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. The findings may explain the wide array of symptoms reported by an estimated 30,000 Gulf War veterans.
When the pesticides DEET and permethrin, and the anti nerve gas agent pyridostigmine bromide (PB) were used in combination, the chemicals caused neurological deficits in the test animals similar to those reported by some Gulf War veterans, according to Mohamed Abou-Donia, a Duke pharmacologist and Tom Kurt, a toxicologist at the University of Texas Southwestern Medical Center in Dallas. The researchers said their findings are similar to those reported in Scotland in March 1996 and by an Israeli team in 1995.
Chickens were selected over rodents as test animals because their susceptibility to neurotoxic chemicals more closely resembles that of humans.
The researchers, led by Abou-Donia and Kurt, have developed a theory to explain why the chemical mix is dangerous. They said their results indicate that 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, headaches, fatigue, muscle and joint pain, weakness, shortness of breath and tremors.
"The decision to use these chemicals was made to protect soldiers from indigenous diseases in the Gulf, such as malaria and leichmaniasis," said Abou-Donia. "Without protection, there may have been many 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 analyse the veterans' symptoms by investigating all potential causes, not only for their sakes but the welfare of future soldiers."
The Duke study is one of a three part investigation in Gulf War illness organised by the University of Texas. "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 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 if 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 stand without showing clinical signs -- a dose representing at least three times the amount soldiers 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, Diarrhoea, 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 of the chickens.
A laboratory analysis of tissues in the central and peripheral nervous systems showed showed that multiple chemical exposure caused enlarged axions and anonal 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 butyryl-cholinesterase (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 neutralise DEET alone or permethrin alone. When multiple chemicals are present, the enzyme is unable to neutralise them all, resulting in a toxic accumulation of chemicals in the bloodstream and thus 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, acetylcholinesterase (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 neutralise Deet and permethrin.
"Pyridostigmine bromide actually pumps more of the other chemicals to the brain," Abou-Donia said. "While PB itself cannot cross the blood brain barrier, it magnifies the effects of the other chemicals by tying up available BuChE."
Abou-Donia said an additional 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 3-4 % 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% of the Gulf War veterans.
The research team is conducting a follow up study analysing blood samples from veterans with and without symptoms to determine if low enzymatic activity is associated with signs of illness.
Thanks to Benita Cranford , St Petersburg, FL, for all the press release and a copy of the study.
For a copy of the 22 page study "Neurotoxicity Resulting from Co-Exposure to Pyridostigmine Bromide, DEET, and permethrin: Implications of Gulf War Chemical Exposure," send $5.20 to CIIN. Order No. 0030-ABOU-06-022
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