ToxSci Advance Access originally published online on November 12, 2008
Toxicological Sciences 2009 107(2):331-341; doi:10.1093/toxsci/kfn234
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Published by Oxford University Press 2008.
Modeling Single and Repeated Dose Pharmacokinetics of PFOA in Mice
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* National Center for Computational Toxicology
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory
Human Exposure and Atmospheric Science Division, National Exposure Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at Mail Drop 67, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4017. E-mail: lau.christopher{at}epa.gov.
Received July 28, 2008; accepted October 31, 2008
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Abstract |
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Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 mice after single, oral doses of 1 and 10 mg/kg of PFOA. When using one- and two-compartment models, the pharmacokinetics for these two dosages are not consistent with serum time-course data from female CD1 mice administered 60 mg/kg, or with serum concentrations following repeated daily doses of 20 mg/kg PFOA. Some consistency between dose regimens could be achieved using the saturable resorption model of Andersen et al. In this model PFOA is cleared from the serum into a filtrate compartment from which it is either excreted or resorbed into the serum by a process presumed transporter mediated with a Michaelis-Menten form. Maximum likelihood estimation found a transport maximum of Tm = 860.9 (1298.3) mg/l/h and half-maximum concentration of KT = 0.0015 (0.0022) mg/l where the estimated standard errors (in parentheses) indicated large uncertainty. The estimated rate of flow into and out of the filtrate compartment, 0.6830 (1.0131) l/h was too large to be consistent with a biological interpretation. For these model parameters a single dose greater than 40 mg/kg, or a daily dose in excess of 5 mg/kg were necessary to observe nonlinear pharmacokinetics for PFOA in female CD1 mice. These data and modeling analyses more fully characterize PFOA in mice for purposes of estimating internal exposure for use in risk assessment.
Key Words: perfluorooctanoic acid (PFOA); compartment model; resorption model; pharmacokinetic parameters; statistical analysis; CD1 mice.
2 Current address: Pfizer, Inc., PDM PK/PD Modeling, Eastern Point Rd., MS 8220-4328, Groton, CT 06340.