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Abou-Donia Study
Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos.
Mohamed B. Abou-Donia, Kenneth R. Wilmarth, Ali A. Abdel-Rahman, Karl F. Jensen, Frederick W. Oehme, and Thomas L. Kurt.
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710. Neurotoxicology Division, U.S. EPA, research Triangle Park, North Carolina 27711. Comparative Toxicology Laboratories, Department of Clinical Sciences, Kansas State University, Manhattan, Kansas 66506-5605; and Department of Internal Medicine, University of Texas, Southwestern Medical School, Dallas, Texas 75235.
Received January 19, 1996; accepted August 20, 1996
Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos. Abou-Donia, M.B., Wilmartin, K.R., Abdel-Rahman, A.A., Jensen, K.F., Oehme, F.W., and Kurt, T.L. (1996) Fundam. Appl. Toxicol. 34, 201-222.
The operating environment of the service personnel during the Persian Gulf War involved psychological, biological, and chemical elementsincluding exposure to pesticides such as the insect repellent DEET (N,N-diethyl-m-toluamide) and the insecticide chlorpyrifos (O,O-diethyl O-3,5,6-trichloropyridinyl phosphorothioate) and to pyridostigmine bromide (PB, 3-dimethylaminocarbonyloxy-N-methylpyridinium bromide) that was administered as a prophylactic agent against possible nerve gas attack. The present study was designed to determine the toxicity produced by individual or coexposure of hens 5 days/week for 2 months to 5 mg PB/kg/day in water, by gavage; 500 mg DEET/kg/day, neat, sc; and 10 mg chlorpyrifos kg/day in corn oil, sc. Coexposure to various binary treatments produced greater neurotoxicity than that caused by individual exposures and was characterized by severe neurologic deficit and neuropathological alterations. ALso, neurotoxicity was further enhanced following concurrent administration of the three chemicals. Severe inhibition of plasma butyrylcholinesterase (BuChE) activity was produced in hens treated with chlorpyrifos (activity 17% of control) compared to those treated with chlorpyrifos (activity 51% of control) or DEET (activity 83% of control). BuChE inhibition was further increased in binary and tertiary treatment groups compared to individual treatment groups. In contrast, a significant inhibition of brain acetylcholinesterase (AChE) was produced in hens administered chlorpyrifos alone (activity 67% of control), while those given chlorpyrifos in combination with other compounds exhibited a significant inhibition of brain AChE activity ranging from 43 to 76%. Brain neurotoxicity target esterase (NTE) was not inhibited in any of the individual treatment groups or PB/DEET, but was significantly inhibited and had activity expressed as a percentage of control in groups administered combined chlorpyrifos with PB of 73% or DEET of 74% and in the tertiary treatment group of 71%. We hypothesize that test compounds may compete for xenobiotic metabolizing enzymes in the liver and blood and may also compromise the inegrity iof the blood-brain barrier, leading to an increase in their "effective concentrations" in the nervous system to levels equivalent to the toxic doses of individual compounds. This is consistent with the prsent observation of increases in (1) the inhibition of brain AChE and NTE, (2) the extent of neurologic lesions in the combined treatment groups compared to those administered individual compounds.
©1996 Society of Toxicology
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