Toxicokinetics of soman stereoisomers after subcutaneous administration to atropinized guinea pigs.
The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were investigated after subcutaneous administration of a 6 LD50 dose (148 micrograms/kg) to anaesthetized, atropinized, and artificially ventilated guinea pigs. Whereas the relatively nontoxic C(+/-)P(+)-isomers were not detected in blood, the highly toxic C(+/-)P(-)-isomers appeared within 1 min in the general circulation and reached maximum levels of 10-15 ng/ml blood within a period of ca. 7 min. In this absorption phase the blood levels of the C(+)P(-)-isomer lag clearly behind those of the C(-)P(-)-isomer. The blood levels of both C(+/-)P(-)-isomers could be mathematically described using non-linear regression by a three-exponential equation, with one exponential term describing the rapid absorption phase and the other two terms describing distribution and elimination. A comparison with the toxicokinetics of the same isomers upon intravenous administration of the same dose shows that the systemic availability upon subcutaneous administration is in the range of 74-83%. Toxicologically relevant concentrations of the C(+/-)P(-)-isomers prevail almost twice as long after subcutaneous than after intravenous administration. From a toxicokinetic point of view, subcutaneous administration of C(+/-)P(+/-)-soman appears not to be a realistic model for the most relevant route of exposure to C(+/-)P(+/-)-soman in case of chemical warfare, i.e. short term respiratory exposure.
Due
A H
AH
TNO Prins Maurits Laboratory, Rijswijk, The Netherlands.
Trap
H C
HC
Langenberg
J P
JP
Benschop
H P
HP
D000818:Animals; D001285:Atropine / Q000008:administration & dosage; D001682:Biological Availability; D006168:Guinea Pigs; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D012999:Soman / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D013237:Stereoisomerism
D001285:Atropine; D012999:Soman