Intravenous and inhalation toxicokinetics of sarin stereoisomers in atropinized guinea pigs

We report the first toxicokinetic studies of (+/-)-sarin. The toxicokinetic s of the stereoisomers of this nerve agent were studied in anesthetized, at ropinized, and restrained guinea pigs after intravenous bolus administratio n 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. Durin g exposure the respiratory minute volume and frequency were monitored. Bloo d samples were taken for gas chromatographic analysis of the nerve agent st ereoisomers and for measurement of the activity of blood acetylcholinestera se (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, (-)-s arin appeared to be rapidly absorbed. The blood AChE activity decreased dur ing the exposure period to ca. 15 and 70% of control activity, respectively . There were no effects on the respiratory parameters. A significant nonlin earity of the toxicokinetics with dose was observed for the respiratory exp eriments. (C) 2000 Academic Press.