cular (i.m.) injection of sarin at one-third of the median lethal dose (LD50)3 (Dasheiff et al., 1977). Catecholamine levels in the nucleus accumbens decreased. All changes, except for the latter, returned to normal within 10 days. It is not clear whether these changes represented the direct action of sarin on enzymes related to noncholinergic neurotransmission or were secondary to the production of excessive ACh (Somani, 1992). Alternatively, stress could activate catecholamine neurons.

Levels of the neurotransmitter serotonin 5-hydroxytryptamine (5-HT) were decreased, and its major metabolite (5-hydroxyindoleacetic acid, or 5-HIAA) increased, in rat striatum after subconvulsive doses of sarin. Since this effect was also seen after administration of the OP nerve agents soman and tabun, it most likely is not agent specific, but rather is a likely consequence of an acute increase of acetylcholine in the striatum (Fernando et al., 1984).

Neuropathological damage in the hippocampus, dorsal thalamus, and piriform cortex was found in about 70 percent of rats within 24 hours of administering a single dose of sarin (95 μg/kg, i.m., or 1 LD50 (Kadar et al., 1995). These animals had prolonged convulsions, whereas the other 30 percent with short convulsive episodes had minimal brain damage. The authors interpreted these results to mean that convulsions may have caused the severe hypoxic damage. The neuropathology in the most affected animals continued to increase for 3 months, involving brain regions previously unaffected. The study attributed the progressive, long-term neuropathology either to delayed neurotoxicity of sarin or to secondary retrograde degeneration. It did not directly investigate potential neurochemical mechanisms underlying the neuropathology.

Toxicokinetics

This section discusses the absorption, distribution, metabolism, and elimination of sarin. In general, these events occur very rapidly after exposure, although there is some variability depending on the route of administration and the species studied (Somani, 1992). Most of the research reported here comes from animal studies, but where possible, human toxicokinetic studies are also reported.

Absorption and Metabolism

Sarin in vapor or liquid form is absorbed rapidly to produce local and systemic effects. Local effects, such as those on the eyes (e.g., miosis) and nose, are the product of sarin vapors directly interacting with AChE at the nerve endings near body surfaces (Sidell and Borak, 1992). Systemic effects, including those within the central nervous system (CNS), occur as a result of absorption of sarin into the circulation from the skin, respiratory tract, or gastrointestinal tract (Lotti, 2000).

3  

LD50 is the lethal dose to half or 50 percent of the test subjects.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement