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.

Figure 1

Results of phenotypic assays of the NTP 1,408-compound library showing the percentage of substances classified as active in each assay. Abbreviations: 12hLO, 12-human lipoxygenase; ALDH1A1, aldehyde dehydrogenase 1 family, member A1; AMPC, b-lactamase/d-alanine carboxypeptidase; AP1, activator protein 1; APE1, apurinic/apyrimidinic endonuclease 1; ATAD5, DNA damage response element; BRCA, breast cancer, early onset; CHO, Chinese hamster ovary; CRE, cAMP response element; ERK, extracellular signal-regulated kinase; HADH560, hydroxyacyl-coenzyme A dehydrogenase, type II; HEK, human embryonic kidney; hERG, human ether-a-go-go–related gene potassium channel; HPGD, hydroxyprostaglandin dehydrogenase; HRE, hypoxia response element; HSDB, hydroxysteroid (17-b) dehydrogenase; HSP90, heat shock protein 90kDa a; IL-8, interleukin 8; IMPase, inositol monophosphatase; i-RGS, G-protein signaling protein RGS12; JNK, c-Jun N-terminal kinase; LDH, l-lactate dehydrogenase; LDR, Locus DeRepression; NPS, neuropeptide S; O-Glc NAc transferase, O-Glc NAc N-acetylcysteine transferase (sOGT); PK, pyruvate kinase; PPAR-a, peroxisome proliferator-activated receptor a; ROR, retinoic acid-related orphan receptor; PRX, peroxiredoxins; SMN2, survival motor neuron protein; TDP1, tyrosyl-DNA phosphodiesterase; TNFa, tumor necrosis factor-a; TSH, thyroid stimulating hormone; YjeE:ADP binding, essential Escherichia coli protein of unknown function that binds adenosine diphosphate.

Figure 2

Results of pathway target assays of the NTP 1,408-compound library showing the percentage of substances classified as active in each assay.

Figure 3

Results of nuclear receptor, DNA damage, cytochrome-p450, and miscellaneous assays of the NTP 1,408- and the U.S. EPA 1,462-compound libraries showing the percentage of substances classified as active in each assay. Abbreviations: AHR, aryl hydrocarbon receptor; AR, androgen receptor; ARE, antioxidant response element; ER, estrogen receptor; esrE, Escherichia coli strain K-12 substrain MG1655; FXR, farnesoid X receptor; GR, glucocorticoid receptor; HSP, heat shock protein; NFkB, nuclear factor-kB; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; TR, thyroid hormone receptor; VDR, vitamin D receptor.