PERCUTANEOUS-ABSORPTION, BIOTRANSFORMATION, AND SYSTEMIC DISPOSITION OF PARATHION IN-VIVO IN SWINE .1. COMPREHENSIVE PHARMACOKINETIC MODEL

Topical exposure to pesticides is a common route of entry for systemic effects. To quantify disposition of parathion (PA) and its major meta bolites in a widely accepted animal model for human dermal risk assess ment, a comprehensive pharmacokinetic model was formulated following [ ring-UL-C-14]PA topical (occluded and nonoccluded dose of 300 mu g, 40 mu g/cm(2) on the abdomen and back) and intravenous (300 mu g) admini stration in vivo in female weanling pigs. The model was then confirmed with an intravenous p-nitrophenol (PNP) study. Total C-14 as well as HPLC-separated PA, paraoxon (PO), PNP, and p-nitrophenyl-beta-D-glucur onide (PNP-G) profiles in plasma and urine, and C-14 in blood, stratum corneum, dosed tissues, dosing device, and evaporative loss were dete rmined. The model quantitates the evaporative loss, dosing device bind ing, percutaneous absorption, first pass metabolism and its impact on the systemic metabolic profile of PA, as well as the distribution and excretion kinetics of both the parent compound and its metabolites. Mo del parameters and the simulated amount-time profiles were reported. O cclusion not only enhanced the partition of both PA and PNP into the s tratum corneum from the dosed skin surface, but also slowed down the d istribution of PA and PNP in the local dosed tissues. A significant fi nding was that occlusion also altered the first pass biotransformation of PA in the epidermis. PA, PO, and PNP were more easily absorbed int o blood from the back than from the abdomen skin. The rate-limiting pr ocess in PA percutaneous absorption is the partitioning from skin surf ace into the stratum corneum. It is also possible to deal with dosing solution contamination with labeled metabolite through this model. Cut aneous and systemic metabolism versus urinary excretion pattern was al so examined. This model provides a powerful tool in clarification of c utaneous versus systemic disposition and in exploring the mechanisms o f the effects of application site and occlusion on both the penetratio n and cutaneous biotransformation of topically applied compounds.