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Low levels of sarin affect the EEG in marmoset monkeys: A pilot study

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Author: Helden, H.H.P.M. van · Vanwersch, R.A.P. · Kuijpers, W.C. · Trap, H.C. · Philippens, I.H.C. · Benschop, H.P.
Type:article
Date:2004
Institution: Prins Maurits Laboratorium TNO
Source:Journal of Applied Toxicology, 6, 24, 475-483
Identifier: 238062
doi: doi:10.1002/jat.1001
Keywords: EEG · Exposure limits · Field alarm · Lowest observable adverse effect level (LOAEL) · Nerve agent · O-isopropyl methylphosphonofluoridate · Pyridostigmine · Sarin · Sleep-spindles · Whole-body exposure · Pyridostigmine · Sarin · Animal experiment · Blood · Cholinergic system · Controlled study · Electroencephalogram · Energy · Female · Male · Marmoset · Nonhuman · Oscillation · Pilot study · Priority journal · Sleep spindle · Animals · Callithrix · Chemical Warfare Agents · Cholinesterase Inhibitors · Dose-Response Relationship, Drug · Electroencephalography · Female · Humans · Inhalation Exposure · Male · Pyridostigmine Bromide · Sarin · Time Factors · Animalia · marmosets · Pyridostigmine, 101-26-8, 155-97-5 · Sarin, 107-44-8 · Chemical warfare agents · Cholinesterase inhibitors · Pyridostigmine Bromide, 101-26-8

Abstract

The main purpose of this pilot study was to estimate the lowest observable adverse effect level (LOAEL) for the electroencephalogram (EEG) upon long-term, low-level exposure of vehicle-pretreated and pyridostigmine-pretreated marmoset monkeys to sarin vapour. This is the C·t value (t = 5 h) of exposure at which the EEG becomes significantly different from that resulting from air exposure of the same animals. The LOAELs for effects on the EEG in vehicle- and pyridostigmine-pretreated marmosets appeared to be 0.2 and 0.1 mg min m -3, respectively. Comparatively, the latter LOAEL values are at least an order of magnitude lower than the previously established LOAEL for miosis and only 2-5 times higher than the lowest observable effect level (LOEL) of bound sarin in blood. The second aim of the study was to analyse the EEG of the same marmosets again during a 5-h exposure to air 1 year after exposure to sarin vapour. All the marmosets still demonstrated significant (P < 0.05) EEG differences. In most vehicle-pretreated marmosets the energy (μV2) per EEG band was higher than that observed 1 year earlier, which might indicate that neurons had become more sensitive to excitation. This phenomenon was less pronounced in pyridostigmine-pretreated animals. Visual examination of the EEG records revealed clear bursts of alpha frequencies (ca. 9 Hz), resembling sleep-spindles, that were present more frequently in both groups of exposed marmosets than in naive animals. These late changes in spindle oscillation might be the result of changes in the cholinergic system due to exposure to sarin vapour 1 year previously. In conclusion, EEG abnormalities persisting for more than 1 year may occur in humans during long-term (5 h) exposure to subclinical levels of sarin that are not detectable by the currently fielded alarm systems. Copyright © 2004 John Wiley & Sons, Ltd.