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AOP Knowledge Base/Wiki Tool Set
Citation:
Edwards, S. AOP Knowledge Base/Wiki Tool Set. Adverse Outcome Pathways, RTP, NC, September 03 - 05, 2014.
Impact/Purpose:
To be presented NIEHS 9/3-5, 2014
Description:
Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals. Hisham A. El-Masri1, Nicole C. Klienstreur2, Linda Adams1, Tamara Tal1, Stephanie Padilla1, Kristin Isaacs3, John Wambaugh4, and Halûk Özkaynak3. National Health and Environmental Effects Research Laboratory1, ILS contractors to NTP2, National Exposure Research Laboratory3, National Center for Computational Toxicology4,RTP, North Carolina Lifestage Physiologically-based pharmacokinetic models, SHEDS-LITE models, and in vitro ToxCast data were used to estimate Adverse Outcome Pathway (AOP)-Based Margin of Exposures (ABME) for a set of chemicals related to vascular disruption. Initially a template Lifestage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include detailed physiological growth processes (e.g., tissue volumes, blood flow rates, breast milk composition and flow rate) whenever relevant during female growth from fetus through childhood through conception and pregnancy. This model was applied to conduct in vitro to in vivo (IVIVE) extrapolation to estimate maternal exposure that will yield fetal blood levels equivalent to the estimated EC50s from in vitro ToxCast Assay related to an AOP of interest. The resulting in vivo dose estimates from the Lifestage PBPK model were then compared to real life exposures using models developed in NERL (SHEDS-LITE). An AOP-based margin of exposure (ABME) was then calculated as the ratio of the PBPK-derived in vivo estimate to the SHEDs-LITE exposure one. This computational framework was utilized for a list of 4 chemicals related to a putative Vascular Disruption AOP. The estimated ABMEs ranged from (10 to 10,000). The lowest values for Triclosan, Pyridaben, and PFOS indicate risks that are within range of environmental exposures while the higher ABME indicated that environmental exposures are well below exposures associated with risk of adverse outcome (Fluazinam). The idea of using ABME is novel in linking biological information related to toxicity (using AOPs), high throughput (HPT) in vitro data (ToxCast), and age-varying physiological and biochemical information (using experimental clearance data or transport kinetics, partitioning in breast milk) to estimate Margins of Exposures that can be used to help regulators in prioritizing and realistically assessing chemicals in view of their toxicity, dosimetry, and real-life exposure. This abstract does not necessarily reflect EPA policy