Toxicokinetics of soman: Species variation and stereospecificity in elimination pathways

Abstract

Blood levels of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman were analyzed gas chromatographically in anaesthetized, artificially respirated and atropinized rats, guinea pigs and marmosets at intravenous doses of C(+/-)P(+/-)-soman corresponding with 1-6 LD50. The relatively nontoxic C(+/-)P(+/-)-isomers disappear within a few minutes from the blood stream of all three species, whereas the levels of the highly toxic C(+/-)P(-)-isomers remain toxicologically relevant for periods of 50-100 min in three species of doses of 2-3 LD50. Elimination pathways were quantified using 14C-labeled soman stereoisomers. Whereas the C(+/-)P(+)-isomers are largely eliminated by way of enzymatic hydrolysis, the major elimination pathway for the C(+/-)P(-)-isomers is binding to various proteins, in competition with binding to target acetylcholinesterase. Intraspecies nonlinearity with dose in the toxicokinetics of the C(+/-)P(-)-isomers is related to heterogeneous reactivity of the binding sites. Interspecies nonlinearity is probably due to decreasing amounts of binding sites in the order rats greater than guinea pigs greater than primates, leading to increasing "toxico-availability" in the reversed order.