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TOXICOLOGY

Acute Toxicity of Organophosphorus Compounds in Guinea Pigs Is Sex- and Age-Dependent and Cannot Be Solely Accounted for by Acetylcholinesterase Inhibition

Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland (W.P.F., Y.A., E.F.R.P., E.X.A.); and Neurobehavioral Toxicology Branch, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (M.A.)

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.

Address correspondence to: Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201. E-mail: ealbuque{at}umaryland.edu