DEVELOPMENT OF A PHYSIOLOGICALLY-BASED MODEL FOR THE TOXICOKINETICS OF C(+ -)P(+/-)-SOMAN IN THE ATROPINIZED GUINEA-PIG/

A physiologically based model was developed which describes the in viv o toxicokinetics of the highly reactive nerve agent C(+/-)P(+/-)-soman at doses corresponding to 0.8-6 LD50 in the atropinized guinea pig. T he model differentiates between the summated highly toxic C(+/-)P(-)-s oman stereoisomers at supralethal doses and the individual nontoxic C( +/-)P(+)-isomers. Several toxicant-specific parameters for the soman s tereoisomers were measured in guinea pig tissue homogenates. Cardiac o utput and blood flow distribution were measured in the atropinized, an esthetized, and artificially ventilated guinea pig. The model was vali dated by comparison of the time courses for the blood concentrations o f the two pairs of stereoisomers in the guinea pig after i.v. bolus ad ministration with the blood concentrations predicted by the model. The predictions put forward for the summated C(+/-)P(-)-isomers are in re asonable agreement with the experimental data obtained after doses cor responding to 2 and 6 LD50. In view of large differences in the rates of hydrolysis of the C(+/-)P(+)isomers, these two isomers had to be di fferentiated for satisfactory modeling of both isomers. In order to mo del the toxicokinetics of C(+/-)P(-)-soman at a dose of 0.8 LD50, the almost instantaneous elimination of the C(+/-)P(-)-isomer at that dose had to be taken into account. The sensitivity of the predictions of t he model to variations in the parameters has been studied with increme ntal sensitivity analysis. The results of this analysis indicate that extension to a model involving four individual stereoisomers is desira ble in view of large differences in the biochemical characteristics of the two C(+/-)P(-)- and C(+/-)P(+)-isomers.