Format

Send to

Choose Destination
Toxicol Sci. 2016 Aug;152(2):323-39. doi: 10.1093/toxsci/kfw092. Epub 2016 May 20.

Editor's Highlight: Analysis of the Effects of Cell Stress and Cytotoxicity on In Vitro Assay Activity Across a Diverse Chemical and Assay Space.

Author information

1
*U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina; Judson.richard@epa.gov.
2
*U.S. EPA, National Center for Computational Toxicology, Research Triangle Park, North Carolina;
3
Contractor to the U.S. EPA National Center for Computational Toxicology, Research Triangle Park, North Carolina;
4
ORISE Fellow at the U.S. EPA National Center for Computational Toxicology, Research Triangle Park, North Carolina;
5
Department of Statistics, North Carolina State University, Raleigh, North Carolina;
6
ILS/NICEATM, Research Triangle Park, North Carolina;
7
National Toxicology Program, Research Triangle Park, North Carolina;
8
NIH National Center for Advancing Translational Sciences, Rockville, Maryland.

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.

KEYWORDS:

In vitro; cell stress; cytotoxicity; high-throughput screening; oxidative stress

PMID:
27208079
PMCID:
PMC6280881
DOI:
10.1093/toxsci/kfw092
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center