TOXICOKINETICS OF SOMAN - SPECIES VARIATION AND STEREOSPECIFICITY IN ELIMINATION PATHWAYS

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 the three species at doses of 2-3 LD50. Elimination pathways were quantified using C-14-labeled soman stereoisomers. Whereas the C(+/-) P(+)-isomers are largely eliminated by the 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 heterogenous reactivity of the binding sites. Interspecies nonlinearity is probably due to decreasing amounts of binding sites in the order rats > guinea pigs > primates, leading to increasing "toxico-availability" in the reversed order.