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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has dose-dependent tissue distribution because of induction of CYP1A2, a TCDD-binding protein, in the liver. Induction requires transcriptional activation of the CYP1A2 gene product by TCDD and the Ah receptor. An empirical model for dose-dependent distribution (Carrier et al., 1995, Toxicol. Appl. Pharmacol. 131, 253-266) included two simple descriptors: one for the maximum liver sequestration (Fmax) and the other for body burden leading to half maximum sequestration (Kd). Physiologically based pharmacokinetic (PBPK) models include specific parameters for protein receptors, protein binding, tissue solubility, and protein induction. We have applied a PBPK model to define two macroscopic constants related to these dose-response curves, i.e., the inflection point, and the maximum values of these curves. The dose-response curves generated from the PBPK model were for the proportion sequestered in liver and the liver to fat concentration ratio. Our analysis assessed the specific biological factors in the PBPK model that governed the values of these two macroscopic constants. For the fraction in liver, the Hill coefficient (a shape exponent describing the relationship between the Ah receptor-TCDD complex with the DNA receptor) resulted in the largest shift in inflection when using PBPK model parameters specific for TCDD. For the liver to fat ratio, the inflection point was most affected by the number of available Ah receptors. Conventional normalized sensitivity coefficients for the liver-to-fat ratio at the maximum were highest for the fat-to-blood partition coefficient, CYP1A2 binding affinity, and maximum extent of induction of CYP1A2. A similar pattern was observed for the liver fraction, except that the sensitivity coefficients were much smaller. The behavior of different TCDD congeners was evaluated by altering the value of key parameters. Our results demonstrate that the inflection point is more related to characteristics of DNA binding/induction steps of the Ah receptor-DNA complex than by the CYP1A2 affinity of TCDD or concentrations of CYP1A2. Surprisingly, the maximum is more sensitive to changes in CYP1A2 concentrations and affinity for TCDD. In addition, the analysis showed that the liver-to-fat ratio is a more useful experimental measure than is proportion in liver because the ratio responds with similar sensitivity over a much wider range of input parameters.

toxicological sciences

Sensitivity Analysis of a Physiological Model for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD): Assessing the Impact of Specific Model Parameters on Sequestration in Liver and Fat in the Rat