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ToxSci Advance Access published online on April 10, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm082
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Published by Oxford University Press 2007.

Predicting Age-Appropriate Pharmacokinetics of Six Volatile Organic Compounds in the Rat Utilizing Physiologically-Based Pharmacokinetic Modeling

Chester E. Rodriguez*, Deirdre A. Mahle{dagger}, Jeff M. Gearhart{ddagger}, David R. Mattie{dagger}, John C. Lipscomb§, Robert S. Cook{dagger} and Hugh A. Barton*,¶

* US Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC 27711 {dagger} AFRL/HEPB, Wright-Patterson Air Force Base, OH 45433 {ddagger} ManTech Environmental Technology, Inc., Dayton, OH 45437 § US Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH

To whom correspondence should be addressed at the National Center for Computational Toxicology, B205-1, Office of Research and Development, US EPA, 109 TW Alexander Drive, Research Triangle Park, North Carolina, 27711. E-mail: barton.hugh{at}epa.gov, Phone: (919) 541-1995. Fax: (919) 541-1194.

Received October 13, 2006; revision received March 22, 2007; accepted March 23, 2007


  Abstract

The capability of physiologically-based pharmacokinetic (PBPK) models to incorporate age-appropriate physiological and chemical-specific parameters was utilized to predict changes in internal dosimetry for six volatile organic compounds (VOCs) across different ages of rats. Typical 6 h animal inhalation exposures to 50 and 500 ppm perchloroethylene, trichloroethylene, benzene, chloroform, methylene chloride, or methyl ethyl ketone (MEK) were simulated for postnatal day 10 (PND10), 2-month old (adult) and 2-year old (aged) rats. With the exception of MEK, predicted venous blood concentrations of VOCs in the aged rat were equal or up to 1.5-fold higher when compared to the adult rat at both exposure levels, whereas levels were predicted to be up to 3.8-fold higher in the case of PND10 at 50 ppm. Predicted blood levels of MEK were similar in the adult and aged rat, but more than 5-fold and 30-fold greater for PND10 rats at 500 ppm and 50 ppm, respectively, reflecting high water solubility along with lower metabolic capability and faster ventilation rate per unit body weight of PND10 animals. Steady state blood levels of VOCs, simulated by modeling constant exposure, were predicted to be achieved in the order PND10 > adult > aged, largely due to increasing fat volume. The dose metric, total amount metabolized per unit liver volume (AMVL) was generally much lower in PND10 than adult rats. The blood:air partition coefficient, fat volume, and fat blood flow were identified as critical determinants for the predicted differences in venous blood concentrations between the adult and aged. The lower metabolic capability, largely due to a smaller liver size, and faster ventilation rate per unit body weight of PND10 animals contribute the most to the differences between PND10 and adult rats. This study highlights the pharmacokinetic differences and the relevant parameters that may contribute to differential susceptibility to the toxic effects of VOCs across life stages of the rat.

Key Words: Volatile organic compounds (VOCs); physiologically-based pharmacokinetic (PBPK) modeling; rat; age-dependent pharmacokinetics.

E-mail addresses: Chester E. Rodriguez: rodriguez.chester{at}epa.gov, Deirdre A. Mahle: Deirdre.Mahle{at}wpafb.af.mil, Jeff M. Gearhart: jeff.gearhart{at}wpafb.af.mil, David Mattie: david.mattie{at}wpafb.af.mil, John C. Lipscomb: lipscomb.john{at}epa.gov, Robert S. Cook: rcook7{at}woh.rr.com

Disclaimer: This manuscript has been subjected to review by the National Center for Computational Toxicology and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.


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