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Gas-Phase Molecular Probe for High Th roughput Screening Brett Winters 1, Michelle Angrish , Sibel Mentese3, Michael Madden , Joachim Pleil The University of North Carolina at Chapel Hill, U.S EPA, RTP, NC, Canakkale Onsekiz Mart University, Turkey The U.S EPA is responsible for evaluating the effects of approximately 80,000 chemicals registered for use in the USA In addition, approximately 1,000 chemicals are added to this list each year Due to the vast number of chemicals, it is impossible to conduct traditional toxicity studies using preclinical species In recent years, High Throughput Screening (HTS) has been used in order to prioritize chemicals for traditional toxicity screening or to complement traditional toxicity studies HTS is an approach of rapidly assaying a large number of chemicals for biochemical activity using robotics and automation HTS is advantageous due to high speed and low cost relative to traditional toxicity studies Additionally HTS assays may provide insight into biomolecular pathways However, HTS assays often have diminished metabolic capacity and uncertainties regarding in vitro to in vivo translation remain Additionally, longitudinal measurements using HTS techniques are not always feasible We propose a technique using gas-phase probe molecule (PrM) techniques to complement existing HTS assays The proposed technique uses chemicals with empirical human pharmacokinetic data as PrMs to study toxicity of molecules with no known data for gas-phase analysis We discuss an example of a gas phase molecular probe using MTBE, a chemical with known pharmacokinetic data in humans MTBE is metabolized by CYP2A6 to tert butyl alcohol (TBA), which can also be analyzed in gas-phase We propose measuring MTBE metabolism to TBA in order to determine whether chemicals with no known data may alter TBA production, indicating the chemical resulted in perturbations of metabolically competent cells, such as hepatocytes [This is an abstract of a proposed presentation and may not represent US EPA official policy.]
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