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ToxSci Advance Access published online on October 24, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl140
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 10, 2006
Accepted October 18, 2006

Biotransformation and Toxicokinetics

A Physiological Toxicokinetic Model for Inhaled Propylene Oxide in Rat and Human with Special Emphasis on the Nose

György A. Csanády 1 and Johannes G. Filser 1 *

1 Institute of Toxicology, GSF National Research Center for Environment and Health, D-85764 Neuherberg, Germany; Institut für Toxikologie und Umwelthygiene, Technische Universität München, München, Germany

* To whom correspondence should be addressed.
Johannes G. Filser, E-mail: johannes.filser{at}gsf.de


  Abstract

Chronic exposure to high concentrations of PO induced inflammation in the respiratory nasal mucosa (RNM) of rodents and, for concentrations ≥300 ppm, caused nasal tumors. Considering the nose to be the most relevant target organ for PO induced tumorigenicity, we developed a physiological toxicokinetic model for PO in rat and human. It includes compartments for arterial, venous and pulmonary blood, liver, muscle, fat, richly perfused tissues, lung and nose. It simulates inhalation of PO, its distribution into tissues by blood flow, and its elimination by exhalation and metabolism. In nose, lung and liver of rats, PO conjugation with glutathione (GSH), PO induced GSH depletion, and formation of PO adducts to DNA are described. Also modeled are PO adducts to hemoglobin of rats and humans. Required partition coefficients and metabolic parameters were derived experimentally or from publications. In rats, simulated PO concentrations in blood and GSH levels in tissues agreed with measured data. If compared with reported values, levels of adducts with hemoglobin were under-predicted up to a factor of about two. Adducts with DNA differed up to a factor of three. Hemoglobin adducts predicted for PO exposed workers were 1.5-1.9 times higher than reported ones. Considering identical conditions of PO exposure, similar PO concentrations in RNM were modeled for rats and humans. Also, PO concentrations in blood, about 1/30th of those in RNM, were similar in both species. Since the model was evaluated on all available data in rats and humans, we consider it to be useful for estimating the risk from inhalation exposure to PO.

Keywords: Physiological toxicokinetic model; Propylene oxide; Glutathione; Hemoglobin and DNA adducts; Respiratory nasal mucosa; Rat and Human.
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J. G. Filser, C. Hutzler, F. Rampf, W. Kessler, T. H. Faller, E. Leibold, C. Putz, S. Halbach, and G. A. Csanady
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[Abstract] [Full Text] [PDF]


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