Abstract
This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD50 values) were estimated by probit analysis. In all animal groups, the rank order of LD50 values was sarin > soman > VX. The LD50 value of soman was not influenced by sex or age of the animals. In contrast, the LD50 values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC50 values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD50 values and IC50 values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD50 values and IC50 values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.
Footnotes
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This work was supported in part by the National Institutes of Health National Institute of Neurological Disorders and Stroke CounterACT Program [Grant U01-NS059344]; and by the United States Army Research Office [Contract W911NF-06-1-0098].
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Opinions or assertions contained herein are the private views of the authors and should not be construed as official or as reflecting the views of the U.S. Army or the Department of Defense.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.146639.
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ABBREVIATIONS: OP, organophosphorus/organophosphate; AChE, acetylcholinesterase; CNS, central nervous system; RBC, red blood cell; PND, postnatal day; iso-OMPA, tetraisopropylpyro-phosphoramide; ANOVA, analysis of variance; AU, absorbance units.
- Received September 25, 2008.
- Accepted October 30, 2008.
- U.S. Government work not protected by U.S. copyright
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