ArticleEnvironmental health perspectives2016
A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways.
Article in Environmental health perspectives, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- High-throughput screening for identifying acetylcholinesterase inhibitors: Insights on novel inhibitors and the use of liver microsomes.SLAS discovery : advancing life sciences R & D · 2022Article
- Designing QSARs for Parameters of High-Throughput Toxicokinetic Models Using Open-Source Descriptors.Environmental science & technology · 2021Article
- A Workflow for Identifying Metabolically Active Chemicals to ComplementComputational toxicology (Amsterdam, Netherlands) · 2018Article
- In vitro to in vivo extrapolation for high throughput prioritization and decision making.Toxicology in vitro : an international journal published in association with BIBRA · 2018Review
- From the exposome to mechanistic understanding of chemical-induced adverse effects.Environment international · 2017Review
- Drug Metabolism in Preclinical Drug Development: A Survey of the Discovery Process, Toxicology, and Computational Tools.Current drug metabolism · 2017Review
- Evaluating the Impact of Uncertainties in Clearance and Exposure When Prioritizing Chemicals Screened in High-Throughput Assays.Environmental science & technology · 2016Article
- Estimating Margin of Exposure to Thyroid Peroxidase Inhibitors Using High-Throughput in vitro Data, High-Throughput Exposure Modeling, and Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling.Toxicological sciences : an official journal of the Society of Toxicology · 2016Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAdverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals.
objectivesWe developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition.
methodsThirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood-brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites.
resultsApplication of the workflow screened 10 "low-priority" chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation.
conclusionsThe incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 "low-priority" chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible "false negatives." CITATION: Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.
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