Extrapolation of a PBPK Model for Dioxins across Dosage Regimen, Gender, Strain, and Species

Xiaofeng Wang 1 Michael J. Santostefano 1 Michael J. DeVito 0 Linda S. Birnbaum 0 0 U.S Environmental Protection Agency, National Health and Environmental Effects Research Laboratory (MD-74), Experimental Toxicology Division , 86 T. W. Alexander Drive, Research Triangle Park, North Carolina 27711 1 Curriculum in Toxicology, University of North Carolina , Chapel Hill, North Carolina 27599-7270 - A physiologically based pharmacodynamic (PBPK) model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was developed based on pharmacokinetic data from acute oral exposures of TCDD to female Sprague-Dawley rats (Wang et al., 1997, Toxicol Appl. Pharmacol 147, 151168). In the present study, the utility of this model to predict the disposition of TCDD in male and female Sprague-Dawley and female Wistar rats exposed to TCDD through different dosage regimens was examined. The ability of the model to predict the disposition of 2-iodo-3,7,8-trichlorodibenzo-p-dioxin (ITrCDD) in mice (Leung, et al., 1990, Toxicol. Appl. Pharmacol. 103, 399 410) was also examined. The ability of the model to predict across routes of exposure was assessed with intravenous injection data (5.6 mg/kg bw) (Li et al., 1995, Fundam. Appl. Toxicol. 27, 70 76) in female rats. Analysis across gender extrapolations used data for male Sprague-Dawley rats exposed intravenously to 9.25 mg TCDD/kg bw (Weber et al., 1993, Fundam. Appl. Toxicol. 21, 523534). The analysis of across-dosage regimen and stains of rats extrapolations were assessed using data from rats exposed to TCDD through a loading/maintenance dosage regimen (Krowke et al., 1989, Arch. Toxicol. 63, 356 360). The physiological differences between gender, strain, and species were taken into account when fitting the PBPK model to these data sets. The results demonstrate that the PBPK model for TCDD developed for female Sprague-Dawley rats exposed by acute oral dosing accurately predicts the disposition of TCDD, for different gender and strain of rats across varying dosage regimens, as well as in a strain of mice. Minimal changes in fitted parameters were required to provide accurate predictions of these data sets. This study This project was supported in part by the National Institute of Environmental Health Sciences, National Institutes of Health, and by the U.S. EPA. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS, NIH. The manuscript has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. However, it does not necessarily reflect the views of the Agency. Mention of trade names or commercial products does not constitute endorsement or use recommendation. 1 Present address: InnaPhase Co., 1700 Race St., Philadelphia, PA 19103. E-mail: . 2 Present address: GlaxoWellcome, Inc., Medicine Safety Evaluation, 5 Moore Drive, PO Box 13398, Building 9, Room 2122, Research Triangle Park, NC 27709-3398. E-mail: . 3 To whom correspondence should be addressed. Fax: 919-541-5394. E-mail: . provides further confirmation of the potential use of physiological modeling in understanding pharmacokinetics and pharmacodynamics. Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; physiologically based pharmacokinetic modeling; pharmacokinetics; species extrapolation; risk assessment. The quality and quantity of dose response and pharmacokinetic data for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has aided in the development of physiologically based pharmacokinetic (PBPK) and biologically based pharmacodynamic (BBPD) models in rats and mice (Andersen and Greenlee, 1991; Andersen et al., 1993; Buckley, 1995; Kedderis et al., 1993; Kohn et al., 1993; Leung et al., 1998; Santostefano et al., 1998; Wang et al., 1997). The overall goal of these modeling efforts is the development of PBPK and BBPD models that can provide accurate predictions of tissue concentrations of environmental contaminants in exposed populations. The published PBPK models have undergone a number of iterations between development, validation, and refinement. However, the BBPD efforts are in the early stages of development. While validation of these models is inherently difficult, their utility can be examined by comparing the ability of the model to predict multiple data sets that employ different dosage regimens as well as different gender, strain, and species of laboratory animals. Models that can predict multiple experimental data sets using different species and different dosage regimens may also provide accurate predictions of tissue concentrations from a variety of human-exposure scenarios. There are a number of consistent findings on the toxicity and pharmacokinetics of TCDD across species, and this consistency increases the confidence that PBPK models may be used in species extrapolations. For example, the biological and toxicological effects of TCDD are mediated through the Ah receptor (Birnbaum, (...truncated)