Determination of Parameters for Development of a Physiologically Based Model for the Toxicokinetics of C(+)P(+)-Soman.

摘要

Toxicant-specific parameters needed for development of a physiologically based model for the toxicokinetics of C(+/-)P(-)-soman in guinea pig were determined in blood, and in homogenates of brain, liver, kidney, lung, and a skeletal muscle (gastrocnemius et soleus). Tissue/blood partition coefficients for the diastereoisomers of C(+/-)P(+/-)-soman were obtained from the partition coefficients determined for blood/air and tissue homogenate/air by gas chromatographic analysis in the air phase. Elimination of C(+/-)P(+/-)-soman by covalent binding was blocked by pretreatment with the very labile crotyl sarin (2-butenyl methylphosphonofluoridate). Enzymatic hydrolysis was stopped by lowering the pH. Relatively high concentrations of sites for covalent binding of C(+/-)P(-)-(14)C-soman were found in liver and kidney homogenates, whereas these concentrations were low in the target organs, i.e., brain and muscle. Only a fraction of the available binding sites reacts rapidly with C(+/-)P(-) soman. Indications were obtained for contribution of C(+/-)P(+)-soman to binding in liver and kidney homogenates. The half-life times of hydrolysis for C(-)P(-)-soman in plasma and in tissue homogenates were similar to the values obtained previously for C(+)P(-)-soman hydrolysis. Physiologically based modelling, Toxicokinetics, C(+/-)P(+/-)-soman, C(+/-)P(-)-soman, C(+/-)P(-)-14C-soman, Toxicant-specific parameters, blood, tissue Homogenates, Partition coefficients, Covalent binding, Hydrolysis, Cardiac output, Tissue blood flows, Stereoselective, Gas chromatography, Microspheres.