A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways

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. A conceptual workflow was developed to consider exposure and ADME properties in relation to an MIE. The utility of this workflow was demonstrated using a previously established AOP, acetylcholinesterase (AChE) inhibition. Thirty chemicals found to inhibit human AChE in the ToxCast(TM) 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. Application of the workflow screened ten “low priority” chemicals out of the thirty active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold above 75% with their nearest active neighbours. Out 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 following metabolism. 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. In addition, workflow increased confidence in interpretation of in vitro results by identifying possible “false negatives.”

Authors: Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. ;Full Source: Environmental Health Perspectives. 2015 May 15. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]