Dermatotoxicokinetic modeling of p-nitrophenol and its conjugation metabolite in swine following topical and intravenous administration

The development of a dermatotoxicokinetic (dTK) model for p-nitrophenol (PN P), a common metabolite from a variety of compounds and a biomarker of orga nophosphate (OP) insecticide exposure, may facilitate the kinetic modeling and risk assessment strategy for its parent compounds. In order to quantify and then clarify in vivo-in vitro correlation of PNP disposition, multicom partment kinetic models were formulated. Female weanling pigs a ere dosed w ith [C-14]PNP intravenously (150 mu g in ethanol, n = 4) or topically onto non-occluded abdominal skin (300 mu g/7.5cm(2) in ethanol, n = 4), PNP and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles were determined in plasma and urine in addition to total C-14 quantitation in many other samples. Di sposition parameters (rate constants, F-top T-1/2, T-1/2Ka, AUG, Vss, C-1p, MAT, and MRT) and the simulated chemical mass-time profiles on the dosed s kin surface and in the local, systemic, and excretory compartments were als o determined. Total recoveries of 97.17 +/- 4.18% and 99.80 +/- 2.41% were obtained from topical and intravenous experiments, respectively. Ninety-six hours after topical and intravenous application, 70.92 +/- 9.72% and 98.65 +/- 2.43% of the dose were excreted via urine, and 0.55 +/- 0.16% and 0.51 +/- 0.10% via the fecal route, respectively. Peak excretion rate and time were also determined. It was suggested by experimental observation and mode ling that urinary C-14 excretion correlates with the systemic tissue deplet ion profile well and may be used as a biomarker of PNP exposure. This study also supports the strategy of using urinary PNP as a biomonitoring tool fo r OP pesticide exposure, although some precautions have to be taken. The st rategy used in this study will be useful in comprehensive dTK modeling in d ermal risk assessment and transdermal drug delivery.