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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines
The fate of sarin in the blood is a major determinant of how much sarin reaches the central nervous system and other sites of systemic toxicity. In the blood, sarin first interacts with several esterases (a class of enzymes). Some of the esterases, such as paraoxonase, hydrolyze sarin to inactive metabolites (Davies et al., 1996; Lotti, 2000). Two other blood esterases—AChE and butyrylcholinesterase (BuChE)—irreversibly bind to sarin. AChE found on the surface of red blood cells (RBCs), although chemically indistinguishable from AChE in the nervous system, has unknown physiological functions (Sidell and Borak, 1992). These esterases in the blood are often described as “false targets”—by binding irreversibly to sarin, AChE and BuChE sequester sarin in the blood, thereby preventing some or all from reaching the CNS (Spencer et al., 2000). However, esterases in the blood can be overwhelmed by high doses of sarin. The acute cholinergic syndrome occurs when RBC AChE is inhibited by 75–80 percent (Sidell and Borak, 1992).
Distribution and Elimination
The tissue distribution of sarin and its metabolites has been studied in rodents. In one study a single sublethal dose (80 μg/kg) of radiolabeled sarin was administered intravenously, after which tissues were examined at distinct points in time for 24 hours (Little et al., 1986). Within 1 minute, sarin was distributed to the brain (and thus crossed the blood–brain barrier), lungs, heart, diaphragm, kidneys, liver, and plasma, with the greatest concentrations found in the last three tissues. Thereafter, the concentrations in all tissues declined. Within 15 minutes, sarin concentrations declined by 85 percent, followed by a second, more gradual decline. Relatedly, within the first minute, about half of the labeled sarin was associated with the major sarin metabolite isopropyl methylphosphonic acid (IMPA). A nonextractable label was present in constant amounts in all tissues, except plasma, throughout the time course of the experiment.
The kidneys are the major route of elimination of sarin or its metabolites. In the above study, Little and colleagues (1986) determined that kidneys contained the highest concentrations of sarin and its metabolites, whereas much lower concentrations of metabolite were detected in the liver. This suggests a minor role for the liver in detoxification of sarin. Shih and colleagues (1994) injected rats subcutaneously with a single dose of 75 μg/kg of sarin. They then measured excretion of the hydrolyzed metabolites, the alkylmethylphosphonic acids, which include IMPA and other methylphosphonic acids. Urinary elimination was found to be quite rapid; the terminal elimination half-life of sarin metabolites in urine was 3.7 ± 0.1 hours. Nearly all of the administered dose of sarin was retrieved from the urine in metabolite form after 2 days.
Distribution, metabolism, and elimination of sarin in humans appear to resemble findings in animals. Minami and colleagues (1997) detected the sarin metabolite IMPA in urine of humans after the terrorist attack on the Tokyo subway system (see later description). They found peak levels of IMPA or methylphosphonic acid in urine 10–18 hours after exposure but did not report meta-