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Long-term, low-level exposure of guinea pigs and marmosets to sarin vapor in air: Lowest observable effect level

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Author: Helden, H.P.M. van · Trap, H.C. · Oostdijk, J.P. · Kuijpers, W.C. · Langenberg, J.P. · Benschop, H.P.
Institution: Prins Maurits Laboratorium TNO
Source:Toxicology and Applied Pharmacology, 3, 189, 170-179
Identifier: 237147
doi: doi:10.1016/S0041-008X(03)00131-5
Keywords: Fluoride-induced reactivation · Guinea pigs · Internal dose · Lowest observable effect level (LOEL) · Marmosets · Nerve agent · O-Isopropyl methylphosphonofluoridate · Occupational exposure limits · Respiratory exposure · Sarin · Worker population limit (WPL) · Cholinesterase · Sarin · Animal experiment · Animal trapping · Article · Binding site · Chemical warfare · Cholinesterase inhibition · Controlled study · Enzyme activity · Gas chromatography · Gas mask · Guinea pig · Long term exposure · Male · Marmoset · Measurement · Nonhuman · Occupational exposure · Species comparison · Vaporization · Worker · Animals · Atmosphere Exposure Chambers · Callithrix · Dose-Response Relationship, Drug · Female · Gases · Guinea Pigs · Male · No-Observed-Adverse-Effect Level · Sarin · Threshold Limit Values · Volatilization · Animalia · Cavia · Cholinesterase, 9001-08-5 · Sarin, 107-44-8 · Gases


Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed for exposing conscious animals to 0.05-1.0 μg/m3 (8-160 ppt) of sarin and other nerve agents. Based on cold trapping of sarin from the exposure air, the concentration could be measured semicontinuously, at 4-min time intervals by means of gas chromatography. We found that the LOEL upon a 5-h whole body exposure of guinea pigs and marmosets to sarin vapor corresponds with the measurement of an internal dose by means of fluoride-induced regeneration of sarin from phosphylated binding sites in plasma, mostly BuChE. For guinea pigs the LOEL was observed at Ct = 0.010 ± 0.002 mg/min/m3, whereas a Ct of 0.04 ± 0.01 mg/min/m3 was established for the LOEL in marmosets. These levels are several orders of magnitude lower than those based on classical measurement of depressed cholinesterase activities. At low exposure levels of guinea pigs and marmosets (≤1 μg/m3), a reasonable linearity was observed between exposure dose and internal dose. The data were addressed in the light of the recently recommended occupational exposure limits to sarin for workers without respiratory protection, which suggests that the exposure limits should be reconsidered if the slightest inhibition of cholinesterases should be prevented. © 2003 Elsevier Science (USA). All rights reserved.