Abstract

Topical exposure to pesticides is a common route of entry for systemic effects. To quantify disposition of parathion (PA) and its major metabolites in a widely accepted animal model for human dermal risk assessment, a comprehensive pharmacokinetic model was formulated following [ring-UL-14C]PA topical (occluded and non-occluded dose of 300 micrograms, 40 micrograms/cm2 on the abdomen and back) and intravenous (300 micrograms) administration in vivo in female weanling pigs. The model was then confirmed with an intravenous p-nitrophenol (PNP) study. Total 14C as well as HPLC-separated PA, paraoxon (PO), PNP, and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles in plasma and urine, and 14C in blood, stratum corneum, dosed tissues, dosing device, and evaporative loss were determined. The model quantitates the evaporative loss, dosing device binding, 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. Model parameters and the simulated amount-time profiles were reported. Occlusion not only enhanced the partition of both PA and PNP into the stratum corneum from the dosed skin surface, but also slowed down the distribution of PA and PNP in the local dosed tissues. A significant finding was that occlusion also altered the first pass biotransformation of PA in the epidermis. PA, PO, and PNP were more easily absorbed into blood from the back than from the abdomen skin. The rate-limiting process in PA percutaneous absorption is the partitioning from skin surface into the stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)