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ToxSci Advance Access published online on February 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi103
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received September 7, 2004
Accepted December 20, 2004

Biotransformation and Toxicokinetics

Derivation of a Human Equivalent Concentration for n-Butanol Using A Physiologically-Based Pharmacokinetic Model for n-Butyl Acetate and Metabolites n-Butanol and n-Butyric Acid

J. G. Teeguarden 1*, P. J. Deisinger 2, T.S. Poet 1, J. C. English 2, W.D. Faber 3, H.A. Barton 4, R.A Corley 2, and H. J. Clewell III5

1 Battelle, Pacific Northwest National Laboratory, Richland, WA, 99352
2 Health and Environmental Laboratories, Eastman Kodak Company, Rochester, NY 14652-6272
3 Willem Faber Toxicology Consulting, Victor, NY 14564
4 NHEERL, USEPA, Research Triangle Park, NC 27709
5 ENVIRON Health Sciences Institute, Ruston, LA 71270

* To whom correspondence should be addressed.
J. G. Teeguarden, E-mail: justin.teeguarden{at}pnl.gov


  Abstract

The metabolic series approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. The metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol and n-butyric acid (the butyl series) was first demonstrated using a provisional PBPK model for the butyl series. The objective of this work was to complete development of the PBPK model for the butyl series. Rats were administered test compounds by i.v. bolus dose, i.v. infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate (100% of alveolar ventilation) and n-butanol (50% of alveolar ventilation) was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following i.v. administration and inhalation exposure to n-butyl acetate and n-butanol in rats and arterial blood n-butanol kinetics following inhalation exposure to n-butanol in humans. These validated inhalation route models can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Human equivalent concentrations of 169 ppm and 1066 ppm n-butanol corresponding to the rat n-butyl acetate NOAELs of 500 and 3000 ppm were derived using the models.

Keywords: PBPK model; Pharmacokinetics; Acetates; Extrapolation; Risk Assessment; Metabolic Series Approach; n-Butyl Acetate; n-Butanol; n-Butyric Acid.
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