NEUROTOXICITY RESULTING FROM COEXPOSURE TO PYRIDOSTIGMINE BROMIDE, DEET, AND PERMETHRIN - IMPLICATIONS OF GULF-WAR CHEMICAL EXPOSURES

Of the three-quarters of a million service personnel involved in the P ersian Gulf War, approximately 30,000 have complained of neurological symptoms of unknown etiology. One contributing factor to the emergence of such symptoms may be the simultaneous exposure to multiple agents used to protect the health oi service personnel, in particular, the an ti-nerve agent pyridostigmine bromide (PB; 3-dimethylaminocarbonyloxy- N-methylpyridinium bromide), the insect repellent DEET (N,N-diethyl-m- toluamide), and the insecticide permethrin chloro-ethenyl)-2,2-dimethy lcyclopropanecarboxylic acid (3-phenoxyphenyl)methyl ester). This stud y investigated neurotoxicity produced in hens by individual or simulta neous exposure to these agents (5 d/wk for 2 months to 5 mg/kg/d PB in water, po; 500 mg/kg/d DEET, neat, sc; and 500 mg/kg/d permethrin in corn oil, sc). At these dosages, exposure to single compounds resulted in minimal toxicity. Combinations of two agents produced greater neur otoxicity than that caused by individual agents. Neurotoxicity was fur ther enhanced following concurrent administration of all three agents. We hypothesize that competition for liver and plasma esterases by the se compounds leads to their decreased breakdown and increased transpor t of the parent compound to nervous tissues. Thus, carbamylation of pe ripheral esterases by PB reduces the hydrolysis of DEET and permethrin and increases their availability to the nervous system. In effect, PB ''pumps'' more DEET and permethrin into the central nervous system. C onsistent with this hypothesis, hens exposed to the combination of the three agents exhibited neuropathological lesions with several charact eristics similar to those previously reported in studies oi near-letha l doses of DEET and permethrin. If this hypothesis is correct, then bl ood and liver esterases play an important ''buffering'' role in protec ting against neurotoxicity in the population at large. It also suggest s that individuals with low plasma esterase activity may be predispose d to neuro-logic deficits produced by exposure to certain chemical mix tures.