicals caused
neurological deficits in the test animals similar to those
reported by some Gulf War veterans, according to Duke
pharmacologist Mohamed Abou-Donia and Tom Kurt, a toxicologist
at The University of Texas Southwestern Medical Center in
Dallas.

Chickens were selected over rodents as test animals because
their susceptibility to neurotoxic chemicals more closely
resembles that of humans, the scientists said.

The findings were prepared for presentation Wednesday at the
annual meeting of the Federation of American Societies for
Experimental Biology and will be published in the May issue of
the Journal of Toxicology and Environmental Health.

The researchers said their findings are similar to those
reported in Scotland last month and by an Israeli team last
year.

Adding to those findings, the Duke and UT Southwestern
scientists have developed a theory to explain why the chemical
mix is dangerous. They said their results indicate the
anti-nerve gas agent reduces the body's normal ability to
inactivate the two pesticides, which can then travel to and
damage the brain and nervous system. Such a mechanism could
explain the wide array of symptoms reported by some Gulf War
veterans, including memory loss, headache, fatigue, muscle and
joint pain, weakness, shortness of breath and tremors, the
researchers said.

"The decision to use these chemicals was made to protect
soldiers from indigenous diseases in the gulf, such as malaria
and leishmaniasis," said Abou-Donia, lead investigator of the
study. "Without protection, there may have been thousands of
deaths. But it appears that, for some veterans, the precautions
prevented one set of problems and created another. Now, our
task is to analyze the veterans' symptoms by investigating all
the potential causes, not only for their sakes but for the
welfare of future soldiers."

The Duke study is one of a three-part investigation on Gulf
War illnesses organized by UT Southwestern. Co-authors of the
Duke study include former Duke researcher Kenneth R. Wilmarth,
now at ENVIRON Corp. in Arlington, Va.; Kurt; Karl F. Jensen of
the Environmental Protection Agency at Research Triangle Park,
N.C.; and Frederick W. Oehme of Kansas State University.

"Together, the three phases of our investigation may solve
the mystery of some Gulf War veterans' illnesses," Kurt said.
"The animal studies are an important component because they
test the biological plausibility of our theory that
combinations of certain chemicals can cause symptoms that are
not caused by individual chemicals alone."

In the Duke study, researchers exposed healthy chickens to
each of the three chemicals -- DEET, permethrin and PB --
individually and then in various combinations.

Doses of each chemical were selected prior to the study by
determining the maximum amount a chicken could withstand
without showing clinical signs -- a dose representing at least
three times the amount soldiers likely received. DEET and
permethrin were administered subcutaneously and PB was given
orally.

"Even if a person was exposed to one chemical alone at three
times the recommended dose, he or she would have remained
healthy," Abou-Donia said. "Our first task was to demonstrate
the safety of each chemical when used individually."

The chickens exposed to individual chemicals showed no
outward signs of illness or debilitation, the researchers said.
But chickens exposed to any two chemical combinations exhibited
varying degrees of weight loss, diarrhea, shortness of breath,
decreased activity, stumbling, leg weakness and a reluctance to
walk, impaired flying or tremors. The combination of all three
chemicals produced the most severe signs, resulting in total
paralysis or death in some chickens.

A laboratory analysis of tissues in the central and
peripheral nervous systems showed that multiple chemical
exposure caused enlarged axons and axonal degeneration, a sign
of widespread nervous system damage.

Tests also suggested that the severity of clinical signs
depends on how active a particular blood enzyme is in removing
the foreign chemicals from the body, the researchers said. This
"scavenger" enzyme, called plasma butyrylcholinesterase
(BuChE), inactivates foreign chemicals such as DEET and
permethrin.

However, the scientists said there is a finite and limited
amount of BuChE in the bloodstream, enough to neutralize DEET
alone or permethrin alone. When multiple chemicals are present,
the enzyme is unable to neutralize them all, resulting in a
toxic accumulation of chemicals in the bloodstream and thus in
the brain and nervous system.

Moreover, the anti-nerve gas agent PB further inhibits the
action of this scavenger enzyme, BuChE. While PB's intended
purpose is to temporarily shield and protect another similar
enzyme, acetylcholine esterase (AChE), from nerve gas damage,
it cannot distinguish between AChE and BuChE and therefore
binds to both, the researchers said. So, even less BuChE is
available to combat and neutralize DEET and permethrin.

"Pyridostigmine bromide actually pumps more of the other
chemicals to the brain," said Abou-Donia. "While PB itself
cannot cross the blood-brain barrier, it magnifies the effects
of the other two chemicals by tying up the available
BuChE."

Abou-Donia said an additional genetic risk factor arises in
some individuals who have a faulty form of BuChE, resulting in
low enzymatic activity and thus a diminished ability to
inactivate drugs or pesticides. This risk factor, which affects
only 3 to 4 percent of the population, may boost the toxicity
of these chemicals.

"Individuals with genetic types of decreased plasma BuChe
activity should be considered potentially at higher risk when
exposed to PB and related compounds, and this may account for
some of the more severe symptoms seen in up to 4 percent of the
Gulf War veterans," said Abou-Donia. An estimated 700,000
military personnel served in the Gulf War.

In addition, soldiers who took higher-than-recommended doses
of PB as an added precaution against nerve gas attacks may have
caused nerve-cell overstimulation, contributing to tremors,
muscle spasms and other symptoms of increased nerve-cell
activity.

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