Toxicokinetics of the four stereoisomers of the nerve agent soman in atropinized rats--influence of a soman simulator.
The toxicokinetics of the four stereoisomers of C(+/-)P(+/-)-soman were investigated in anesthetized, atropinized, and artificially ventilated rats at iv doses of 6 (495 micrograms/kg) and 3 LD50. By integration of a thermodesorption/cold trap injector into our GLC analysis, the soman stereoisomers could be followed in rat blood down to a minimum detectable concentration, i.e., 1.5 pg/ml (8.3 pM), 55-fold lower than that published previously. This new detection limit is probably near or below the minimum concentration relevant for survival. Whereas C(+)P(+)-soman disappears in vivo from rat blood within 0.25 min, the toxicokinetics of C(-)P(+)-soman could be described by a two-compartment model, with a biological half-life of 1-1.5 min. The extremely toxic C(+/-)P(-)-isomers could be followed in rat blood for greater than 4 and 2 hr at doses of 6 and 3 LD50, respectively. The toxicokinetics of the P(-)-isomers are best described with a three-compartment model, with terminal half-lives of 40-64 and 16-22 min at doses of 6 and 3 LD50, respectively. Administration of a 13.6-fold molar excess of the soman simulator 1,2,2-trimethylpropyl dimethylphosphinate (PDP) 10 min prior to administration of 6 LD50 of C(+/-)P(+/-)-soman reduces the terminal half-lives of the C(+/-)P(-)-isomers to the values measured at the dose of 3 LD50 without PDP pretreatment. Previous investigations showed that, without PDP pretreatment, rats suffer from endogenous reintoxication 4-6 hr after initially successful therapy, at C(+/-)P(+/)-soman doses greater than or equal to 6 LD50. Both this reintoxication phenomenon due to the presence of toxicologically significant C(+/-)P(-)-soman levels up to 4 hr after intoxication and its antagonism via PDP pretreatment can be understood on the basis of our toxicokinetic measurements. This shows that such investigations can contribute to insight into the toxicology of C(+/-)P(+/-)-soman and to a better treatment of intoxications with this agent.
Benschop
H P
HP
Prins Maurits Laboratory TNO, Rijswijk, The Netherlands.
Bijleveld
E C
EC
De Jong
L P
LP
Van der Wiel
H J
HJ
Van Helden
H P
HP
D000818:Animals; D001285:Atropine / Q000494:pharmacology*; D001794:Blood Pressure; D006207:Half-Life; D006400:Hematocrit; D007928:Lethal Dose 50; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D013237:Stereoisomerism
D001285:Atropine; C048957:pinacolyl dimethylphosphinate; D012999:Soman