Scientists from EPA, NCATS, and NIEHS/NTP are using high speed, automated screening technologies called high-throughput screening (HTS) assays to rapidly test whether some of the thousands of chemicals in use may affect human health. However, since current HTS assays do not fully incorporate chemical metabolism, they may miss chemicals that are metabolized to a more toxic form.
To help capture that information, in January 2016, EPA launched the Transform Toxicity Testing Challenge along with their partners, the National Institutes of Health, National Center for Advancing Translational Sciences, and the National Toxicology Program housed within the National Institute for Environmental Health Science.
The Transform Toxicity Challenge asked teams of scientists to develop techniques to retrofit existing HTS assays to incorporate processes that reflect how chemicals are broken down and metabolized by the body. After selecting semi-finalists in May 2017, the EPA and its partners have selected the Transform Toxicity Challenge Stage Two winners.
Stage two winners have produced practical designs that bring us one step closer to turning existing, commonly used in vitro high-throughput chemical screening assays into tests which will evaluate both parent chemical and metabolite effects in the assay responses. Each Stage Two winner will receive a $100,000 prize.
The Stage Two winners are:
- Dr. Brian Johnson, Onexio Biosystems LLC created MICRO MT (Metabolism Integrated Cell RepOrter MicroTiter plate), a system that uses the natural metabolic activity of human liver cell lines to generate chemical metabolites and then deliver these metabolites to existing reporter assays in a highly reproducible fashion. The MICRO MT format is technically simple, requires little additional equipment and is amenable to the high volume and high throughput needs of 21st century toxicology.
- Dr. Moo-Yeal Lee, Cleveland State University and Mr. Rayton Gerald, Solidus Biosciencesdeveloped a 384-pillar plate that supports 3D cell cultures and comprises an array of human hepatic cells for gene expression and high-content toxicity screening. The plate can be a robust and flexible system for High Throughput screening of compounds and will enable retrofitting of existing ToxCast assays to have metabolic competence.
- Dr. Lawrence Vernetti, HanKayTox Consulting developed a 96 and 384 well microtiter plate with capabilities to:
- supply rodent or human hepatocytes in an on-demand format suitable to co-culture with a second cell or cell free assay;
- supply 96 or 384 well microtiter plates of hepatocytes in an on-demand format suitable to pre-condition test agents for the sequential transfer of test agents and metabolites directly to the assay test plates, and;
- prepare and store 384 and 1536 well daughter plates for on-demand use of test agents in media pre-conditioned by hepatocytes.
- Dr. Hongbing Wang, University of Maryland School of Pharmacy developed a human primary hepatocyte (HPH)-immortalized cell co-culture model by using a transwell platform that can be scaled up to a HTS format, allowing currently used, cell culture-based screening assays to run in an environment that produces physiologically relevant metabolites.
- Dr. Albert Li, In Vitro ADMET Laboratories LLC developed the IVAL Exogenous Metabolism System (patent-pending), which consists of a transwell insert containing human or animal hepatocytes. The EXM insert is placed into a cell culture well containing the target cells used for toxicity evaluation, serving as an exogenous hepatic metabolic system. The chemical to be evaluated is added to the EXM transwell, allowing metabolism by the hepatocytes in the insert. Both the parent chemical and its metabolites migrate across the semi-permeable membrane of the EXM transwell insert to interact with the target cells in the culture well. The IVAL EXM is compatible with current ToxCast assays which employ multi-well (e.g. 96-well) plates. Designing tests that produce physiologically-relevant metabolites helps researchers more accurately assess effects of chemicals and better protect human health.