You are here:
Sensitivity Analysis for Studying Impacts of Aging on Population Toxicokinetics and Toxicodynamics
Citation:
Sasso, A. F., S. S. Isukapalli, E. M. KENYON, AND P. G. Georgopoulos. Sensitivity Analysis for Studying Impacts of Aging on Population Toxicokinetics and Toxicodynamics. Presented at International Society for Exposure Analysis (ISEA) Meeting, Durham, NC, October 15 - 18, 2007.
Impact/Purpose:
Global sensitivity analyses using available quantitative and qualitative information can help in prioritizing research needs relevant to toxicokinetic modeling and risk assessment for the elderly. Sensitivities of physiological and metabolic parameters on output metrics of interest (e.g.. AUC-blood, amount metabolized in liver) are estimated in the presence of population variability in activity profiles, ventilation rates, blood flows, organ and tissue volumes.
Description:
Assessing the impacts of toxicant exposures upon susceptible populations such as the elderly requires adequate characterization of prior long-term exposures, reductions in various organ functions, and potential intake of multiple drugs. Additionally, significant uncertainties and variability are present in physiology, activity, and lifestyle characteristics among healthy and diseased aged individuals. When physiologically-based toxicokinetic (PBTK) and toxicodynamic models are applied for chemical health risk assessments for the elderly, the uncertainties and variabilities propagate through the modules characterizing absorption, diffusion, metabolism, and elimination of environmental toxins. Data on different age-related parameters are limited vis-a-vis the needs of environmental health risk assessments. Global sensitivity analyses using available quantitative and qualitative information can help in prioritizing research needs relevant to toxicokinetic modeling and risk assessment for the elderly. A case study is presented involving the application of the “generalized” MENTOR-3P system [Modeling ENvironment for TOtal Risk (MENTOR) with Physiologically-based Pharmacokinetic modules for Populations (3P)] for global sensitivity analysis of toluene toxicokinetics in aged populations. MENTOR-3P is currently linked to population databases describing physiological parameters and incorporates different techniques for sensitivity and uncertainty analyses, including brute force sampling methods as well as computationally efficient methods such as the High Dimensional Model Representation (HDMR). Sensitivities of physiological and metabolic parameters on output metrics of interest (i.e. AUC-blood, amount metabolized in liver) are estimated in the presence of population variability in activity profiles, ventilation rates, blood flows, organ and tissue volumes. Additional focus will be on "polypharmacy" scenarios, where drug pharmacokinetic models and dose regimens are included in the analysis, along with hypothetical drug-toxicant metabolic interactions.