Improving the Human Hazard Characterization of Chemicals: A Tox21 Update

Abstract

Background: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency’s National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health Chemical Genomics Center entered into an agreement on “high throughput screening, toxicity pathway profiling, and biological interpretation of findings.” In 2010, the U.S. Food and Drug Administration (FDA) joined the collaboration, known informally as Tox21.Objectives: The Tox21 partners agreed to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards away from traditional experimental animal toxicology studies to one based on target-specific, mechanism-based, biological observations largely obtained using in vitro assays.Discussion: Here we outline the efforts of the Tox21 partners up to the time the FDA joined the collaboration, describe the approaches taken to develop the science and technologies that are currently being used, assess the current status, and identify problems that could impede further progress as well as suggest approaches to address those problems.Conclusion: Tox21 faces some very difficult issues. However, we are making progress in integrating data from diverse technologies and end points into what is effectively a systems-biology approach to toxicology. This can be accomplished only when comprehensive knowledge is obtained with broad coverage of chemical and biological/toxicological space. The efforts thus far reflect the initial stage of an exceedingly complicated program, one that will likely take decades to fully achieve its goals. However, even at this stage, the information obtained has attracted the attention of the international scientific community, and we believe these efforts foretell the future of toxicology.

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

“…The Toxicology in the 21st Century (Tox21) is a unique collaboration among several US Federal Government partners created to develop a vision and devise an implementation strategy to shift the assessment of chemical hazards from traditional experimental animal toxicology studies to target-specific, mechanism-based biological observations largely obtained using in vitro assays [82]. In 2008, in response to the National Academy of Sciences' (NAS) report, Toxicity Testing in the 21st Century: A Vision and a Strategy [83], a collaboration was established between the National Institute of Environmental Health Sciences' (NIEHS) National Toxicology Program (NTP), the US Environmental Protection Agency's (EPA) National Center for Computational Toxicology (NCCT), and the National Human Genome Research Institute's (NHGRI) NIH Chemical Genomics Center (NCGC), presently part of the National Center for Advancing Translational Sciences (NCATS) [84].…”

“…Efforts are underway to combine the use of iPSC models along with high-throughput screening assays using reporter gene assays [82], 3D organotypic cultures [94], human on a chip (www.ncats.nih.gov/research/reengineering/tissue-chip/ tissue-chip.html), and complementary animal models such as zebrafish [95,96] and C. elegans [97], and to incorporate human dosimetry and exposure to better predict toxicity across different organ systems [98]. As these multiple assay domains are being populated with data from the testing of chemicals, they are being anchored to relevant phenotypes from in vivo rodent and nonrodent animal studies as found in the EPA ToxRefDB [85,99], the NTP rodent database (CEBS) (www.niehs.nih.gov/research/resources/databases/ cebs), and whenever possible to the relevant phenotype in humans to develop better prediction models of toxicity.…”

Cancer Biology, Toxicology and Alternative Methods Development Go Hand‐in‐Hand

“…Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12]. Summarized under a concept termed 'Toxicity Testing in the 21st Century' or 'Tox21', biochemical and cell-based in vitro assays coupled with bioinformatics and modelling-driven in silico assays are now considered key to transforming toxicology from a previously animal-based testing practice into a computational science built on systems biology [2,4,6,[9][10][11]13]. The resulting novel research field is variably termed 'systems toxicology', 'toxicogenomics' or 'computational toxicology' [3,4,8,14,15].…”

“…A constantly increasing number of chemicals and engineered nanomaterials (ENMs) emphasize the need of applying novel tools and screening technologies outside of the standard, both lengthy and expensive, rodent toxicological tests traditionally used in such work [1][2][3][4][5][6][7][8][9][10][11][12][13]. Especially considered for the future innovation of novel ENMs, safety evaluations should be integrated proactively and efficiently already in the material and product development phase [9,12].…”

“…Such effort typically relies on informatics-driven and modelling-based analyses of results from several experimental systems and data-rich technologies for measuring pools of biological molecules, such as mRNAs, the overall aim being to interdependently analyse toxicity data and profiling results for understanding and predicting toxicity. Optimally, such efforts can define the 'bioidentity' or 'hazard identity' of chemicals or ENMs, serving then as an 'activity' counterpart to the 'physiochemical identity' deduced from structural and physiochemical descriptors [5,6,8,12]. Problematic to advancement of the field, the much needed fusion of high-throughput in vitro and in silico technologies in toxicology has advanced slowly due to limited comprehensive data collections and a lack of tools and solution-oriented approaches to assess existing data.…”