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Overview of Dioxin Kinetics and Application of Dioxin Physiologically Based Phannacokinetic (PBPK) Models to Risk Assessment
Citation:
EL-MASRI, H. A. Overview of Dioxin Kinetics and Application of Dioxin Physiologically Based Phannacokinetic (PBPK) Models to Risk Assessment. Presented at Dioxin 2010 International Meeting, San Antonio, TX, September 12 - 17, 2010.
Impact/Purpose:
This presentation provides an in depth evaluation of TCDD toxicokinetic models, exploring their differences and commonalities and their possible application for the derivation of dose metrics relevant to TCDD mode of action (MOA).
Description:
The available data on the pharmacokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals and humans have been thoroughly reviewed in literature. It is evident based on these reviews and other analyses that three distinctive features of TCDD play important roles in determining its pharmacokinetic behavior: (1) TCDD is highly lipophilic, (2) TCDD is slowly metabolized, and (3) TCDD induces binding protein in the liver. Increased understanding of these features warranted an evaluation of current kinetic modeling of TCDD to determine if the use of such models would improve the dose-response assessment for TCDD. This presentation provides an in depth evaluation of TCDD toxicokinetic models, exploring their differences and commonalities and their possible application for the derivation of dose metrics relevant to TCDD mode of action (MOA). Assuming a constant half life value for the clearance in long term or chronic TCDD exposure is not biologically supported, given the observed data indicating early influence of CYP1A2 induction and binding to TCDD in the liver and delayed redistribution of TCDD to fat tissue. Therefore, using half-life estimates based on observed terminal steady state levels of TCDD will not account for the possibility of accelerated dose-dependent clearance of the chemical at early high exposure stages. The use of measures of internal dose in dose-response modeling is considered to be superior to that of administered dose (or uptake) because the former is more closely related to the response. The dynamic change in half-life due to dose-dependent excretion at the early stages of TCDD exposure, and its later steady state redistribution to fat tissues, are better described using physiologically based pharmacokinetic (PBPK) models than by simple first order kinetic models. The PBPK model can be applied to estimate dose metrics other than body burden that may be more directly related to response or mode of action, e.g., tissue levels, serum levels, or even dose metrics related to TCDD-protein receptor binding. The inclusion of explicit descriptions of physiological and biochemical parameters in the PBPK model provides an excellent tool for investigating differences in species uptake and disposition of TCDD. Additionally, the PBPK model includes quantitative information that is suitable for addressing the impact of physiological (e.g., body weight or fat tissue volume), or biochemical (e.g., induction of CYP1A2) variability on overall risk of TCDD between species. This abstract has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for presentation. Approval does not signify that the contents necessarily reflect the views and policiesof the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.