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. 2006 Sep;114(9):1394-400.
doi: 10.1289/ehp.8805.

Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD

Claude Emond  1 , Linda S Birnbaum, Michael J DeVito
Affiliations

Use of a physiologically based pharmacokinetic model for rats to study the influence of body fat mass and induction of CYP1A2 on the pharmacokinetics of TCDD

Claude Emond et al. Environ Health Perspect. 2006 Sep.

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.

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Figures

Figure 1
Figure 1
Conceptual representation of PBPK model for rat exposed to TCDD. GI, gastrointestinal.
Figure 2
Figure 2
The relationship between terminal elimination t1/2 and dose using (A) a fixed elimination rate with and without CYP1A2 sequestration and (B) an inducible elimination rate with and without CYP1A2 sequestration. Triangles in B represent the TCDD t1/2 values determined experimentally (see Table 2).
Figure 3
Figure 3
Comparisons of model predictions to experimental data using a fixed elimination rate model with hepatic sequestration (A) and an inducible elimination rate model with (B) and without (C) hepatic sequestration. EXBL, experimental blood levels. Model predictions were compared with the data of Santostefano et al. (1998), where female rats were exposed to a single oral dose of 10 μg of TCDD/ kg BW. Error bars are ± SD.
Figure 4
Figure 4
Simulation of hepatic TCDD concentrations (ppb) during a chronic exposure to TCDD at 50, 150, 500, or 1,750 ng TCDD/kg BW (Walker et al. 1999) using the fixed elimination rate model (A) or the inducible elimination rate model at (B) compared with the experimental data measured at the end of the exposures. Solid lines represent model simulations.
Figure 5
Figure 5
The influence of adipose tissue mass fraction on the predicted terminal elimination t1/2 after a single dose of 10 μg TCDD/kg. Simulations were performed with adipose tissue mass fraction ranging from 6.9 to 70% of body fat. Simulations using a fixed elimination model are presented with (A) and without (B) hepatic sequestration. Simulations using an inducible elimination model are presented with (C) and without (D) hepatic sequestrations.
Figure 6
Figure 6
Sensitivity analysis was performed on the fixed elimination rate model (A and B) and the inducible elimination rate model (C and D). The analysis was performed at 0.001 μg/kg (A and C) and at 10 μg/kg (B and D). Abbreviations: BW_T0, body weight at time zero (other parameter symbols are defined in Table 1); var, variation. This sensitivity recorded the percentage of variation (≥ 2%) of TCDD concentrations in the blood compartment when parameters were varied by ±10%.
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