Improving the human hazard characterization of chemicals: A Tox21 update

Environmental Health Perspectives

Volumn 121, Issue 7, 2013, Pages 756-765

  Tice, Raymond R ^a   Austin, Christopher P ^b   Kavlock, Robert J ^c   Bucher, John R ^a  

^a NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

^b NATIONAL INSTITUTES OF HEALTH   (United States)

^c U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

Author keywords

Chemical hazard characterization; Computational biology; High throughput testing; In vitro models; Systems biology; Tox21

Indexed keywords

ANDROGEN RECEPTOR; ARACHIDONATE 12 LIPOXYGENASE; ARACHIDONATE 15 LIPOXYGENASE; AROMATIC HYDROCARBON RECEPTOR; CASPASE 3; CASPASE 7; CRUZIPAIN; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; ESTROGEN RECEPTOR ALPHA; FARNESOID X RECEPTOR; HYPOXIA INDUCIBLE FACTOR 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 8; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 10; NEUROPEPTIDE S; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PREGNANE X RECEPTOR; RETINOID RELATED ORPHAN RECEPTOR GAMMA; THYROID HORMONE RECEPTOR BETA; THYROTROPIN RECEPTOR; TRANSCRIPTION FACTOR RUNX1; TUMOR NECROSIS FACTOR ALPHA; UNINDEXED DRUG; VITAMIN D RECEPTOR;

ANTIOXIDANT RESPONSIVE ELEMENT; CYTOTOXICITY; FOOD AND DRUG ADMINISTRATION; GOVERNMENT; HEALTH HAZARD; HUMAN; MITOCHONDRIAL TOXICITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; TOXICOLOGY;

ANIMALIA;

EID: 84879599189     PISSN: 00916765     EISSN: 15529924     Source Type: Journal    
DOI: 10.1289/ehp.1205784     Document Type: Review

References (66)

1. Chandler KJ, Barrier M, Jeffay SC, Nichols HP, Kleinstreuer N, Singh A, et al. 2011. Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay. PLoS ONE 6:e1840; doi:10.1371/journal.pone.0018540 [Online 7 June 2011].
2. Collins FS, Gray GM, Bucher JR. 2008. Transforming environmental health protection. Science 319:906-907.
3. Dix DJ, Houck KA, Martin M, Richard AM, Setzer RW, Kavlock RJ. 2007. The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci 95:5-12.
4. Fox JT, Sakamuru S, Huang R, Teneva N, Simmons SO, Xia M, et al. 2013. High-throughput genotoxicity assay identifies antioxidants as inducers of DNA damage response and cell death. Proc Natl Acad Sci USA 109: 5423-5428.
5. Gohlke JM, Thomas R, Zhang Y, Rosenstein MC, Davis AP, Murphy C, et al. 2009. Genetic and environmental pathways to complex diseases. BMC Syst Biol 3:46; doi:10.1186/1752-0509-3-46 [Online 5 May 2009].
6. Hill AV. 1910. The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J Physiol (London) 40:4-7.
7. Houck KA, Dix DJ, Judson R, Kavlock RJ, Yang J, Berg EL. 2009. Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. J Biomol Screen 14:1054-1066.
8. Huang R, Cho MH, Sakamuru S, Shinn P, Houck KA, Dix DJ, et al. 2011a. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 119:1142-1148.
9. Huang R, Southall N, Cho MH, Xia M, Inglese J, Austin CP. 2008. Characterization of diversity in toxicity mechanism using in vitro cytotoxicity assays in quantitative high throughput screening. Chem Res Toxicol 21:659-667.
10. Huang R, Southall N, Wang Y, Yasgar A, Shinn P, Jadhav A, et al. 2011b. The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Science Transl Med 3:80ps16; doi:10.1126/scitranslmed.3001862 [Online 27 April 2011].
11. Huang R, Southall N, Xia M, Cho MH, Jadhav A, Nguyen DT, et al. 2009. Weighted Feature Significance (WFS): a simple, interpretable model of compound toxicity based on the statistical enrichment of structural features. Toxicol Sci 112:385-393.
12. Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, et al. 2006. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. Proc Natl Acad Sci USA 103:11473-11478.
13. Judson R, Elloumi F, Serzer RW, Li Z, Shah IA. 2008. A comparison of machine learning algorithms for chemical toxicity classification using a simulated multi-scale data model. BMC Bioinformatics 9:241.
14. Judson R, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, Mortensen HM, et al. 2010. In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project. Environ Health Perspect 118:485-492.
15. Judson R, Kavlock RJ, Setzer RW, Cohen-Hubal EA, Martin MT, Knudsen TB, et al. 2011. Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chemical Res Toxicol 24:451-462.
16. Judson RS, Martin MT, Egeghy PP, Gangwal S, Reif DM, Kothiya P, et al. 2012. Aggregating data for computational toxicology applications: the U.S. Environmental Protection Agency (U.S. EPA) Aggregated Computational Toxicology Resource (ACToR) system. Inter J Molec Sci 13:1805-1831.
17. Kanebratt KP, Andersson TB. 2008. HepaRG cells as an in vitro model for evaluation of cytochrome P450 induction in humans. Drug Metab Dispos 36:137-145.
18. Kleinstreuer NC, Dix DJ, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, et al. 2013. In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis. Toxicol Sci 131:40-55.
19. Kleinstreuer NC, Judson RS, Reif DM, Sipes NS, Singh AV, Chandler KJ, et al. 2011a. Environmental impact on vascular development predicted by high throughput screening. Environ Health Perspect 119:1596-1603.
20. Kleinstreuer NC, Smith AM, West PR, Conard K, Fontaine B, Weir-Hauptman AM, et al. 2011b. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics. Toxicol Appl Pharmacol 257:111-121.
21. Knight AW, Little S, Houck KA, Dix DJ, Judson R, Richard AM, et al. 2009. Evaluation of high-throughput genotoxicity assays used in profiling the US EPA ToxCast chemicals. Regul Toxicol Pharmacol 55:188-199.
22. Knudsen TB, Houck KA, Sipes N, Singh AV, Judson R, Martin MT, et al. 2011. Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets. Toxicology 282:1-15.
23. Lock EF, Abdo N, Huang R, Xia M, Kosyk O, O'Shea SH, et al. 2012. Quantitative high-throughput screening for chemical toxicity in a population-based in vitro model. Toxicol Sci 126:578-588.
24. Martin MT, Dix DJ, Judson R, Kavlock RJ, Reif D, Richard AM, et al. 2010. Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA's ToxCast program. Chem Res Toxicol 23:578-590.
25. Martin MT, Judson R, Reif D, Kavlock RJ, Dix DJ. 2009a. Profiling chemicals based on chronic toxicity results from the U.S. EPA ToxRef database. Environ Health Perspect 117:392-399.
26. Martin MT, Knudsen TB, Reif D, Houck KA, Judson R, Kavlock RJ, et al. 2011. Predictive model of rat reproductive toxicity from ToxCast high throughput screening. Biol Reprod 85:327-339.
27. Martin MT, Mendez E, Corum DG, Judson R, Kavlock RJ, Rotroff D, et al. 2009b. Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database. Toxicol Sci 110:181-190.
28. Merrick BA, Auerbach SS, Stockton PS, Foley JF, Malarkey DE, Sills RC, et al. 2012. Testing an aflatoxin B1 gene signature in rat archival tissues. Chem Res Toxicol 25:1132-1144.
29. NCATS (National Center for Advancing Translational Sciences). 2013a. High-Throughput Screening Assay Guidance Criteria. Available: http://www.ncats.nih.gov/research/reengineering/ncgc/assay/criteria/criteria.html [accessed 1 April 2013].
30. NCATS (National Center for Advancing Translational Sciences) 2013b. Tox21 Chemical Browser. Available: http://tripod.nih. gov/tox21chem/[accessed 1 April 2013].
31. NCATS (National Center for Advancing Translational Sciences) 2013c. Toxicology in the 21st Century. Available: http://www.ncats.nih.gov/research/reengineering/tox21/tox21. html [accessed 1 April 2013].
32. NIEHS (National Institute of Environmental Health Sciences). 2011a. 10 Mar 2011: New Robot System to Test 10,000 Chemicals for Toxicity [Press Release]. Available: http://www.niehs.nih.gov/news/newsroom/releases/2011/march10/[accessed 1 April 2013].
33. NIEHS (National Institute of Environmental Health Sciences). 2011b. 7 Dec 2011: US Tox21 to Begin Screening 10,000 Chemicals [Press Release]. Available: http://www.niehs.nih. gov/news/newsroom/releases/2011/december07/index.cfm [accessed 1 April 2013].
34. NIEHS (National Institute of Environmental Health Sciences). 2012. Tox21: Transforming Environmental Health. Available: http://www.niehs.nih.gov/health/assets/docs_p_z/tox21_transforming_environmental_health_508.pdf [accessed 1 April 2013].
35. NIH (National Institutes of Health). 2013a. Molecular Libraries Program. Available: http://mli.nih.gov/mli/[accessed 1 April 2013].
36. NIH (National Institutes of Health). 2013b. Welcome to the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Programs at the National Institutes of Health. Available: http://grants.nih.gov/grants/funding/sbir.htm [accessed 1 April 2013].
37. NRC (National Research Council). 2006. Toxicity Testing for Assessment of Environmental Agents: Interim Report. Washington, DC:National Academies Press. Available: http://www.nap.edu/openbook.php?isbn=0309100925 [accessed 7 May 2013].
38. NRC (National Research Council). 2007. Toxicity Testing in the 21st Century: A Vision and A Strategy. Washington, DC:National Academies Press. Available: http://www.nap. edu/openbook.php?record_id=11970 [accessed 7 May 2013].
39. NTP (National Toxicology Program). 2013a. Chemical Effects in Biological Systems (CEBS). Available: http://cebs.niehs.nih. gov [accessed 1 April 2013].
40. NTP (National Toxicology Program). 2013b. DrugMatrix®. Available: https://ntp.niehs.nih.gov/drugmatrix/index.html [accessed 1 April 2013].
41. NTP (National Toxicology Program). 2013c. ToxFX®. Available: https://ntp.niehs.nih.gov/toxfx/[accessed 1 April 2013].
42. NTP (National Toxicology Program). 2013d. Nominate to NTP. Available: http://ntp.niehs.nih.gov/go/27911 [accessed 1 April 2013].
43. Padilla S, Corum D, Padnos B, Hunter DL, Beam A, Houck KA, et al. 2012. Zebrafish developmental screening of the ToxCast™ Phase I chemical library. Reprod Toxicol 33:174-187.
44. Parham F, Austin C, Southall N, Xia M, Tice R, Portier C. 2009. Dose-response modeling of high-throughput screening data. J Biomol Screen 14:1216-1227.
45. Reif DM, Martin MT, Tan SW, Houck KA, Judson RS, Richard AM, et al. 2010. Endocrine profiling and prioritization of environmental chemicals using ToxCast data. Environ Health Perspect 118:1714-1720.
46. Rotroff D, Beam AL, Dix DJ, Farmer A, Freeman KM, Houck KA, et al. 2010. Xenobiotic-metabolizing enzyme and transporter gene expression in primary cultures of human hepatocytes modulated by ToxCast chemicals. J Toxicol Environ Health B Crit Rev 1:329-346.
47. Rotroff DM, Dix DJ, Houck KA, Knudsen TB, Martin MT, McLaurin KM, et al. 2013. Using in vitro high throughput screening assays to identify potential endocrine-disrupting chemicals. Environ Health Perspect 121:7-14.
48. Sakamuru S, Li X, Attene-Ramos MS, Huang R, Lu J, Shou L, et al. 2012. Application of a homogenous membrane potential assay to assess mitochondrial function. Physiol Genomics 44:495-503.
49. Shockley KR. 2012. A three-stage algorithm to make toxicologically relevant activity calls from quantitative high throughput screening data. Environ Health Perspect 120:1107-1115.
50. Shukla SJ, Huang R, Simmons SO, Tice RR, Witt KL, VanLeer D, et al. 2012. Profiling environmental chemicals for activity in the antioxidant response element signaling pathway using a high-throughput screening approach. Environ Health Perspect 120:1150-1156.
51. Simmons SO, Fan C-Y, Ramabhadran R. 2009. Cellular stress response pathway system as a sentinel ensemble in toxicological screening. Toxicol Sci 111:202-225.
52. Sipes NS, Martin MT, Reif DM, Kleinstreuer NC, Judson RS, Singh AV, et al. 2011. Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data. Toxicol Sci 124:109-127.
53. Sun H, Veith H, Xia M, Austin CP, Tice RR, Kavlock RJ, et al. 2012. Prediction of cytochrome P450 profiles of environmental chemicals with QSAR models built from drug-like molecules. Mol Inform 31:783-792.
54. U.S. EPA (U.S. Environmental Protection Agency). 2011. Endocrine Disruptor Screening Program for the 21st Century: (EDSP21 Work Plan). The Incorporation of in Silico Models and in Vitro High Throughput Assays in the Endocrine Disruptor Screening Program (EDSP) for Prioritization and Screening. Summary Overview. Available: http://www.epa.gov/endo/pubs/edsp21_work_plan_summary%20_overview_final.pdf (accessed 1 April 2013).
55. U.S. EPA (U.S. Environmental Protection Agency). 2013a. ACToR. Available: http://actor.epa.gov/actor/faces/ACToRHome.jsp [accessed 1 April 2013].
56. U.S. EPA (U.S. Environmental Protection Agency). 2013b. Endocrine Disruptor Screening Program Comprehensive Management Plan. Available: http://www.epa.gov/endo/pubs/EDSP-comprehensive-management-plan.pdf (accessed 1 April 2013).
57. U.S. EPA (U.S. Environmental Protection Agency). 2013c. Small Business Innovation Research (SBIR) Program. Available: http://www.epa.gov/ncer/sbir/[accessed 1 April 2013].
58. U.S. EPA (U.S. Environmental Protection Agency). 2013d. Tox21. Available: http://www.epa.gov/ncct/Tox21/[accessed 1 April 2013].
59. U.S. EPA (U.S. Environmental Protection Agency). 2013e. TOX21S: Tox21 Chemical Inventory for High-Throughput Screening Structure-Index File. Available: http://www.epa.gov/ncct/dsstox/sdf_tox21s.html [accessed 1 April 2013].
60. U.S. EPA (U.S. Environmental Protection Agency). 2013f. ToxCast™ Chemicals. Available: http://www.epa.gov/ncct/toxcast/chemicals.html [accessed 1 April 2013].
61. U.S. EPA (U.S. Environmental Protection Agency). 2013g. Virtual Embryo Project (v-Embryo™). Available: http://www.epa. gov/ncct/v-Embryo/[accessed 1 April 2013].
62. U.S. EPA (U.S. Environmental Protection Agency). 2013h. Virtual Liver Project (v-Liver™). Available: http://www.epa.gov/ncct/virtual_liver/[accessed 1 April 2013].
63. Xia M, Huang R, Sun Y, Semenza GL, Aldred SF, Witt KL, et al. 2009. Identification of chemical compounds that induce HIF-1α activity. Toxicol Sci 112:153-163.
64. Xia M, Huang R, Witt KL, Southall N, Fostel J, Cho MH, et al. 2008. Compound cytotoxicity profiling using quantitative highthroughput screening. Environ Health Perspect 116:284-291.
65. Xia M, Shahane S, Huang R, Titus SA, Shum E, Zhao Y, et al. 2011. Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels. Toxicol Appl Pharmacol 252:250-258.
66. Yamamoto KN, Hirota K, Kono K, Takeda S, Sakamuru S, Xia M, et al. 2011. Characterization of environmental chemicals with potential for DNA damage using isogenic DNA repairdeficient chicken DT40 cell lines. Environ Mol Mutagen 52:547-561.