Toxicological Sciences 54, 284-294 (2000)
Copyright © 2000 by the Society of Toxicology
Dermatotoxicokinetic Modeling of p-Nitrophenol and Its Conjugation Metabolite in Swine following Topical and Intravenous Administration
* National Institute for Occupational Safety and Health (NIOSH), CDC, Morgantown, West Virginia 26505;
Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, Republic of China; and
Center for Cutaneous Toxicology and Residue Pharmacology, North Carolina State University, Raleigh, North Carolina 27606
The development of a dermatotoxicokinetic (dTK) model for p-nitrophenol (PNP), a common metabolite from a variety of compounds and a biomarker of organophosphate (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, multicompartment kinetic models were formulated. Female weanling pigs were dosed with [14C]PNP intravenously (150 µg in ethanol, n = 4) or topically onto non-occluded abdominal skin (300 µg/7.5cm2 in ethanol, n = 4). PNP and p-nitrophenyl-ß-D-glucuronide (PNP-G) profiles were determined in plasma and urine in addition to total 14C quantitation in many other samples. Disposition parameters (rate constants, Ftop, T1/2, T1/2Ka, AUC, Vss, Clp, MAT, and MRT) and the simulated chemical mass-time profiles on the dosed skin surface and in the local, systemic, and excretory compartments were also 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 modeling that urinary 14C excretion correlates with the systemic tissue depletion 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 for OP pesticide exposure, although some precautions have to be taken. The strategy used in this study will be useful in comprehensive dTK modeling in dermal risk assessment and transdermal drug delivery.
Key Words: p-nitrophenol (PNP); toxicokinetics; skin absorption; metabolism; pig.
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