Adverse outcome pathways for regulatory applications: Examination of four case studies with different degrees of completeness and scientific confidence

Toxicological Sciences

Volumn 148, Issue 1, 2015, Pages 14-25

  Perkins, Edward J ^a   Antczak, Philipp ^b   Burgoon, Lyle ^a   Falciani, Francesco ^b   Garcia Reyero, Natàlia ^c   Gutsell, Steve ^d   Hodges, Geoff ^d   Kienzler, Aude ^e   Knapen, Dries ^f   McBride, Mary ^g   Willett, Catherine ^h  

^a U S ARMY ENGINEER RESEARCH AND DEVELOPMENT CENTER   (United States)

^b UNIVERSITY OF LIVERPOOL   (United Kingdom)

^c MISSISSIPPI STATE UNIVERSITY   (United States)

^d UNILEVER RESEARCH   (United Kingdom)

^e JOINT RESEARCH CENTRE   (Italy)

^f UNIVERSITY OF ANTWERP   (Belgium)

^g AGILENT TECHNOLOGIES   (United States)

^h Humane Society of the United States   (United States)

Author keywords

hazard assessment; Mode of action; regulatory toxicology; risk assessment; tox21

Indexed keywords

AROMATASE; AROMATASE INHIBITOR; CARCINOGEN; POLLUTANT;

ADVERSE OUTCOME; ADVERSE OUTCOME PATHWAY; ARTICLE; COVALENT BOND; DECISION MAKING; ENZYME INHIBITION; HUMAN; LIVER CELL CARCINOMA; MEMBRANE DAMAGE; REGULATORY DECISION MAKING; RESPIRATORY FAILURE; RISK ASSESSMENT; SKIN SENSITIZATION; ANIMAL; BIOLOGICAL MODEL; BIOLOGY; CELL MEMBRANE; CELL PROLIFERATION; CYTOLOGY; DERMATITIS, ALLERGIC CONTACT; DRUG EFFECTS; ECOTOXICOLOGY; ENZYMOLOGY; EVIDENCE BASED PRACTICE; IMMUNOLOGY; LEGISLATION AND JURISPRUDENCE; LIVER CELL; METABOLISM; ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT; ORGANIZATION; PATHOLOGY; POLLUTANT; PROCEDURES; SKIN; STANDARDS; TOXICITY; TOXICITY TESTING;

ANIMALS; AROMATASE INHIBITORS; CARCINOGENS, ENVIRONMENTAL; CELL MEMBRANE; CELL PROLIFERATION; COMPUTATIONAL BIOLOGY; CONGRESSES AS TOPIC; DECISION MAKING, ORGANIZATIONAL; DERMATITIS, ALLERGIC CONTACT; ECOTOXICOLOGY; ENVIRONMENTAL POLLUTANTS; EVIDENCE-BASED PRACTICE; HEPATOCYTES; HUMANS; MODELS, BIOLOGICAL; ORGANISATION FOR ECONOMIC CO-OPERATION AND DEVELOPMENT; RISK ASSESSMENT; SKIN; TOXICITY TESTS, ACUTE; TOXICITY TESTS, CHRONIC;

EID: 84947807458     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfv181     Document Type: Article

References (91)

1. 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., et al. (2010). Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem. 29, 730-741.
2. Ankley, G.T., and Jensen, K. M. (2014). A novel framework for interpretation of data from the fish short-term reproduction assay (FSTRA) for the detection of endocrine-disrupting chemicals. Environ. Toxicol. Chem. 33, 2529-2540.
3. Antczak, P., White, T., Giri, A., Cronin, M. T. D., Michelangeli, F., Viant, M., Vulpe, C., Falciani, F. (2015). A systems biology approach reveals a novel calcium-dependent mechanism for basal toxicity in Daphnia magna. Environ. Sci. Technol. 49, 11132-11140.
4. Api, A. M., Basketter, D. A., Cadby, P. A., Cano, M-F., Ellis, G., Gerberick, G. F., Griem, P., McNamee, P. M., Ryan, C. A., and Safford, R. (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Regul. Toxicol. Pharmacol. 52, 3-23.
5. Argese, E., Bettiol, C., Agnoli, F., Zambon, A., Mazzola, M., and Ghirardini, A. V. (2001). Assessment of chloroaniline toxicity by the submitochondrial particle assay. Environ. Toxicol. Chem. 20, 826-832.
6. Austin, T. J., and Eadsforth, C. V. (2014). Development of a chronic fish toxicity model for predicting sub-lethal NOEC values for non-polar narcotics. SAR QSAR Environ. Res. 25, 147-160.
7. Becker, R. A., Ankley, G. T., Edwards, S. W., Kennedy, S. W., Linkov, I., Meek, B., Sachana, M., Segner, H., van der Burg, B., Villeneuve, D. L., et al. (2015). Increasing scientific confidence in adverse outcome pathways: Application of tailored bradford-hill considerations for evaluating weight of evidence. Regul. Toxicol. Pharmacol. 72, 514-537.
8. Bhattacharya, S., Zhang, Q., Carmichael P. L., Boekelheide K., and Andersen M. E. (2011). Toxicity testing in the 21st century: Defining new risk assessment approaches based on perturbation of intracellular toxicity pathways. PLoS One 6, e20887.
9. Black, S. M., DeVol, J. M., and Wedgwood S. (2008). Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation. Am. J. Physiol. Cell Physiol. 294, C345-C354.
10. Boobis, A. R., Cohen, S. M., Dellarco, V., McGregor, D., Meek, M. E., Vickers, C., Willcocks, D., and Farland, W. (2006). IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit. Rev. Toxicol. 36, 781-792.
11. Boobis, A. R., Doe, J. E., Heinrich-Hirsch, B., Meek, M. E., Munn, S., Ruchirawat, M., Schlatter J., Seed J., Vickers, C. (2008). IPCS framework for analysing the relevance of a noncancer mode of action for humans. Crit. Rev. Toxicol. 38, 87-96.
12. Breen, M., Villeneuve, D. L., Ankley, G. T., Bencic, D. C., Breen, M. S., Watanabe, K. H., Lloyd, A. L., and Conolly, R. B. (2013). Developing predictive approaches to characterize adaptive responses of the reproductive endocrine axis to aromatase inhibition: II. Computational modeling. Toxicol. Sci. 133, 234-247.
13. Claeys L., Iaccino, F., Janssen, C. R., Van Sprang, P., and Verdonck, F. (2013). Development and validation of a quantitative structure-activity relationship for chronic narcosis to fish. Environ. Toxicol. Chem. 32, 2217-2225.
14. Cote, I., Anastas, P. T., Birnbaum, L. S., Clark, R. M., Dix, D. J., Edwards, S. W., and Preuss, P. W. (2012). Advancing the next generation of health risk assessment. Environ. Health Perspect. 120, 1499-1502.
15. Dom, N., Vergauwen, L., Vandenbrouck, T., Jansen, M., Blust, R., and Knapen, D. (2012a). Physiological and molecular effect assessment versus physico-chemistry based mode of action schemes: Daphnia magna exposed to narcotics and polar narcotics. Environ. Sci. Technol. 46, 10-18.
16. Dom, N., Knapen, D., Blust, R. (2012b). Assessment of aquatic experimental versus predicted and extrapolated chronic toxicity data of four structural analogues. Chemosphere 86, 56-64.
17. Dourson, M., Reichard, J., Nance, P., Burleigh-Flayerb, H., Parkera, A., Vincenta, M., and McConnell, E. E. (2014). Mode of action analysis for liver tumors from oral 1, 4-dioxane exposures and evidence-based dose response assessment. Regul. Toxicol. Pharmacol. 68, 387-401.
18. Elsharkawy, A. M., and Mann, D. A. (2007). Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology. 46, 590-597.
19. Escher, B. I., and Schwarzenbach, R. P. (2002). Mechanistic studies on baseline toxicity and uncoupling of organic compounds as a basis for modeling effective membrane concentrations in aquatic organisms. Aquat. Sci. 64, 20-35.
20. European Parliament. (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. O. J. Eur. Union 396, 1-849.
21. Falanga, A., Marchetti, M., and Vignoli, A. (2013). Coagulation and cancer: Biological and clinical aspects. J. Thromb. Haemost. 11, 223-233.
22. Fautz, R., Husein, B., and Hechenberger, C. (1991). Application of the neutral red assay (NR assay) to monolayer cultures of primary hepatocytes: Rapid colorimetric viability determination for the unscheduled DNA synthesis test (UDS). Mutat. Res. 253, 173-179.
23. Garcia-Reyero, N. (2015). Are adverse outcome pathways here to stay? Environ. Sci. Technol. 49, 3-9.
24. Gerberick, G. F., Ryan, C. A., Dearman, R. J., and Kimber, I. (2007). Local Lymph Node Assay (LLNA) for detection of sensitization capacity of chemicals. Methods, 41, 54-60.
25. Groh, K. J., Carvalho, R. N., Chipman, J. K., Denslow, N. D., Halder, M., Murphy, C. A., Roelofs, D., Rolaki, A., Schirmer, K., and Watanabe, K. H. (2015a). Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: I. Challenges and research needs in ecotoxicology. Chemosphere 120, 764-777.
26. Groh, K. J., Carvalho, R. N., Chipman, J. K., Denslow, N. D., Halder, M., Murphy, C. A., Roelofs, D., Rolaki, A., Schirmer, K., and Watanabe, K. H. (2015b). Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish. Chemosphere 120, 778-792.
27. Hecker, M., Hollert, H., Cooper, R., Vinggaard, A. M., Akahori, Y., Murphy, M., Nellemann, C., Higley, E., Newsted, J., Laskey, J., et al. (2011). The OECD validation program of the H295R steroidogenesis assay: Phase 3. Final inter-laboratory validation study. Environ. Sci. Pollut. Res. Int. 18, 503-515.
28. Hill, A. B. (1965). The environment and disease: Association or causation. Proc. R. Soc. Med. 58, 295-300.
29. Jaworska, J., Dancik, Y., Kern, P., Gerberick, F., and Natsch, A. (2013). Bayesian integrated testing strategy to assess skin sensitization potency: From theory to practice. J. Appl. Toxicol. 11, 1353-1364.
30. JBRC, Japan Bioassay Research Center. (1998). Two-year studies of 1, 4-dioxane in F344 rats and BDF1 mice (drinking water). Technical report of the Japan Bioassay Research Center, Kanagawa, Japan.
31. Judson, R. S., Kavlock, R. J., Setzer, R. W., Hubal, E. A., Martin, M. T., Knudsen, T. B., Houck, K. A., Thomas, R. S., Wetmore, B. A., and Dix, D. J. (2011). Estimating toxicity-related biological pathway altering doses for high-throughput chemical risk assessment. Chem. Res. Toxicol. 24, 451-462.
32. Julien, E., Boobis, A. R., Olin, S. S., and Ilsi Research Foundation Threshold Working Group. (2009). The Key Events Dose-Response Framework: A cross-disciplinary mode-of-action based approach to examining dose-response and thresholds. Crit. Rev. Food. Sci. Nutr. 49, 682-689.
33. Kano, H., Umeda, Y., Kasai, T., Sasaki, T., Matsumoto, M., Yamazaki, K., Nagano, K., Arito, H., and Fukushima, S. (2009). Carcinogenicity studies of 1, 4-dioxane administered in drinking-water to rats and mice for 2 years. Food Chem. Toxicol. 47, 2776-2784.
34. Kasai, T., Kano, H., Umeda, Y., Sasaki, T., Ikawa, N., Nishizawa, T., Nagano, K., Arito, H., Nagashima, H., and Fukushima, S. (2009). Two-year inhalation study of carcinogenicity and chronic toxicity of 1, 4-dioxane in male rats. Inhal. Toxicol. 21, 889-897.
35. Kasthuri, R. S., Taubman, M. B., and Mackman, N. (2009). Role of tissue factor in cancer. J. Clin. Oncol. 27, 4834-4838.
36. Katoh, M. (2007). Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev. 3, 30-38.
37. Kimber I., and Weisenberger, C. (1989). A murine local lymph node assay for the identification of contact allergens. Arch. Toxicol. 63, 274-282.
38. King, M. E., Shefner, A. M., and Bates, R.R. (1973). Carcinogenesis bioassay of chlorinated dibenzodioxins and related chemicals. Environ. Health Perspect. 5, 163-170.
39. 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., et al. (2014). Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat. Biotechnol. 32, 583-591.
40. Kociba, R. J., McCollister, S. B., Park, C., Torkelson, T. R., and Gehring, P. J. (1974). 1, 4-dioxane. I. Results of a 2-year ingestion study in rats. Toxicol. Appl. Pharmacol. 30, 275-286.
41. Kramer, V. J., Etterson, M. A., Hecker, M., Murphy, C. A., Roesijadi, G., Spade, D. J., Spromberg, J. A., Wang, M., and Ankley, G. T. (2010). Adverse outcome pathways and ecological risk assessment: Bridging to population-level effects. Environ. Toxicol. Chem. 30, 64-76.
42. Kvolik, S., Jukic, M., Matijevic, M., Marjanovic, K., and Glavas-Obrovac, L. (2010) An overview of coagulation disorders in cancer patients. Surg. Oncol. 19, e33-e46.
43. Kleensang, A., Maertens, A., Rosenberg, M., Fitzpatrick, S., Lamb, J., Auerbach, S., Brennan, R., Crofton, K. M., Gordon, B., Fornace, A. J. Jr., et al. (2013). t4 workshop report: Pathways of Toxicity. ALTEX. 31, 53-61.
44. Linkov, I., Massey, O., Keisler, J., Rusyn, I., and Hartung, T. (2015). From "weight of evidence" to quantitative data integration using multicriteria decision analysis and Bayesian methods. ALTEX 32, 3-8.
45. Lundberg, I., Hogberg, J., Kronevi, T., and Holmberg, B. (1987). Three industrial solvents investigated for tumor promoting activity in the rat liver. Cancer Lett. 36, 29-33.
46. MacKay, D., Arnot, J., Petkova, E. P., Wallace, K. B., Call, D. J., Brooke, L. T., and Veith, G. D. (2009). The physicochemical basis of QSARs for baseline toxicity. SAR QSAR Environ. Res. 20, 393-394.
47. MacKay, C., Davies, M., Summerfield, V., and Maxwell, G. (2013). From pathways to people: Applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment. ALTEX. 30, 473-486.
48. Matsumoto, H., Yakabe, Y., Saito, K., Sumida, K., Sekijima, M., Nakayama, K., Miyaura, H., Saito, F., Otsuka, M., and Shirai, T. (2009). Discrimination of carcinogens by hepatic transcript profiling in rats following 28-day administration. Cancer Inform. 7, 253-269.
49. Maxwell, G., MacKay, C., Cubberley, R., Davies, M., Gellatly, N., Glavin, S., Gouin, T., Jacquoilleot, S., Moore, C., Pendlington, R., et al. (2014). Applying the skin sensitisation adverse outcome pathway (AOP) to quantitative risk assessment. Toxicol. in vitro. 28, 8-12.
50. Meek, M. E., Boobis, A., Cote, I., Dellarco, V., Fotakis, G., Munn, S., Seed, J., Vickers, C. (2014). New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J. Appl. Toxicol. 34, 1-18.
51. Miller, D. H., Jensen, K. M., Villeneuve, D. L., Kahl, M. D., Makynen, E. A., Durhan, E. J., Ankley, G.T. (2007). Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ. Toxicol. Chem. 26, 521-527.
52. Moeini, A., Cornellà, H., and Villanueva, A. (2012). Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer 1, 83-93.
53. Nannelli, A., De Rubertis, A., Longo, V., and Gervasi, P. G. (2005). Effects of dioxane on cytochrome P450 enzymes in liver, kidney, lung and nasal mucosa of rat. Arch. Toxicol. 79, 74-82.
54. NCI, National Cancer Institute. (1978). Bioassay of 1, 4-dioxane for possible carcinogenicity. (78-1330 NCICGTR-80). Bethesda, MD. Available at: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr080.pdf. Accessed January 25, 2015.
55. NRC, National Research Council US Committee on Toxicity. (2007). Toxicity Testing in the 21st Century. Washington, DC, The National Academies Press.
56. Nukada, Y., Miyazawa, M., Kazutoshi, S., Sakaguchi, H., Nishiyama, N. (2013). Data Integration of non-animal test for the development of a test battery to predict the skin sensitizing potential and potency of chemicals. Toxicol. In vitro. 27, 609-618.
57. OECD, Organization for Economic Cooperation and Development. (2009a). Report of the Expert Consultation to Evaluate an Estrogen Receptor Binding Affinity Model for Hazard Identification. OECD, Environment Directorate, Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. Available at: http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono(2009)33&doclanguage=en. Accessed January 25, 2015.
58. OECD, Organization for Economic Co-operation and Development. (2009b). Guidance document for using the OECD (Q)SAR application toolbox to develop chemical categories according to the OECD guidance on grouping of chemicals. OECD Series on Testing and Assessment Number 102. Paris, France.
59. OECD, Organization for Economic Co-operation and Development. (2012). Series on Testing and Assessment No. 168 ENV/JM/MONO(2012)10/PART1 The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins. Paris, France.
60. OECD, Organisation for Economic Co-operation and Development. (2013a). Guidance document on developing and assessing adverse outcome pathways. Series on testing and assessment, No. 184. Paris, France. Available at: http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono(2013)6&doclanguage=en. Accessed May 20, 2015.
61. OECD, Organisation for Economic Co-operation and Development. (2013b). Users' handbook supplement to the guidance document for developing and assessing AOPs. Available at: https://aopkb.org/common/AOP_Handbook.pdf. Accessed May 20, 2015.
62. Patlewicz, G., Simon, T. W., Rowlands, J. C., Budinsky, R. A., and Becker, R. A. (2015). Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes. Regul. Toxicol. Pharmacol. 71, 463-477.
63. Pirone, J. R., Smith, M., Kleinstreuer, N. C., Burns, T. A., Strickland, J., Dancik, Y., Morris, R., Rinckel, L. A., Casey, W., and Jaworska, J. S. (2014). Open source software implementation of an integrated testing strategy for skin sensitization potency based on a Bayesian network. ALTEX 31, 336-340.
64. Roberts, D. W., Aptula, A.O., and Patlewicz, G.Y. (2011). Chemistry-based risk assessment for skin sensitization: Quantitative mechanistic modeling for the S(N)Ar domain. Chem. Res. Toxicol. 24, 1003-1011.
65. Rotroff, D. M., Dix, D. J., Houck, K. A., Knudsen, T. B., Martin, M.T., McLaurin, K. W., Reif, D. M., Crofton, K. M., and Singh, A. V., et al. (2013). Using in vitro high throughput screening assays to identify potential endocrine-disrupting chemicals. Environ. Health Perspect. 121, 7-14.
66. Rovida, C., Asakura, S., Daneshian, M., Hofman-Huether, H., Leist, M., Meunier, L., Reif, D., Rossi, A., Schmutz, M., Valentin, J.-P., et al. (2015). Toxicity testing in the 21st century beyond environmental chemicals. ALTEX. 32, 171-181.
67. Russom, C. L., Bradbury, S. P., Broderius S. J., Drummond, R. A., and Hammermeister, D. E. (1997). Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas). Environ. Toxicol. Chem. 16, 948-967.
68. Sandermann, H. (2008). Ecotoxicology of narcosis: Stereoselectivity and potential target sites. Chemosphere 72, 1256-1259.
69. Schmitt, C. J., and Dethloff, G. M. (2000). Biomonitoring of Environmental Status and Trends (BEST) Program: Selected methods for monitoring chemical contaminants and their effects in aquatic ecosystems. U.S. Geological Survey, Biological Resources Division, Columbia, (MO): Information and Technology Report USGS/BRD (2000) 0005. 81 p.
70. Shoemaker, J. E., Gayen, K., Garcia-Reyero, N., Perkins, E. J., Villeneuve, D. L., Liu, L., Doyle, F. J. (2010). Fathead minnow steroidogenesis: In silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk. BMC Syst. Biol. 4, 89.
71. Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S., Amarneh, B., Ito, Y., Fisher, C. R., Michael, M. D., Mendelson C. R., et al. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Rev. 15, 342-355.
72. Sonich-Mullin, C., Fielder, R., Wiltse, J., Baetcke, K., Dempsey, J., Fenner-Crisp, P., Grant, D., Hartley, M., Knaap, A., and Kroese, D., et al. (2001). IPCS Conceptual Framework for Evaluating a Mode of Action for Chemical Carcinogenesis. Regul. Toxicol. Pharmacol. 34, 146-152.
73. Tatsumi, K., Ohashi, K., Taminishi, S., Takagi, S., Utoh, R., Yoshioka, A., Shima, M., and Okano, T. (2009). Effects on coagulation factor production following primary hepatomitogen-induced direct hyperplasia. World J. Gastroenterol. 15, 5307-5315.
74. Tollefsen, K.E., Scholz, S., Cronin, M.T., Edwards, S.W., de Knecht, J., Crofton, K., Garcia-Reyero, N., Hartung, T., Worth, A., et al. (2014). Applying adverse outcome pathways (AOPs) to support integrated approaches to testing and assessment (IATA). Reg. Toxicol. Pharmacol. 70, 629-640.
75. Törönen, P., Kolehmainen, W., Wong, G., and Castrén, E. (1999). Analysis of gene expression data using self-organizing maps. FEBS Lett. 451, 142-146.
76. USEPA, United States Environmental Protection Agency. (1998). EDSTAC: Endocrine disruptor screening and testing advisory committee final report U.S. Environmental Protection Agency. Available at: http://www.epa.gov/endo/pubs/edspoverview/finalrpt.htm. Accessed May 18, 2015.
77. USEPA, U.S. Environmental Protection Agency. (2005). Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum. Washington, DC. Available at: http://www.epa.gov/ttnatw01/cancer_guidelines_final_3-25-05.pdf. Accessed May 15, 2015.
78. USEPA, United States Environmental Protection Agency. (2009). ECOSARTM. Office of Pollution and Toxic Substances, Washington, DC.
79. USEPA, United States Environmental Protection Agency. (2011). Endocrine Disruptor Screening Program, Weight of Evidence: Results of EDSP Tier 1 Screening to Identify the Need for Tier 2 Testing. Available at: http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2010-0877-0021. Accessed May 20, 2015.
80. USEPA, United States Environmental Protection Agency. (2012). Prioritization of the Endocrine Disruptor Screening Program Universe of Chemicals for an Estrogen Receptor Adverse Outcome Pathway Using Computational Toxicology Tools. Availabel at: http://www.epa.gov/endo/pubs/edsp_chemical_universe_and_general_validations_white_paper_11_12.pdf. Accessed May 10, 2015.
81. USEPA, United State Environmental Protection Agency. (2013). Toxicological review of 1, 4-Dioxane (with inhalation update) (CAS No. 123-91-1) in support of summary information on the Integrated Risk Information System (IRIS), Report EPA-635/R-11/003-F. US Environmental Protection Agency. Washington, DC.
82. van der Veen, J. W., Soeteman-Hernández, L. G., Ezendam, J., Stierum, R., Kuper, F. C., and van Loveren, H. (2014). Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data. Crit. Rev. Toxicol. 44, 590-599.
83. van Wezel, A. P., and Opperhuizen, A. (1995). Narcosis due to environmental pollutants in aquatic organisms: Residue-based toxicity, mechanisms, and membrane burdens. Crit. Rev. Toxicol. 25, 255-279.
84. Veith, G. D., Call, D. J., and Brooke, L. T. (1983). Structure-toxicity relationships for the fathead minnow, Pimephales promelas: Narcotic industrial chemicals. Can. J. Fish. Aquat. Sci. 40, 743-748.
85. Verhaar, H. J., Van Leeuwen, C. J., and Hermens, J. L. (1992). Classifying environmental pollutants. 1: Structure-activity relationships for prediction of aquatic toxicity. Chemosphere 25, 471-491.
86. Villeneuve, D., Crump, D., Garcia-Reyero, N., Hecker, M., Hutchinson, T. H., LaLone, C.A., Landesmann, B., Lettieri, T., Munn, S., Nepelska, M., et al. (2014a). Adverse outcome pathway (AOP) development I: Strategies and principles. Tox. Sci. 142, 312-320.
87. Villeneuve, D., Crump, D., Garcia-Reyero, N., Hecker, M., Hutchinson, T. H., LaLone, C. A., Landesmann, B., Lettieri, T., Munn, S., Nepelska, M., et al. (2014b). Adverse outcome pathway (AOP) development II: Best practices. Tox. Sci. 142, 321-330.
88. Villeneuve, D., Volz, D. C., Embry, M. R., Ankley, G. T., Belanger, S. E., Léonard, M., Schirmer, K., Tanguay, R., Truong, L., and Wehmas, L. (2014c). Investigating alternatives to the fish early-life stage test: A strategy for discovering and annotating adverse outcome pathways for early fish development. Environ. Toxicol. Chem. 33, 158-169.
89. Volz, D. C., Belanger, S., Embry, M., Padilla, S., Sanderson, H., Schirmer, K., Scholz, S., Villeneuve, D. L. (2011). Adverse outcome pathways during early fish development: A conceptual framework for identification of chemical screening and prioritization strategies. Toxicol. Sci. 123, 349-358.
90. Willett, C., Rae, J. C., Goyak, K. O., and Landesmann, B. (2014). Pathway-based toxicity: History, current approaches and liver fibrosis and steatosis as prototypes. ALTEX. Available at: http://dx.doi.org/10.14573/altex.1401283. Accessed May 15, 2015.
91. Zoppoli, P., Morganella, S., and Ceccarelli, M., (2010). TimeDelay-ARACNE: Reverse engineering of gene networks from timecourse data by an information theoretic approach. BMC Bioinform. 11, 154.