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Gas-Phase Molecular Probe For High Throughput Screening
Citation:
Winters, B., M. Angrish, S. Mentese, M. Madden, AND J. Pleil. Gas-Phase Molecular Probe For High Throughput Screening. Gordon Conference Drug Safety, Easton, MA, June 25 - July 01, 2016.
Impact/Purpose:
This abstract is for a poster presentation at the Gordon Research Conference related to High Throughput Screening of chemicals. The poster describes a new exposure system/biological response system to speed up high through put technology.
Description:
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.]