Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA)

Regulatory Toxicology and Pharmacology

Volumn 70, Issue 3, 2014, Pages 629-640

  Tollefsen, Knut Erik ^a   Scholz, Stefan ^b   Cronin, Mark T ^c   Edwards, Stephen W ^d   de Knecht, Joop ^e   Crofton, Kevin ^d   Garcia Reyero, Natalia ^f   Hartung, Thomas ^g   Worth, Andrew ^h   Patlewicz, Grace ⁱ  

^a NORWEGIAN INSTITUTE FOR WATER RESEARCH   (Norway)

^b HELMHOLTZ CENTRE FOR ENVIRONMENTAL RESEARCH UFZ   (Germany)

^c LIVERPOOL JOHN MOORES UNIVERSITY   (United Kingdom)

^d U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^e OECD   (France)

^f MISSISSIPPI STATE UNIVERSITY   (United States)

^g JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^h JOINT RESEARCH CENTRE   (Italy)

ⁱ DUPONT COMPANY   (United States)

Author keywords

(Q)SAR; Adverse outcome pathway (AOP); Cross species extrapolation; High content screening (HCS); High throughput screening (HTS); Integrated approaches to testing and assessment (IATA); Read across

Indexed keywords

ACETYLCHOLINE; ACETYLCHOLINESTERASE; ANDROGEN; ENDOCRINE DISRUPTOR; ESTROGEN; THYROID HORMONE;

ADVERSE OUTCOME; ADVERSE OUTCOME PATHWAY; ARTICLE; BIOACCUMULATION; COMPUTER MODEL; DECISION MAKING; ENZYME INHIBITION; HAZARD ASSESSMENT; HEALTH HAZARD; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; INTEGRATED APPROACHES TO TESTING AND ASSESSMENT; LEGAL ASPECT; LETHALITY; MOLECULAR DOCKING; NONHUMAN; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REGULATORY DECISION MAKING; RISK ASSESSMENT; SKIN SENSITIZATION; TOXICITY TESTING; TOXICOLOGY; ANIMAL; ANIMAL TESTING ALTERNATIVE; COMPUTER SIMULATION; GOVERNMENT REGULATION; PROCEDURES;

ANIMALIA;

ANIMAL TESTING ALTERNATIVES; ANIMALS; COMPUTER SIMULATION; DECISION MAKING; GOVERNMENT REGULATION; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; RISK ASSESSMENT; TOXICITY TESTS;

EID: 84922433050     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2014.09.009     Document Type: Article

References (113)

1. Adler S., Basketter D., Creton S., Pelkonen O., van Benthem J., Zuang V., Andersen K.E., Angers-Loustau A., Aptula A., Bal-Price A., Benfenati E., Bernauer U., Bessems J., Bois F.Y., Boobis A., Brandon E., Bremer S., Broschard T., Casati S., Coecke S., Corvi R., Cronin M., Daston G., Dekant W., Felter S., Grignard E., Gundert-Remy U., Heinonen T., Kimber I., Kleinjans J., Komulainen H., Kreiling R., Kreysa J., Leite S.B., Loizou G., Maxwell G., Mazzatorta P., Munn S., Pfuhler S., Phrakonkham P., Piersma A., Poth A., Prieto P., Repetto G., Rogiers V., Schoeters G., Schwarz M., Serafimova R., Tähti H., Testai E., van Delft J., van Loveren H., Vinken M., Worth A., Zaldivar J.M. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch. Toxicol. 2011, 85:367-485.
2. Ahlers J., Stock F., Werschkun B. Integrated testing and intelligent assessment-new challenges under REACH. Environ. Sci. Pollut. Res. 2008, 15:565-572.
3. Ankley G.T., Jensen K.M., Durhan E.J., Makynen E.A., Butterworth B.C., Kahl M.D., Villeneuve D.L., Linnum A., Gray L.E., Cardon M., Wilson V.S. Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas). Toxicol. Sci. 2005, 86:300-308.
4. Ankley G.T., Bennett R.S., Erickson R.J., Hoff D.J., Hornung M.W., Johnson R.D., Mount D.R., Nichols J.W., Russom C.L., Schmieder P.K., Serrrano J.A., Tietge J.E., Villeneuve D.L. Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem. 2010, 29:730-741.
5. Aptula A.O., Roberts D.W. Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity. Chem. Res. Toxicol. 2006, 19:1097-1105.
6. Aylward L.L., Hays S.M. Consideration of dosimetry in evaluation of ToxCast data. J. Appl. Toxicol. 2011, 31:741-751.
7. Balls M., Amcoff P., Bremer S., Casati S., Coecke S., Clothier R., Combes R., Corvi R., Curren R., Eskes C., Fentem J., Gribaldo L., Halder M., Hartung T., Hoffman S., Schechtman L., Scott L., Spielmann H., Stokes W., Tice R., Wagner D., Zuang Z. The principles of weight of evidence validation of test methods and testing strategies: the report and recommendations of ECVAM workshop 58. Altern. Lab. Anim. 2006, 34:603-620.
8. Barata C., Solayan A., Porte C. Role of B-esterases in assessing toxicity of organophosphorus (chlorpyrifos, malathion) and carbamate (carbofuran) pesticides to Daphnia magna. Aquat. Toxicol. 2004, 66:125-139.
9. Barton-Maclaren, T., Becker, R., van der Burg, B., Kennedy, S., Meek, M. E., Ankley, G., Linkov, I., Segner, H., Watanabe, K., Sachana, M., Villeneuve, D., Edwards, S. Weight of evidence evaluation to define uncertainties associated with predictive relationships represented in an AOP (Unpublished-in preparation).
10. Becker, R.A., Rowlands, J.C., Patlewicz, G., Simon, T., 2014. Enhancing the utility of T21 assessment methods by employing a scientific confidence framework and exposure: activity profiling. Presented at ICCA-JRC Workshop, June 17-18, 2014 Lugano, Switzerland.
11. Bhattacharya S., Zhang Q., Carmichael P.L., Boekelheide K., Andersen M.E. Toxicity testing in the 21st century: defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. PLoS One 2011, 6:e20887.
12. Bianco K., Yusseppone M.S., Otero S., Luquet C., Rios de Molina M.C., Kristoff G. Cholinesterases and neurotoxicity as highly sensitive biomarkers for an organophosphate insecticide in freshwater gastropod (Chilina gibbosa) with low sensitivity carboxylesterases. Aquat. Toxicol. 2013, 26-35:144-145. 10.1016/j.aquatox.2013.09.025.
13. Blackburn K., Stuard S.B. A framework to facilitate consistent characterization of read across uncertainty. Reg. Toxicol. Pharmacol. 2014, 68:353-362.
14. Bradbury, S.P., Carlson, R.W., Henry, T.R., Padilla, S., Cowden, J., 2008. Toxic responses of the fish nervous system. In: Di Giulio, R.T., Hinton, D.E. (Eds.), The Toxicology of Fishes, CRC Press, pp. 417-455.
15. Capen C.C. Mechanistic data and risk assessment of selected toxic end points of the thyroid gland. Toxicol. Pathol. 1997, 25:39-48.
16. Costa L.G. Current issues in organophosphate toxicology. Clin. Chim. Acta 2006, 366:1-13.
17. Cox L.A., Douglas D., Marty S., Rowlands J.C., Patlewicz G., Goyak K.O., Becker R.A. Applying a scientific confidence framework to a HTS-derived prediction model for endocrine endpoints: lessons learned from a case study. Reg. Toxicol. Pharmacol. 2014, 69:443-450.
18. Crofton K.M. Thyroid disrupting chemicals: mechanisms and mixtures. Int. J. Androl. 2008, 31:209-223.
19. Crofton K.M., Zoeller R.T. Mode of action: neurotoxicity induced by thyroid hormone disruption during development-hearing loss resulting from exposure to PHAHs. Crit. Rev. Toxicol. 2005, 35:757-769.
20. Cronin, M.T.D., Madden, J.C., 2010. In Silico Toxicology: Principles and Applications, Royal Society of Chemistry, Cambridge.
21. Cronin M.T.D., Bajot F., Enoch S.J., Madden J.C., Roberts D.W., Schwöbel J. The in chemico-in silico interface: challenges for integrating experimental and computational chemistry to identify toxicity. Altern. Lab. Anim. 2009, 37:513-521.
22. de Bruijn J., Hermens J. Inhibition of acetylcholinesterase and acute toxicity of organophosphorous compounds to fish: a preliminary structure-activity analysis. Aquat. Toxicol. 1993, 24:257-274.
23. EC, 2006. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. Off. J. Eur. Union. L396/1 of 30.12.2006. Commission of the European Communities.
24. ECHA, 2008. Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals. Available at: (last accessed 16.09.14). http://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf.
25. El Yazal J., Rao S.N., Mehl A., Slikker W. Prediction of organophosphorus acetylcholinesterase inhibition using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. Toxicol. Sci. 2001, 63:223-232.
26. Emter R., Ellis G., Natsch A. Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. Toxicol. Appl. Pharmacol. 2010, 245:281-290.
27. Emter R., van der Veen J.W., Adamson G., Ezendam J., van Loveren H., Natsch A. Gene expression changes induced by skin sensitizers in the KeratinoSens™ cell line: discriminating Nrf2-dependent and Nrf2-independent events. Toxicol. In Vitro 2013, 27:2225-2232.
28. Escher B., Schwarzenbach P. Mechanistic studies on baseline toxicity and uncoupling of organic compounds as a basis for modeling effective membrane concentrations in aquatic organisms. Aquat. Sci. 2002, 64:20-35.
29. Fukuto T.R. Mechanism of action of organophosphorus and carbamate insecticides. Environ. Health Perspect. 1990, 87:245-254.
30. Fulton M.H., Key P.B. Acetylcholinesterase inhibition in estuarine fish and invertebrates as an indicator of organophosphorus insecticide exposure and effects. Environ. Toxicol. Chem. 2001, 20:37-45.
31. Garcia-Reyero N., Kennedy A.J., Escalon B.L., Habib T., Laird J.G., Rawat A., Wiseman S., Hecker M., Denslow N., Steevens J.A., Perkins E.J. Differential effects and potential adverse outcomes of ionic silver and silver nanoparticles in vivo and in vitro. Environ. Sci. Technol. 2014, 48:4546-4555.
32. Garcia-Reyero N., Escalon B.L., Prats E., Stanley J.K., Thienpont B., Melby N.L., Barón E., Eljarrat E., Barceló D., Mestres J., Babin P.J., Perkins E.J., Raldúa D. Effects of BDE-209 contaminated sediments on zebrafish development and potential implications to human health. Environ. Int. 2014, 63:216-223.
33. Gerberick G.F., Vassallo J.D., Bailey R.E., Chaney J.G., Morrall S.W., Lepoittevin J.-P. Development of a peptide reactivity assay for screening contact allergens. Toxicol. Sci. 2004, 81:332-343.
34. Gerberick G.F., Vassallo J.D., Foertsch L.M., Price B.B., Chaney J.G., Lepoittevin J.-P. Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. Toxicol. Sci. 2007, 97:417-427.
35. Hartung T., Luechtefeld T., Maertens A., Kleensang A. Integrated testing strategies for safety assessments. ALTEX 2013, 30:3-18.
36. Hartung T., Hoffmann S., Stephens M. Mechanistic validation. ALTEX 2013, 30:119-130.
37. Hill A.B. The environment and disease: association or causation?. Proc. R. Soc. Med. 1965, 58:295-300.
38. Holth T.F., Tollefsen K.E. Acetylcholine esterase inhibitors in effluents from oil production platforms in the North Sea. Aquat. Toxicol. 2012, 112-113:92-98.
39. Hunt K.A., Bird D.M., Mineau P., Shutt L. Secondary poisoning hazard of fenthion to American kestrels. Arch. Environ. Contam. Toxicol. 1991, 21:84-90.
40. Institute of Medicine (IOM), 2010. Evaluation of biomarkers and surrogate endpoints in chronic disease. ISBN: 978-0-309-15129-0.
41. Irons T.D., MacPhail R.C., Hunter D.L., Padilla S. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish. Neurotoxicol. Teratol. 2010, 32:84-90.
42. Judson R., Kavlock R.J., Martin M.T., Reif D., Houck K.A., Knudsen T.B., Richard A.M., Tice R.R., Whelan M., Xia M., Huang R., Austin C.P., Daston G.P., Hartung T., Fowle J., Wooge W., Tong W., Dix D.J. Perspectives on validation of high-throughput assays supporting 21st century toxicity testing. ALTEX 2013, 30:51-66.
43. Judson R., Houck K., Martin M., Knudsen T., Thomas R.S., Sipes N., Shah I., Wambaugh J., Crofton K. In vitro and modelling approaches to risk assessment from the U.S. environmental protection agency ToxCast program. Basic Clin. Pharmacol. Toxicol. 2014, 115:69-76.
44. Kavlock R.J., Dix D.J., Houck K.A., Judson R.S., Martin M.T., Richard A.M. ToxCast™: developing predictive signatures for chemical toxicity. ALTEX 2007, 14:623-627.
45. Kleinstreuer N.C., Yang J., Berg E.L., Knudsen T.B., Richard A.M., Martin M.T., Reif D.M., Judson R.S., Polokoff M., Dix D.J., Kavlock R.J., Houck K.A. Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat. Biotechnol. 2014, 32:583-591.
46. Knudsen T.B., Houck K.A., Sipes N.S., Singh A.V., Judson R.S., Martin M.T., Weissman A., Kleinstreuer N.C., Mortensen H.M., Reif D.M., Rabinowitz J.R., Woodrow Setzer R., Richard A.M., Dix D.J., Kavlock R.J. Activity profiles of 309 ToxCast™ chemicals evaluated across 292 biochemical targets. Toxicology 2011, 282:1-15.
47. Kobayashi H., Yuyama A., Kajita T., Shimura K., Ohkawa T., Satoh K. Effects of insecticidal carbamates on brain acetylcholine content, acetylcholinesterase activity and behavior in mice. Toxicol. Lett. 1985, 29:153-159.
48. Kobayashi H., Sato I., Akatsu Y., Fujii S.I., Suzuki T., Matsusaka N., Yuyama A. Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats. J. Appl. Toxicol. 1994, 14:185-190.
49. Kokel D., Bryan J., Laggner C., White R., Cheung C.Y., Mateus R., Healey D., Kim S., Werdich A.A., Haggarty S.J., Macrae C., Shoichet B., Peterson R. Rapid behavior-based identification of neuroactive small molecules in the zebrafish. Nat. Chem. Biol. 2010, 6:231-237.
50. Körner W., Hanf V., Schuller W., Bartsch H., Zwirner M., Hagenmaier H. Validation and application of a rapid in vitro assay for assessing the estrogenic potency of halogenated phenolic chemicals. Chemosphere 1998, 37:2395-2407.
51. Lalone C.A., Villeneuve D.L., Burgoon L.D., Russom C.L., Helgen H.W., Berninger J.P., Tietge J.E., Severson M.N., Cavallin J.E., Ankley G.T. Molecular target sequence similarity as a basis for species extrapolation to assess the ecological risk of chemicals with known modes of action. Aquat. Toxicol. 2013, 144-145:141-154.
52. Legler J., van den Brink C., Brouwer A., Murk A., van der Saag P., Vethaak A., van der Burg B. Development of a stably transfected estrogen receptor-mediated luciferase reporter gene assay in the human T47D breast cancer cell line. Toxicol. Sci. 1999, 48:55-66.
53. Lepoittevin J.-P., Basketter D.A., Goossens A., Karlberg A.-T. Allergic contact dermatitis. The molecular basis 1997, Springer, Heidelberg.
54. Leung M.C.K., Williams P.L., Benedetto A., Au C., Helmcke K.J., Aschner M., Meyer J.N. Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology. Toxicol. Sci. 2008, 106:5-28.
55. Lo Piparo, E., Worth, A., 2010. Review of QSAR models and software tools for predicting developmental and reproductive toxicity. JRC report EUR 24522 EN. Publications Office of the European Union.
56. McHenery J.G., Linley-Adams G.E., Moore D.C., Rodger G.K., Davies I.M. Experimental and field studies of effects of dichlorvos exposure on acetylcholinesterase activity in the gills of the mussel, Mytilus edulis L. Aquat. Toxicol. 1997, 38:125-143.
57. McKim J.M., Schmieder P.K., Niemi G.J., Carlson R.W., Henry T.R. Use of respiratory-cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 2. Malathion, carbaryl, acrolein, and benzaldehyde. Environ. Toxicol. Chem. 1987, 6:313-328.
58. Meek M.E., Boobis A., Cote I., Dellarco V., Fotakis G., Munn S., Seed J., Vickers C. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J. Appl. Toxicol. 2014, 34:1-18.
59. Meek M.E., Palermo C.M., Bachman A.N., North C.M., Lewis R.J. Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J. Appl. Toxicol. 2014, 34:595-606.
60. Miller M.D., Crofton K.M., Rice D.C., Zoeller R.T. Thyroid-disrupting chemicals: interpreting upstream biomarkers of adverse outcomes. Environ. Health Perspect. 2009, 2117:1033-1041.
61. Mombelli E. Evaluation of the OECD (Q)SAR application toolbox for the profiling of estrogen receptor binding affinities. SAR QSAR Environ. Res. 2012, 23:37-57.
62. Munn, S., Goumenou, M., 2013. Key scientific issues relevant to the identification and characterisation of endocrine disrupting substances. Report of the Endocrine Disrupters Expert Advisory Group. JRC Scientific and Policy Report EUR 25919 EN. Publications Office of the European Union, Luxembourg. Available from: . http://publications.jrc.ec.europa.eu/repository/.
63. Murk A.J., Rijntjes E., Blaauboer B.J., Clewell R., Crofton K.M., Dingemans M.M., Furlow J.D., Kavlock R., Kohrle J., Opitz R., Traas T., Visser T.J., Xia M., Gutleb A.C. Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. Toxicol. In Vitro 2013, 27:1320-1346.
64. Nelms, M.D, Ates, G., Madden, J.C, Vinken, M., Cronin, M.T, Rogiers, V., Enoch, S.J., 2014. Proposal of an in silico profiler for categorisation of repeat dose toxicity data of hair dyes. Arch. Toxicol. (in press). http://dx.doi.org/10.1007/s00204-014-1277-8.
65. Novic M., Vracko M. QSAR models for reproductive toxicity and endocrine disruption activity. Molecules 2010, 15:1987-1999.
66. Organisation for Economic Cooperation and Development, (OECD), 2004. OECD Principles for the Validation, for Regulatory Purposes, of (Quantitative) Structure-Activity Relationship Models. Available at: . http://www.oecd.org/env/ehs/risk-assessment/37849783.pdf.
67. Organisation for Economic Cooperation and Development, (OECD). 2007. Guidance Document on the Validation of (Q)SAR Models. OECD Series on Testing and Assessment No. 69. Organisation for Economic Co-operation and Development, Paris, France.
68. Organisation for Economic Cooperation and Development, (OECD), 2008. Workshop on Integrated Approaches to Testing and Assessment. OECD Series on Testing and Assessment No. 88. Organisation for Economic Co-operation and Development, Paris, France.
69. Organisation for Economic Cooperation and Development, (OECD), 2012a The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins Part 1: Scientific Evidence. Series on Testing and Assessment No. 168 ENV/JM/MONO(2012) 10/PART1.
70. Organisation for Economic Cooperation and Development, (OECD), 2012b. The Adverse Outcome Pathway for Skin Sensitisation by Covalent Binding to Proteins. Part 2: Use of the AOP to Develop Chemical Categories and Integrated Testing and Assessment Approaches. Organisation for Economic Co-operation and Development Paris, France.
71. Organisation for Economic Cooperation and Development, (OECD), 2012c. OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters. Organisation for Economic Co-operation and Development Paris, France.
72. Organisation for Economic Cooperation and Development (OECD), 2013. Guidance Document on Developing and Assessing Adverse Outcome Pathways. Organisation for Economic Co-operation and Development Paris, France.
73. Organisation for Economic Cooperation and Development, (OECD), 2014a. New Guidance Document on an Integrated Approach on Testing and Assessment (IATA) for Skin Corrosion and Irritation. Series on Testing and Assessment No. 203. Organisation for Economic Co-operation and Development, Paris, France.
74. Organisation for Economic Cooperation and Development, (OECD), 2014b. Guidance on grouping of chemicals, second edition. Series on Testing and Assessment No. 194. Organisation for Economic Co-operation and Development, Paris, France.
75. Opitz R., Maquet E., Huisken J., Antonica F., Trubiroha A., Pottier G., Janssens V., Costagliola S. Transgenic zebrafish illuminate the dynamics of thyroid morphogenesis and its relationship to cardiovascular development. Dev. Biol. 2012, 372:203-216.
76. Oyama Y., Hori N., Evans M.L., Allen C.N., Carpenter D.O. Electrophysiological estimation of the actions of acetylcholinesterase inhibitors on acetylcholine receptor and cholinesterase in physically isolated Aplysia neurons. Br. J. Pharmacol. 1989, 96:573-582.
77. Patlewicz G., Simon T., Goyak K., Phillips R.D., Rowlands J.C., Seidel S., Becker R.A. Use and validation of HT/HC assays to support 21st century toxicity evaluations. Regul. Toxicol. Pharmacol. 2013, 65:259-268.
78. Patlewicz G., Kuseva C., Kesova A., Popova I., Zhechev T., Pavlov T., Roberts D.W., Mekenyan O.M. Towards AOP application - implementation of an integrated approach to testing and assessment (IATA) into a pipeline tool for skin sensitization. Reg. Toxicol. Pharmacol. 2014, 69:529-545.
79. Patlewicz, G., Simon, T., Rowlands, J.C., Budinsky, R.A., Becker, R.A. Using a scientific confidence framework to support application of adverse outcome pathways for regulatory purposes. Reg. Toxicol. Pharmacol. (Unpublished - submitted).
80. Patlewicz, G., Ball, N., Blackburn, K., Aptula, A, Lampi, M., Boogaard, P., Becker, R.A., Hubesch, B. Building scientific confidence in the development and evaluation of read-across. (Unpublished - in preparation).
81. Perkins E.J., Ankley G.T., Crofton K.M., Garcia-Reyero N., LaLone C.A., Johnson M.S., Tietge J.E., Villeneuve D.L. Current perspectives on the use of alternative species in human health and ecological hazard assessments. Environ. Health Perspect. 2013, 121:1002-1010.
82. Perkins, E.J., Antczak, P., Burgoon, L., Falciani, F., Gutsell, S., Hodges, G., Kienzler, A., Knapen, D., McBride, M., Willett, C., 2014. Using adverse outcome pathways for regulatory applications. Toxicol. Sci. (Unpublished - submitted).
83. Python F., Goebel C., Aeby P. Assessment of the U937 cell line for the detection of contact allergens. Toxicol. Appl. Pharmacol. 2007, 220:113-124.
84. Raldua D., Babin P.J. Simple, rapid zebrafish larva bioassay for assessing the potential of chemical pollutants and drugs to disrupt thyroid gland function. Environ. Sci. Technol. 2009, 43:6844-6850.
85. Roberts D.W., Aptula A.O., Patlewicz G., Pease C. Chemical reactivity indices and mechanism-based read across for non-animal based assessment of skin sensitization potential. J. Appl. Toxicol. 2008, 28:443-454.
86. Romanov S., Medvedev A., Gambarian M., Poltoratskaya N., Moeser M., Medvedeva L., Gambarian M., Diatchenko L., Makarov S. Homogeneous reporter system enables quantitative functional assessment of multiple transcription factors. Nat. Methods 2008, 5:253-260.
87. Rostkowski P., Horwood J., Shears J.A., Lange A., Oladapo F.O., Besselink H.T., Tyler C.R., Hill E.M. Bioassay-directed identification of novel antiandrogenic compounds in bile of fish exposed to wastewater effluents. Environ. Sci. Technol. 2011, 45:10660-10667.
88. Russom C.L., LaLone C.A., Villeneuve D.L., Ankley G.T. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality. Environ Toxicol Chem. 2014, 33:2157-2169. 10.1002/etc.2662.
89. Sakaguchi H., Ashikaga T., Kosaka N., Sono S., Nishiyama N., Itagaki H. The in vitro skin sensitization test; human cell line activation test (h-CLAT) using THP-1 cells. Toxicol. Lett. 2007, 172:S93.
90. Schmieder P.K., Ankley G., Mekenyan O., Walker J.D., Bradbury S. Quantitative structure-activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals. Environ. Toxicol. Chem. 2003, 22:1844-1854.
91. Scholz S. Zebrafish embryos as an alternative model for screening of drug-induced organ toxicity. Arch. Toxicol. 2013, 87:767-769.
92. Scholz S., Sela E., Blaha L., Braunbeck T., Galay-Burgos M., Garcia-Franco M., Guinea J., Kluver N., Schirmer K., Tanneberger K., Tobor-Kaplon M., Witters H., Belanger S., Benfenati E., Creton S., Cronin M.T., Eggen R.I., Embry M., Ekman D., Gourmelon A., Halder M., Hardy B., Hartung T., Hubesch B., Jungmann D., Lampi M.A., Lee L., Leonard M., Kuster E., Lillicrap A., Luckenbach T., Murk A.J., Navas J.M., Peijnenburg W., Repetto G., Salinas E., Schuurmann G., Spielmann H., Tollefsen K.E., Walter-Rohde S., Whale G., Wheeler J.R., Winter M.J. A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment. Regul. Toxicol. Pharmacol. 2013, 67:506-530.
93. Schultz T.W., Yarbrough J.W., Johnson E.L. Structure-activity relationships for reactivity of carbonyl compounds with glutathione, SAR QSAR. Environ. Res. 2005, 16:313-322.
94. Schwöbel J.A., Koleva Y.K., Enoch S.J., Bajot F., Hewitt M., Madden J.C., Roberts D.W., Schultz T.W., Cronin M.T. Measurement and estimation of electrophilic reactivity for predictive toxicology. Chem. Rev. 2011, 111:2562-2596.
95. Simmons S.O., Fan C.-Y., Ramabhadran R. Cellular stress response pathway system as a sentinel ensemble in toxicological screening. Toxicol. Sci. 2009, 111:202-225.
96. Smith Pease C.K. From xenobiotic chemistry and metabolism towards better risk assessment in skin allergy. Toxicology 2003, 192:1-22.
97. Thaens D., Heinzelmann D., Böhme A., Paschke A., Schüürmann G. Chemoassay screening of DNA-reactive mutagenicity with 4-(4-nitrobenzyl)pyridine - application to epoxides, oxetanes and sulfur heterocycles. Chem. Res. Toxicol. 2012, 25:2092-2102.
98. Thienpont B., Tingaud-Sequeira A., Prats E., Barata C., Babin P.J., Raldua D. Zebrafish eleutheroembryos provide a suitable vertebrate model for screening chemicals that impair thyroid hormone synthesis. Environ. Sci. Technol. 2011, 45:7525-7532.
99. Tollefsen K.E., Nilsen A.J. Binding of alkylated phenols and non-phenolics to the hepatic estrogen receptor in rainbow trout (Oncorhynchus mykiss). Ecotoxicol. Environ. Saf. 2008, 69:163-172.
100. Tollefsen K.E., Eikvar S., Finne E.F., Fogelberg O., Gregersen I.K. Estrogenicity of alkylphenols and alkylated non-phenolics in a rainbow trout (Oncorhynchus mykiss) primary hepatocyte culture. Ecotoxicol. Environ. Saf. 2008, 71:370-383.
101. Truong L., Reif D.M., St Mary L., Geier M.C., Truong H.D., Tanguay R.L. Multidimensional in vivo hazard assessment using zebrafish. Toxicol. Sci. 2014, 137:212-233.
102. US EPA, 2011. Integrated approaches to testing and assessment strategy: use of new computational and molecular tools us environmental protection agency. FIFRA Scientific Advisory Panel Consultation May 24-26, 2011. Available at: (accessed 16.09.14). http://yosemite.epa.gov/sab/sabproduct.nsf/373C1DB0E0591296852579F2005BECB3/$File/OPP+SAP+document-May2011.pdf.
103. Villeneuve D.L., Ankley G.T., Makynen E.A., Blake L.S., Greene K.J., Higley E.B., Newsted J.L., Giesy J.P., Hecker M. Comparison of fathead minnow ovary explant and H295R cell-based steroidogenesis assays for identifying endocrine-active chemicals. Ecotoxicol. Environ. Saf. 2007, 68:20-32.
104. Vinggaard A.M., Hnida C., Breinholt V., Larsen J.C. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro. Toxicol. In Vitro 2000, 14:227-234.
105. Volz D.C., Belanger S., Embry M., Padilla S., Sanderson H., Schirmer K., Scholz S., Villeneuve D. Adverse outcome pathways during early fish development: a conceptual framework for identification of chemical screening and prioritization strategies. Toxicol. Sci. 2011, 123:349-358.
106. Wambaugh J.F., Setzer R.W., Reif D.M., Gangwal S., Mitchell-Blackwood J., Arnot J.A., Joliet O., Frame A., Rabinowitz J., Knudsen T.B., Judson R.S., Egeghy P., Vallero D., Cohen Hubal E.A. High-throughput models for exposure-based chemical prioritization in the ExpoCast project. Environ. Sci. Technol. 2013, 47:8479-8488.
107. Weinberg A.M. Science and trans-science. Ciba Found. Symp. 1971, 1:105-122.
108. Wong K.Y., Duchowicz P.R., Mercader A.G., Castro E.A. QSAR applications during last decade on inhibitors of acetylcholinesterase in Alzheimer's disease. Mini Rev. Med. Chem. 2012, 12:936-946.
109. Worth, A.P., Patlewicz., G., 2014. Integrated approaches to testing and assessment. In: Whelan, M., Chantra E., (Eds.), Validation of Alternative Methods, Springer. (Unpublished - submitted).
110. Wu S., Fisher J., Naciff J., Laufersweiler M., Lester C., Daston G., Blackburn K.B. Framework for identifying chemicals with structural features associated with the potential to act as developmental or reproductive toxicants. Chem. Res. Toxicol. 2013, 26:1840-1861.
111. Zaldívar, J.M., Mennecozzi, M., Marcelino Rodrigues, R., Bouhifd, M., 2010. A biology-based dynamic approach for the modelling of toxicity in cell-based assays. Part I: Fate modelling. Available from: . http://publications.jrc.ec.europa.eu/repository/.
112. Zaldívar, J. M., Menecozzi, M., Macko, P., Rodriguez, R., Bouhifd, M., Baraibar Fentanes, J., 2011. A Biology-Based Dynamic Approach for the Modelling of Toxicity in Cell Assays: Part II: Models for Cell Population Growth and Toxicity. Available from: http://publications.jrc.ec.europa.eu/repository/.
113. Zhao S., Narang A., Gierthy J., Eadon G. Detection and characterization of DNA adducts formed from metabolites of the fungicide ortho-phenylphenol. J. Agric. Food Chem. 2002, 50:3351-3358.