ToxSci Advance Access originally published online on April 2, 2008
Toxicological Sciences 2008 104(1):54-66; doi:10.1093/toxsci/kfn064
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Physiologically based Pharmacokinetic Modeling of Chloroethane Disposition in Mice, Rats, and Women
* The Sapphire Group, Inc., Dayton, Ohio 45431
DuPont Haskell Laboratory, Newark, Delaware 19714
Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674
National Center for Environmental Assessment, Office of Research and Development, U.S. EPA, Washington, D.C. 20004
1 To whom correspondence should be addressed at 2661 Commons Blvd., Suite 239, Dayton, OH 45431. Fax: (937) 458-0050. E-mail: MLG{at}thesapphiregroup.com.
Received April 22, 2007; accepted March 22, 2008
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Abstract |
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Chloroethane was observed in a chronic cancer bioassay to be a mouse-specific uterine carcinogen at a single high inhaled concentration (15,000 ppm). Although high incidence occurred in the female mouse (86%), no uterine tumor increases were observed in female rats. Chloroethane is a weak alkylating agent and has low acute toxicity. No genotoxicity potential has been observed below 40,000 ppm. Chloroethane is eliminated from the body by pulmonary exhalation and metabolically by oxidation via cytochrome P-450 (likely producing acetaldehyde) and conjugation with glutathione (GSH). The mode of action for the mouse-specific uterine tumors is not definitively known and could involve parent chemical and/or metabolite(s). A physiologically based pharmacokinetic (PBPK) model for chloroethane disposition in the rat was developed previously, but no such models have been described for mice or humans. For the work reported here, the existing PBPK model for chloroethane in rats was expanded and refined, and PBPK models for chloroethane disposition in mice and humans were developed to allow species comparisons of internal dosimetry and for possible insights into the carcinogenic mode of action. The amounts metabolized via glutathione-S-transferase (GST) versus cytochrome P-450, and the total amount of chloroethane absorbed, were most consistent with the observations made concerning uterine tumors, with amounts metabolized via GST providing the larger quantitative difference between the two rodent species. Choice of the most relevant dose metric for risk assessments involving uterine tumors in mice will require pharmacodynamic considerations in the mode of action in addition to the pharmacokinetic differences reported here.
Key Words: physiologically based pharmacokinetic model; PBPK model; chloroethane; P450; GST; glutathione.
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