title: A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways.
abstract: BACKGROUND
  Adverse 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.
  
  
  OBJECTIVE
  We 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.
  
  
  METHODS
  Thirty 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.
  
  
  RESULTS
  Application 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.
  
  
  CONCLUSIONS
  The 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."
  
  
  BACKGROUND
  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.
authors.affiliation: Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Phillips
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Leonard
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grulke
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Edwards
authors.forename: Raina
authors.initials: R
authors.lastname: Brooks
authors.forename: Michael-Rock
authors.initials: MR
authors.lastname: Goldsmith
authors.forename: Hisham
authors.initials: H
authors.lastname: El-Masri
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000493:pharmacokinetics*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D018570:Risk Assessment; D057188:Workflow
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase