Intravenous and inhalation toxicokinetics of sarin stereoisomers in atropinized guinea pigs.
We report the first toxicokinetic studies of (+/-)-sarin. The toxicokinetics of the stereoisomers of this nerve agent were studied in anesthetized, atropinized, and restrained guinea pigs after intravenous bolus administration of a dose corresponding to 0.8 LD50 and after nose-only exposure to vapor concentrations yielding 0.4 and 0.8 LCt50 in an 8-min exposure time. During exposure the respiratory minute volume and frequency were monitored. Blood samples were taken for gas chromatographic analysis of the nerve agent stereoisomers and for measurement of the activity of blood acetylcholinesterase (AChE). In all experiments, the concentration of (+)-sarin was below the detection limit (<5 pg/ml). The concentration-time profile of the toxic isomer, i.e., (-)-sarin, after an intravenous bolus was adequately described with a two-exponential equation. (-)-Sarin is distributed ca. 10-fold faster than C(-)P(-)-soman, whereas its elimination proceeds almost 10-fold slower. During nose-only exposure to 0.4 and 0.8 LCt50 of (+/-)-sarin in 8 min, (-)-sarin appeared to be rapidly absorbed. The blood AChE activity decreased during the exposure period to ca. 15 and 70% of control activity, respectively. There were no effects on the respiratory parameters. A significant nonlinearity of the toxicokinetics with dose was observed for the respiratory experiments.
Spruit
H E
HE
TNO Prins Maurits Laboratory, 2280 AA Rijswijk, The Netherlands.
Langenberg
J P
JP
Trap
H C
HC
van der Wiel
H J
HJ
Helmich
R B
RB
van Helden
H P
HP
Benschop
H P
HP
D000110:Acetylcholinesterase / Q000097:blood; D000280:Administration, Inhalation; D000818:Animals; D019540:Area Under Curve; D001285:Atropine / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008297:Male; D012524:Sarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D013237:Stereoisomerism
D002619:Chemical Warfare Agents; D001285:Atropine; D012524:Sarin; D000110:Acetylcholinesterase