Toxicokinetics of the four stereoisomers of soman in the rat, guinea pig, and marmoset. Final report
report
Methods for stabilization and work up of the soman isomers in blood and other biological materials were developed. In combination with chiral gas chromatography, a verified minimum detectable 8.3 pM concentration of each highly toxic C(±)P(-)-soman isomer in blood can be measured.
Toxicokinetic investigations involved:
1. Measurement of the blood levels of the four stereoisomers of soman as a function of time after iv administration of C(±)P(±)-soman at a dose equivalent to 6 LD50 to anaesthetized, atropinized, and artificially ventilated rats (495 pg/kg), guinea pigs (165 pg/kg), and marmosets (60 pg/kg).
2. Further toxicokinetic investigations in rats with regard to (i) the levels of soman stereoisomers in brain and diaphragm; (ii) the influence of pretreatment with the soman simulant pinacolyl dimethylphosphinate on the blood levels; and (iii) the influence of dose reduction of C(±)P(±)-soman on the blood levels.
In vitro studies to characterize (K and V ) the hydrolysis of the four stereoisomers of soman catalyzed by phosphoryIphosphatases in plasma and liver homogenates of rats guinea pigs, and marmosets, as well as in human plasma.
In contrast with the relatively nontoxic C(±)P(+)-isomers, which disappear within 4 min from blood, the extremely toxic C(±)P(-j-isomers could be followed in blood for several hours. The decay of the blood levels is described with a three-exponential function. A considerable "interspecies nonlinearity1' is observed when the toxicokinetics of C(±)P(-)- soman is compared at doses equivalent to 6 LD50, in the sense that blood levels in guinea pigs, and especially in marmosets, are higher than might be expected on the basis of blood levels in rats.
The relative rates /K ) of in vitro hydrolysis of the C(±)P(-)-soman isomers in plasma and liver homogenates or the three animal species do not correlate with the relative rates of in vivo elimination in these species.
Toxicokinetic investigations involved:
1. Measurement of the blood levels of the four stereoisomers of soman as a function of time after iv administration of C(±)P(±)-soman at a dose equivalent to 6 LD50 to anaesthetized, atropinized, and artificially ventilated rats (495 pg/kg), guinea pigs (165 pg/kg), and marmosets (60 pg/kg).
2. Further toxicokinetic investigations in rats with regard to (i) the levels of soman stereoisomers in brain and diaphragm; (ii) the influence of pretreatment with the soman simulant pinacolyl dimethylphosphinate on the blood levels; and (iii) the influence of dose reduction of C(±)P(±)-soman on the blood levels.
In vitro studies to characterize (K and V ) the hydrolysis of the four stereoisomers of soman catalyzed by phosphoryIphosphatases in plasma and liver homogenates of rats guinea pigs, and marmosets, as well as in human plasma.
In contrast with the relatively nontoxic C(±)P(+)-isomers, which disappear within 4 min from blood, the extremely toxic C(±)P(-j-isomers could be followed in blood for several hours. The decay of the blood levels is described with a three-exponential function. A considerable "interspecies nonlinearity1' is observed when the toxicokinetics of C(±)P(-)- soman is compared at doses equivalent to 6 LD50, in the sense that blood levels in guinea pigs, and especially in marmosets, are higher than might be expected on the basis of blood levels in rats.
The relative rates /K ) of in vitro hydrolysis of the C(±)P(-)-soman isomers in plasma and liver homogenates or the three animal species do not correlate with the relative rates of in vivo elimination in these species.
Topics
StereochemistryG agentsRatsGuinea pigsBloodBrainDiaphragm (anatomy)ProphylaxisStabilityExcretionUrineHydrolysisReaction kineticsGC - Gas chromatographySomanSoman stereoisomersD13-C(±)P(±)-somanD3-C(-)P(+)-somanSoman simulantChiral gas chromatographyStabilizationAnalysisBloodBrainDiaphragmUrineToxicokineticsPigMarmosetC(+)P(+)-somanC(-)P(+)-somanC(+)P(-)-somanPhosphonylphosphatases
TNO Identifier
110659
Publisher
TNO
Collation
221 p.
Place of publication
Rijswijk
Files
To receive the publication files, please send an e-mail request to TNO Repository.