title: Editor's Highlight: Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space.
abstract: Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, responses of 1060 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a battery of 815 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to distinguish between these types of activities. Both cell-based and cell-free assays showed a rapid increase in the frequency of responses at concentrations where cell stress/cytotoxicity responses were observed in cell-based assays. Chemicals that were positive on at least 2 viability/cytotoxicity assays within the concentration range tested (typically up to 100 μM) activated a median of 12% of assay endpoints whereas those that were not cytotoxic in this concentration range activated 1.3% of the assays endpoints. The results suggest that activity can be broadly divided into: (1) specific biomolecular interactions against one or more targets (eg, receptors or enzymes) at concentrations below which overt cytotoxicity-associated activity is observed; and (2) activity associated with cell stress or cytotoxicity, which may result from triggering specific cell stress pathways, chemical reactivity, physico-chemical disruption of proteins or membranes, or broad low-affinity non-covalent interactions. Chemicals showing a greater number of specific biomolecular interactions are generally designed to be bioactive (pharmaceuticals or pesticidal active ingredients), whereas intentional food-use chemicals tended to show the fewest specific interactions. The analyses presented here provide context for use of these data in ongoing studies to predict in vivo toxicity from chemicals lacking extensive hazard assessment.
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina; Judson.richard@epa.gov.
authors.forename: Richard
authors.initials: R
authors.lastname: Judson
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Keith
authors.initials: K
authors.lastname: Houck
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Matt
authors.initials: M
authors.lastname: Martin
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Ann M
authors.initials: AM
authors.lastname: Richard
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Knudsen
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Imran
authors.initials: I
authors.lastname: Shah
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Stephen
authors.initials: S
authors.lastname: Little
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: John
authors.initials: J
authors.lastname: Wambaugh
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: R
authors.initials: R
authors.lastname: Woodrow Setzer
authors.affiliation: Contractor to the U.S. EPA National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Parth
authors.initials: P
authors.lastname: Kothiya
authors.affiliation: Contractor to the U.S. EPA National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Jimmy
authors.initials: J
authors.lastname: Phuong
authors.affiliation: ORISE Fellow at the U.S. EPA National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Dayne
authors.initials: D
authors.lastname: Filer
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Doris
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Statistics, North Carolina State University, Raleigh, North Carolina;
authors.forename: David
authors.initials: D
authors.lastname: Reif
authors.affiliation: Department of Statistics, North Carolina State University, Raleigh, North Carolina;
authors.forename: Daniel
authors.initials: D
authors.lastname: Rotroff
authors.affiliation: ILS/NICEATM, Research Triangle Park, North Carolina;
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
authors.affiliation: National Toxicology Program, Research Triangle Park, North Carolina;
authors.forename: Nisha
authors.initials: N
authors.lastname: Sipes
authors.affiliation: NIH National Center for Advancing Translational Sciences, Rockville, Maryland.
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.affiliation: NIH National Center for Advancing Translational Sciences, Rockville, Maryland.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Kevin
authors.initials: K
authors.lastname: Crofton
authors.affiliation: *U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
mesh_terms: D001681:Biological Assay / Q000379:methods*; D006801:Humans; D066298:In Vitro Techniques; D013312:Stress, Physiological; D018675:Toxicity Tests / Q000379:methods*
keywords: In vitro; cell stress; cytotoxicity; high-throughput screening; oxidative stress