Toxicokinetics of inhaled soman and sarin in guinea pigs. Final report
report
The inhalation toxicokinetics of C(±)P(±)-soman and (±)-sarin were studied in anesthetized, atropinized guinea pigs. An apparatus was constructed for continuous generation of nerve agent vapor in air and nose-only exposure. During exposure the respiratory minute volume (RMV) and respiratory frequency (RF) were monitored. Blood samples were taken for gas chromatographic analysis of the concentrations of nerve agent stereoisomers, and to measure the progressive inhibition of acetylcholinesterase (AChE). The animals were exposed for 4-8 min to 0.4 or 0.8 LCt50 of C(±)P(±)-soman or (±)-sarin. The toxicokinetics of intravenous bolus administration of doses corresponding with 0.8 LD50 were studied as references for the inhalation experiments.
Concentrations of the P(-)-isomers increased rapidly during exposure, up to several ng/ml blood. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer. The measured progression of AChE inhibition was approximately in accordance with the observed blood levels of C(±)P(-)-soman. The results obtained of the various inhalation experiments with C(±)P(±)-soman indicated nonlinearity of the toxicokinetics, both with dose and with exposure time. Upon 8-min exposure to concentrations of (±)-sarin vapor in air yielding 0.4 and 0.8 LCtSO, (-)-sarin was detectable in blood up to 2 h after exposure, whereas (+)-sarin was not detectable at all. Nonlinearity of the toxicokinetics with the (±)-sarin dose was observed.
P(-)-isomers were detected in blood upon nose-only exposure of guinea pigs for 5 h to 0.1 LCtSO of C(±)P(±)-soman, with maximum concentrations of ca. 40 pg/ml. Blood AChE was gradually inhibited up to ca. 95 % during the 5 h exposure, whereas brain AChE was not significantly inhibited. Nerve agent-related effects on RMV and RF were absent in all of the inhalation experiments. Intravenous infusion of C(±)P(±)-soman appeared to be a suitable substitute for the absorption phase in the technically involved respiratory exposure, unlike intramuscular bolus administration.
Concentrations of the P(-)-isomers increased rapidly during exposure, up to several ng/ml blood. The absorption phase of C(+)P(-)-soman lagged behind that of the C(-)P(-)-isomer. The measured progression of AChE inhibition was approximately in accordance with the observed blood levels of C(±)P(-)-soman. The results obtained of the various inhalation experiments with C(±)P(±)-soman indicated nonlinearity of the toxicokinetics, both with dose and with exposure time. Upon 8-min exposure to concentrations of (±)-sarin vapor in air yielding 0.4 and 0.8 LCtSO, (-)-sarin was detectable in blood up to 2 h after exposure, whereas (+)-sarin was not detectable at all. Nonlinearity of the toxicokinetics with the (±)-sarin dose was observed.
P(-)-isomers were detected in blood upon nose-only exposure of guinea pigs for 5 h to 0.1 LCtSO of C(±)P(±)-soman, with maximum concentrations of ca. 40 pg/ml. Blood AChE was gradually inhibited up to ca. 95 % during the 5 h exposure, whereas brain AChE was not significantly inhibited. Nerve agent-related effects on RMV and RF were absent in all of the inhalation experiments. Intravenous infusion of C(±)P(±)-soman appeared to be a suitable substitute for the absorption phase in the technically involved respiratory exposure, unlike intramuscular bolus administration.
Topics
ToxicokineticsSoman / GD agentGB agentGuinea pigsStereochemistryBloodAnalyzingGC - Gas chromatographyRespirationNerve agentsInhibitionAcetylcholinesteraseExposureExperimentationSynthesisSoman stereoisomersSarinSarin stereoisomersAnalysisTwo-dimensional gas chromatographyThermodesorption/cold-trap injectionLarge-volume injectionD13-C(±)P(+)-SomanD7-(-)-SarinInhalation toxicityLCt5ONerve agent vaporGeneration apparatusExposure apparatusNose-only exposureShort-term exposureLong-term exposureRespiratory parametersAcetylcholinesterase (AChE) activityRadiometryIntravenous bolusIntravenous infusionIntramuscular bolus
TNO Identifier
122807
Publisher
TNO
Collation
174 p.
Place of publication
Rijswijk