Chemicals of military deployments: revisiting Gulf War Syndrome in light of new information.

Despite the amount of hard work that has gone into elucidating a toxicological basis for Gulf War Illness, we do not appear to have reached a mechanistic understanding. Investigation of long-term low-level exposure as a basis does not seem to have provided an answer. Nor does the deployment-related toxic soup idea, where exposure to a mixture of toxic chemicals not usually encountered in the same physical vicinity, seems to have explained the symptoms developed by Gulf War Veterans. The idea that an overabundance of CNS acetylcholine leftover from excessive cholinesterase inhibition is at the basis of this syndrome is intellectually appealing and offers a level of neurochemical complexity that may be just beyond the reach of our technical understanding. But no one has yet assembled a coherent mechanism from it either. It seems reasonable that chemical warfare agents were involved. They were not included in early work because it was felt that the toxicant plumes produced during the destruction of stockpiled Iraqi chemical weapons had not been large enough to cause an exposure of US forces and those of our allies. That misconception was disproven, and it is now accepted that people could very well have been exposed to low levels of massive quantities of sarin, cyclosarin, and sulfur mustard. It also seems reasonable that excess acetylcholine or neurological consequences of its presence that we do not fully understand were involved. The combination of nerve agents and the insecticidal anticholinesterases plus the pyridostigmine bromide given prophylactically were probably sufficient to cause the problem. However, the most notable thing is the result of recent work on the toxic mechanism of sulfur mustard showing that it can inhibit the microsomal electron transport chain as a result of sulfonium ion reduction to carbon free radicals by NADPH-cytochrome P450 reductase. This information was not available during the work on Gulf War Illness. So this provides an opportunity to discuss the effects of the general inhibition of the cytochrome P450 system superimposed on the conditions encountered by the participants in Desert Storm and Desert Shield as an approach to the toxicology of mixtures.