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

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 aceta...

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Bibliographic Details
Published in:Toxicological sciences 2005-05, Vol.85 (1), p.429-446
Main Authors: Teeguarden, J. G., Deisinger, P. J., Poet, T. S., English, J. C., Faber, W. D., Barton, H. A., Corley, R. A., Clewell, H. J.
Format: Article
Language:English
Subjects:
1-Butanol - blood
1-Butanol - pharmacokinetics
acetates
Acetates - blood
Acetates - pharmacokinetics
Administration, Inhalation
Animals
Butyric Acid - blood
Butyric Acid - pharmacokinetics
extrapolation
Humans
Infusions, Intravenous
Injections, Intravenous
Male
metabolic series approach
Models, Biological
n-butanol
n-butyl acetate
n-butyric acid
PBPK model
pharmacokinetics
Rats
Rats, Sprague-Dawley
Risk Assessment
Tissue Distribution
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Summary: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 physiologically based pharmacokinetic (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 iv bolus dose, iv 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 iv 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.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfi103