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Low level nose-only exposure to the nerve agent soman: Toxicokinetics of soman stereoisomers and cholinesterase inhibition in atropinized guinea pigs

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Author: Benschop, H.P. · Trap, H.C. · Spruit, H.E.T. · Wiel, H.J. van der · Langenberg, J.P. · Jong, L.P.A. de
Type:article
Date:1998
Institution: Prins Maurits Laboratorium TNO
Source:Toxicology and Applied Pharmacology, 2, 153, 179-185
Identifier: 234727
doi: DOI:10.1006/taap.1998.8490
Keywords: Perception · Atropine · Carboxylesterase · Cholinesterase · Animal cell · Blood level · Enzyme inhibition · Exposure · Guinea pig · Inhalation · Male · Neurotoxicity · Nonhuman · Stereoisomerism · Toxicokinetics · Administration, Inhalation · Animals · Carboxylic ester hydrolases · Chemical warfare agents · Dose-response relationship · Drugs · Erythrocytes · Soman · Stereoisomerism · Time factors · Atropine, 51-55-8 · Carboxylesterase, EC 3.1.1.1 · Carboxylic ester hydrolases, EC 3.1.1.- · Soman, 96-64-0

Abstract

In order to initiate a quantitative basis for the toxicology of low level exposure to nerve agents, the toxicokinetics of soman stereoisomers during nose-only exposure for 5 h to 20 ppb (160 μg/m3) of C(±)P(±)- soman in air were studied in restrained, anesthetized, and atropinized guinea pigs. The concentrations of the toxic C(±)P(-)-soman stereoisomers in blood increased according to a biexponential function, after an initial lag time of ca. 30 min for C(+)P(-)-soman, with final concentrations ≤ 36 pg/ml. It is hypothesized that the lag time is due to binding to carboxylesterases (CaE), partly in the airways prior to systemic uptake. The gradual inhibition of acetylcholinesterase (ACHE) in erythrocytes during the exposure appeared to be in satisfactory accordance with the observed levels of the C(±)P(-)- soman stereoisomers in blood. Inhibition of AChE in brain and diaphragm is insignificant at the end of the exposure period. This result suggests that neuropsychological disorders are unlikely to develop in this exposure scenario. However, incapacitating miosis due to direct penetration of nerve agent into the eye would probably occur. Our experiments should be reconsidered for exposure of primates, which lack scavenging CaE in their blood. It is argued that the same challenge level in primates might give rise to higher blood levels of C(±)P(-)-soman stereoisomers and concomitantly higher inhibition levels of ACHE. Therefore, the critical Ct (mg · min/m3) values for nonsystemic effects on eyes and airways and systemic effects might be less divergent than in guinea pigs.