Research Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, USA.
Prog Mol Biol Transl Sci. 2012;112:209-30. doi: 10.1016/B978-0-12-415813-9.00007-6.
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.
尽管在阐明海湾战争疾病的毒理学基础方面付出了大量努力，但我们似乎仍未达到机制理解的程度。作为基础的长期低水平暴露调查似乎没有提供答案。也没有部署相关的有毒汤的想法，即接触通常不会在同一物理环境中遇到的混合有毒化学物质，似乎无法解释海湾战争退伍军人所出现的症状。过量的中枢神经系统乙酰胆碱残留在过度抑制胆碱酯酶的基础上的想法在智力上是有吸引力的，并提供了一种神经化学复杂性的水平，可能超出了我们技术理解的范围。但是，也没有人从这方面提出一个连贯的机制。化学战剂的参与似乎是合理的。它们没有包含在早期的工作中，因为人们认为在销毁伊拉克库存的化学武器时产生的有毒烟雾云团还不够大，不会对美国军队和我们的盟国军队造成暴露。这种误解被证明是错误的，现在人们普遍认为，人们很可能接触到大量的沙林、梭曼和硫芥子气，只是接触的水平较低。另外，也有理由认为，过量的乙酰胆碱或我们不完全理解的其存在的神经后果也参与其中。神经毒剂和杀虫剂抗胆碱酯酶以及预防性给予的溴吡斯的明的组合可能足以引起这个问题。然而，最近对硫芥子气的毒性机制的研究结果最为引人注目，该研究表明，由于 NADPH-细胞色素 P450 还原酶将硫翁离子还原为碳自由基，硫芥子气可以抑制微粒体电子传递链。在海湾战争疾病的研究中，这些信息是无法获得的。因此，这提供了一个机会，即讨论细胞色素 P450 系统的普遍抑制对沙漠风暴和沙漠盾牌行动参与者所遇到的情况的影响，作为一种混合物毒理学的方法。
