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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, 151-168). 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 microg/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 microg TCDD/kg bw (Weber et al., 1993, Fundam. Appl. Toxicol. 21, 523-534). 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 provides further confirmation of the potential use of physiological modeling in understanding pharmacokinetics and pharmacodynamics.

Dose-response relationships for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suggest a differential sensitivity of liver cell types to the induction of cytochrome P450 gene expression, and that the induction of hepatic protein CYP1A2 causes sequestration of TCDD. In addition, immunolocalization of hepatic CYP1A1/1B1/1A2 proteins is not uniform after exposure to TCDD. The mechanism for the regio-specific induction of hepatic P450s by TCDD is unknown, but may involve the differential distribution of participants in the AhR-mediated pathway and/or regional P450 isozymes, as well as, non-uniform distribution/sequestration of TCDD. Therefore, this study examined the effects of TCDD in unfractionated, centrilobular and periportal hepatocytes isolated from female Sprague-Dawley rats acutely exposed (3 days) to a single oral dose of 0.01-10.0 microg [3H]TCDD/kg. A dose-dependent increase in concentration of TCDD was accompanied by a dose-dependent increase in CYP1A1, CYP1A2, and CYP1B1 mRNA expression and associated enzymes in all liver-cell populations. Centrilobular hepatocytes showed a 2.7- to 4.5-fold higher concentration of TCDD as compared to the periportal hepatocytes at doses up to 0.3 microg TCDD/kg. Centrilobular hepatocytes also exhibited an elevated MROD activity as compared to the periportal hepatocytes at doses up to 0.3 microg TCDD/kg. Furthermore, centrilobular hepatocytes showed an elevated concentration of induced CYP1A2 and CYP1B1 mRNA as compared to periportal hepatocytes within the 0.01- and 0.3-microg TCDD/kg-treatment groups. This is the first study to demonstrate that a dose-dependent difference in distribution of TCDD exists between centrilobular and periportal cells that might be related to regional differences in P450 induction.

There is currently little information concerning the time-dependent relationship between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) protein concentration in vivo. Therefore, female Sprague-Dawley rats were given a single oral dose of TCDD (10 micrograms/kg), and the AHR and ARNT protein concentrations in liver, spleen, thymus, and lung determined by Western blotting. In liver, the concentration of AHR protein was significantly reduced 8 and 24 h postdosing as compared to time-matched controls. In spleen and lung, the concentration of AHR protein was reduced 3, 8, 24, and 168 h posttreatment compared to time-matched controls but returned to control levels by 336 h. In thymus, reductions in AHR protein concentration were observed 8, 24, 168, and 336 h postdosing as compared to time-matched controls. Significant reductions in the concentration of ARNT protein were not observed in any of the TCDD-exposed tissues. Functional studies in cell culture showed that exposure of a mouse hepatoma cell line (Hepa-1c1c7) and a rat smooth muscle cell line (A-7) to TCDD (1 nM) for 12 days resulted in a 50% reduction in TCDD-inducible reporter gene expression following subsequent challenge by an additional dose of TCDD (1 nM). Collectively, these results show that (i) TCDD-mediated depletion of AHR occurs in vivo, (ii) AHR protein does not rapidly recover to pretreatment levels even though the tissue concentration of TCDD has fallen, and (iii) reduction in AHR protein concentration correlates with reduction in TCDD-mediated reporter gene expression in mammalian culture cells.