cortisol (an indicator of stress), there was no inhibition of brain AChE. There was also no autoradiographic evidence that PB had entered the CNS. Hence, stress in guinea pigs fails to enhance PB penetration, while in mice (Friedman et al., 1996) and rats (Sharma et al., 1992), stress appears to permit entry of the drug. Whether these differences stem from species differences, age of the animals used, or other variables remains to be determined.

Interactions with Other Agents

Interactions between agents present during the Gulf War have been hypothesized or suspected to contribute to the illnesses of Gulf War veterans (IOM, 1995; PAC, 1996, 1997). Several mechanisms exist whereby other chemical compounds may influence the pharmacological and toxicological actions of PB. These may occur through pharmacological antagonism, synergism, addition, and so forth, presumably by actions on entirely different receptor types. Alternatively, the presence of other chemical(s) may enhance absorption or interfere with detoxification processes, leading in either case to an exaggeration of the pharmacological and/or toxicological effects of PB. The possible outcomes of the interactions of several relevant chemicals have recently been discussed (Golomb, 1999).

Pharmacological Interactions

There have been limited studies of possible toxic interactions between PB and other agents to which there was reported or putative exposure during the Gulf War. Co-exposure of hens to total cumulative doses of 200, 400, and 20,000 mg/kg of PB, chlorpyrifos, and N,N-diethyl-m-toluamide (DEET) respectively, over 2 months resulted in increased indices of toxicity (Abou-Donia et al., 1996a). Neurological indices of dysfunction were more severe in birds receiving the combined exposures, paralleling perhaps the more prominent neuropathology observed in the sciatic nerve and spinal cord and the greater degree of inhibition of plasma ChE and brain AChE. It is noteworthy that the pathology and the neurological impairment are hallmarks of OPIDN, but symptoms of this neurotoxic disorder are not consistent with those reported in Gulf War veterans’ illnesses. Also, in this study (Abou-Donia et al., 1996a), neither PB nor DEET inhibited NTE (neuropathy target esterase), consistent with observations that neither produces OPIDN. Chlorpyrifos, an organophosphate pesticide used in the Gulf War, does inhibit NTE, but only by 27–29 percent, which is below the threshold of inhibition required to precipitate OPIDN.

An analogous study by the same authors (Abou-Donia et al., 1996b) exposed hens to combinations of PB and DEET, but with administration of permethrin (total dose 20,000 mg/kg) rather than chloropyrifos. Again, combinations of the agents proved more toxic than single exposures, and with the substitution of permethrin for chlorpyrifos, weaker inhibition of ChE was noted.



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