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Gulf War and Health: Insecticides and Solvents, Volume 2
metabolite, 2,5-hexanedione. In contrast, carbon disulfide does not share that metabolite and does not require metabolism for its toxicity. Review of the solvents sent to the Gulf War provides no evidence that military personnel were exposed to n-hexane, methyl-n-butyl ketone, or carbon disulfide. Furthermore, none of the solvents used in the Gulf War is expected to be neurotoxic through a mechanism similar to that of n-hexane, because none of them has a γ-diketone metabolite thought to be required to produce an “n-hexane-like” neuropathy.
In most settings, exposures occur to mixtures of solvents (Bruckner and Warren, 2001). Because many solvents have a common mechanism of action for some outcomes (for example, CNS depression), there can be additive effects. Some solvents (such as ethanol) can induce metabolic enzymes. Those enzymes can catalyze the metabolic activation of some solvents and the metabolic detoxification of others. Therefore, the induction of those enzymes can lead to a potentiation of the toxicity of some solvents and reduce the magnitude and duration of the toxicity of other solvents. Interactions can also occur between compounds that have similar toxic outcomes (for example, carbon tetrachloride and chloroform and their effects on the liver).
Genetic Polymorphisms and Individual Susceptibility
Numerous genetic polymorphisms in metabolic enzymes can alter the toxicokinetics, and consequently the toxicity, of solvents that they metabolized (Bruckner and Warren, 2001; Löf and Johanson, 1998). People who take medications or are exposed to other chemicals that affect those enzymes might have altered susceptibility to some solvents, and people with such conditions as liver disease or kidney disease might be more susceptible to the toxicity of solvents.
Aromatic hydrocarbons are a class of compounds that contain an unsaturated ring structure (Bruckner and Warren, 2001). Benzene, toluene, and xylenes are aromatic hydrocarbons that were or are widely used as solvents and that are thought to have been sent to the Gulf War (see Figure 4.1 for structures). Although no longer used widely as a general-purpose solvent because of concerns about its toxicity, benzene is still used in the synthesis of other chemicals and is a component of gasoline and JP-8 jet fuel. The metabolism of benzene, which occurs in the liver and to a lesser extent in the bone marrow, plays an important role in its toxicity. Benzene is metabolized to benzene oxide, an epoxide, through an oxidation reaction catalyzed primarily by cytochrome P450 2E1. Cytochrome P450 2E11/6 also participates in benzene biotransformation. Benzene oxide can then be metabolized to various compounds, including o-benzoquinone and p-benzoquinone, which are thought to be the two main metabolites that mediate the toxicity of benzene.