Five winners of stage two of the Transform Toxicity Testing Challenge: Innovating for Metabolism were named Nov. 1 by the National Toxicology Program (NTP), which is headquartered at NIEHS; the National Center for Advancing Translational Sciences (NCATS); and the U.S. Environmental Protection Agency (EPA). Each of the five winners receives $100,000.
Stage two winners produced practical designs for new technologies that can rapidly test whether some of the thousands of chemicals in use may harm human health. These high speed, automated screening technologies are called high-throughput screening (HTS) assays.
Current HTS assays measure toxicity of the chemicals themselves, but do not fully test for metabolites, which are altered forms of chemicals produced as the body breaks down the original compound. Metabolites are sometimes more toxic than the original chemical.
"By considering the effects of metabolites, researchers can more accurately assess the toxicity of chemicals and better protect human health," said Richard S. Paules, Ph.D., acting head of the NTP Biomolecular Screening Branch.
The stage two winners are:
- Brian Johnson, Ph.D., Onexio Biosystems, LLC. Johnson created a system that uses the natural metabolic activity of human liver cells to generate chemical metabolites and then deliver these metabolites to existing assays. Called Metabolism Integrated Cell RepOrter MicroTiter plate (MICRO MT), the system is technically simple and requires little additional equipment.
- Moo-Yeal Lee, Ph.D., Cleveland State University and Rayton Gerald, Solidus Biosciences. Lee and Gerald developed a 384-well plate that supports three-dimensional cell cultures. It includes an array of human liver cells for both gene expression and high-content toxicity screening.
- Albert Li, Ph.D., In Vitro ADMET Laboratories (IVAL), LLC. Li developed the MetMax Human Hepatocytes system to serve as an external liver metabolism system. The test chemical is added to allow metabolism by liver cells. Both the parent chemical and its metabolites then migrate across a semi-permeable membrane to interact with the target cells.
- Lawrence Vernetti, Ph.D., University of Pittsburgh Drug Discovery Institute. Vernetti developed a system to supply rodent or human liver cells for co-culture with a second cell or cell-free assay. It allows both test agents and metabolites to be transferred directly to the test plates.
- Hongbing Wang, Ph.D., University of Maryland School of Pharmacy. Wang developed a cell culture model that uses a type of cell called human primary hepatocyte. The platform can be scaled up to an HTS format, which allows current cell culture-based assays to produce physiologically relevant metabolites.
Advancing toxicity testing with alternatives to animal testing
Historically, animal studies have been used to evaluate whether a chemical can cause adverse health effects. Thousands of priority chemicals have not been fully evaluated due to the time and expense of animal testing.
Scientists from NTP, NCATS, and EPA are currently using HTS to evaluate the potential health effects of environmental and industrial chemicals as part of the Toxicology in the 21st Century, or Tox21, program.
HTS assays expose living cells or isolated proteins to chemicals. The cells or proteins are then screened for changes in biological activity that may suggest potential toxicity. These assays may limit the number of required laboratory animal-based toxicity tests while quickly and efficiently screening thousands of chemicals.
(Virginia Guidry, Ph.D., is a technical writer and public information specialist in the NIEHS Office of Communications and Public Liaison and a regular contributor to the Environmental Factor.)