Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space

Chemical toxicity can arise from disruption of specific biomolecular functions or through more generalized cell stress and cytotoxicity-mediated processes. Here, concentration-dependent responses of 1063 chemicals including pharmaceuticals, natural products, pesticidals, consumer, and industrial chemicals across a diverse battery of 821 in vitro assay endpoints from 7 high-throughput assay technology platforms were analyzed in order to better 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 two viability/cytotoxicity assays within the concentration range tested (typically up to 100 M) activated a median of 12% of assay endpoints while 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 (e.g., 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 of 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), while 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. This dataset is associated with the following publication: Judson , R., K. Houck , M. Martin , A. Richard , T. Knudsen , I. Shah , S. Little , J. Wambaugh , W. Setzer , P. Kothiya , J. Phuong , D. Filer , D. Smith , D. Reif, D. Rotroff, N. Kleinstreuer, N. Sipes, M. Xia, R. Huang, K. Crofton , and R. Thomas. (Toxicological Sciences) Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space. TOXICOLOGICAL SCIENCES. Society of Toxicology, 1-47, (2016).

                                            [
  "020:00"
]
                                        

                                            {
  "fn": "Keith Houck",
  "hasEmail": "mailto:houck.keith@epa.gov"
}
                                        

                                            [
  {
    "title": "https://gaftp.epa.gov/COMPTOX/NCCT_Publication_Data/Judson/CytotoxBurst",
    "accessURL": "https://gaftp.epa.gov/COMPTOX/NCCT_Publication_Data/Judson/CytotoxBurst"
  }
]
                                        

                                            [
  "ToxCast",
  "chemical safety for sustainablity",
  "chemical safety research",
  "computational toxicology",
  "cytotoxicity",
  "high-throughput toxicology"
]
                                        

                                            [
  "020:095"
]
                                        

                                            {
  "name": "U.S. EPA Office of Research and Development (ORD)",
  "subOrganizationOf": {
    "name": "U.S. Environmental Protection Agency",
    "subOrganizationOf": {
      "name": "U.S. Government"
    }
  }
}
                                        

                                            [
  "https://doi.org/10.1093/toxsci/kfw092"
]
                                        

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