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A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment pp 349–378Cite as

Use of Adverse Outcome Pathways in Human Risk Assessment and Toxicology

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Abstract

Mechanistic information has been used for many years to inform chemical hazard and risk assessments. NRC reports and several agency strategic plans in recent years promote the large-scale use of mechanistic information, organized in the form of pathways at different levels of biological organization as a basis to underpin a dramatic change in the way chemical assessment is performed. As a result, there now exist international collaborations to develop the data and knowledge bases, guidance and principles for development and use of “Adverse Outcome Pathways” (AOPs). Many of the principles for developing and using pathways are based on experience with Mode of Action frameworks for human health risk assessment. Expert groups within the Organization for Economic Cooperation and Development (OECD) are publishing guidance and partnering with the US EPA and European Commissions Joint Research Centre (JRC) to develop a public knowledge base for building AOPs on a large scale. Although this direction is fairly new, there are many pathways already in development. In addition, pathway-based approaches are increasingly being applied to a variety of assessments of hazard in a number of sectors. This chapter describes the genesis of the AOP concept, the development of the necessary tools based on international collaborations, and provides some examples of the use of AOPs in human health risk assessment.

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Notes

  1. 1.

    http://aopkb.org/

  2. 2.

    https://eurl-ecvam.jrc.ec.europa.eu/validation-regulatory-acceptance/topical-toxicity/skin-sensitisation

  3. 3.

    European Commission Directive 76/768/EEC covering regulation of cosmetics as amended by Directive 2003/15/EC introducing a test ban from 2004 and sales ban from 2009, later postponed until 2013. http://ec.europa.eu/growth/sectors/cosmetics/index_en.htm

  4. 4.

    Testing ban in force from May 2014: Drugs & Cosmetics Act, Rule 148-C; sales ban in force from October 2014: Drugs & Cosmetics Act, Rule 135-B (import ban).

  5. 5.

    Testing ban in force since Jan 2013: Amendment to the Animal Experimentation Law; Sales ban in force since Jan 2015: Draft Pharmacists’ Regulations (Cosmetics) 2012–5773.

  6. 6.

    Act relating to cosmetic products and body care products, etc. 2005: http://app.uio.no/ub/ujur/oversatte-lover/data/lov-20051221-126-eng.pdf, see also http://www.mattilsynet.no/language/english/cosmetics/import_of_cosmetics_to_norway/importing_cosmetics_to_norway.8321

  7. 7.

    New Zealand: Animal Welfare Legislation Recognizes Animals as Sentient, Bans Cosmetic Testing: http://www.loc.gov/lawweb/servlet/lloc_news?disp3_l205404408_text

  8. 8.

    E.g. Framework Programme 6 projects ACuteTox, Sens-it-iv, Re-Pro-Tect; Framework Programme 7 projects SEURAT-1).

References

  • Allen TEH, Goodman JM et al (2014) Defining molecular initiating events in the adverse outcome pathway framework for risk assessment. Chem Res Toxicol 27(12):2100–2112

    Article  PubMed  CAS  Google Scholar 

  • Ankley GT, Bennett RS et al (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29:730–741

    Article  PubMed  CAS  Google Scholar 

  • Bauch C, Kolle SN et al (2012) Putting the parts together: combining in vitro methods to test for skin sensitizing potentials. Regul Toxicol Pharmacol 63:489–504

    Article  PubMed  CAS  Google Scholar 

  • Becker RA, Ankley GT et al (2015) Increasing scientific confidence in adverse outcome pathways: application of tailored Bradford-Hill considerations for evaluating weight of evidence. Reg Toxicol Pharmacol 72:514–537

    Article  Google Scholar 

  • Becking GC (1995) Use of mechanistic information in risk assessment for toxic chemicals. Toxicol Lett 77:15–24

    Article  PubMed  CAS  Google Scholar 

  • Benigni R (2014) Predicting the carcinogenicity of chemicals with alternative approaches: recent advances. Expert Opin Drug Metab Toxicol 10(9):1199–1208

    Article  PubMed  CAS  Google Scholar 

  • Boobis AR, Cohen SM et al (2006) IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit Rev Toxicol 36:781–792

    Article  PubMed  Google Scholar 

  • Boobis AR, Doe JE et al (2008) IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol 38:87–96

    Article  PubMed  CAS  Google Scholar 

  • Bradford-Hill A (1965) The environment and disease: association or causation? Proc R Soc Med 58:295–300

    Google Scholar 

  • Browne P, Judson RS et al (2015) Screening chemicals for estrogen receptor bioactivity using a computational model. Environ Sci Technol Environ Sci Technol 49:8804–8814

    Article  PubMed  CAS  Google Scholar 

  • Carmichael N, Bausen M et al (2011) Using mode of action information to improve regulatory decision making: an ECETOC/ILSI/HESI workshop overview. Crit Rev Toxicol 41:175–186

    Article  PubMed  Google Scholar 

  • Clewell HJ, Gentry PR et al (1995) Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl chloride and trichloroethylene. Chemosphere 31:2561–2578

    Article  PubMed  CAS  Google Scholar 

  • Committee on Carcinogenicity (COC) (2004) Guidance on a strategy for the risk assessment of chemical carcinogens. Department of Health, London

    Google Scholar 

  • Conolly RB, Andersen ME (1993) An approach to mechanism barred cancer risk assessment for formaldehyde. Environ Health Perspect 101(Suppl. 6):169–176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cox LA, Douglas D et al (2014) Applying a scientific confidence framework to a HTS-derived prediction model for endocrine endpoints: lessons learned from a case study. Regul Toxicol Pharmacol 69:443–450

    Article  PubMed  Google Scholar 

  • Dellarco VL, Baetcke K (2005) A risk assessment perspective: application of mode of action and human relevance frameworks to the analysis of rodent tumor data. Toxicol Sci 86:1–3

    Article  PubMed  CAS  Google Scholar 

  • EC (2006) EC Regulation 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

    Google Scholar 

  • EC (2014) Defining criteria for identifying endocrine disruptors in the context of the implementation of the plant protection product regulation and biocidal products regulation. DG Environment and DG SANCO. Available via http://ec.europa.eu/dgs/health_food-safety/dgs_consultations/food/consultation_20150116_endocrine-disruptors_en.htm. Accessed 28 Nov 2015

  • ECHA (2015) Guidance on information requirements and chemical safety assessment Chapter R.7a and R.7b: endpoint specific guidance. Available via http://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment. Assessed 28 Nov 2015 (note that both of these documents are undergoing revision in 2015)

  • EC (2016a) Commission Regulation (EU) 2016/1688 of 20 September 2016 amending Annex VII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards skin sensitization. Available via: http://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=uriserv%3AOJ.L_.2016.255.01.0014.01.ENG. Accessed 5 Sept 2017

  • ED (2016b) Communication from the Commission to the European Palriment and the Council on endocrine disruptors and the draft Commission acts setting out scientific criteria for their determination in the context of the EU legislation on plant protection products and biocidal products. COM(2016) 350 European Commission, Brussels. Available via: https://ec.europa.eu/health/sites/health/files/endocrine_disruptors/docs/com_2016_350_en.pdf. Accessed 5 Sept 2016

  • EC (2017) EURL ECVAM Recommendation on the use of nonanimal approaches for skin sensitisation assessment (March 2017 Draft). Available from: https://eurl-ecvam.jrc.ec.europa.eu/eurl-ecvam-recommendations/publiccomments/draft-recommendation-on-the-use-of-non-animal-approaches-for-skin-sensitisation-testing. Accessed 6 Sept 2017

  • European Chemicals Agency (ECHA) (2008) Guidance on information requirements and chemical safety assessment. Chapter R.6: QSARs and grouping of chemicals. Available via http://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf. Accessed 28 Nov 2015

  • European Commission (EC) (2003) Technical guidance document on risk assessment. European Commission Joint Research Centre, Ispra

    Google Scholar 

  • European Food Safety Agency (EFSA) (2006) Opinion of the scientific panel on plant health, plant protection products and their residues on the scientific principles in the assessment and guidance provided in the field of human toxicology between 2003 and 2006. EFSA J 346:1–13

    Google Scholar 

  • Garcia-Reyero N (2015) Are adverse outcome pathways here to stay? Environ Sci Technol 49:3–9

    Article  PubMed  CAS  Google Scholar 

  • Groh K, Carvalho RN et al (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

    Article  PubMed  CAS  Google Scholar 

  • Groh K, Carvalho RN et al (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

    Article  PubMed  CAS  Google Scholar 

  • Haber LT, Maier A et al (2001) Applications of mechanistic data in risk assessment: the past, present, and future. Toxicol Sci 61:32–39

    Article  PubMed  CAS  Google Scholar 

  • Huang R, Southall N et al (2011) The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3:80ps16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • International Programme on Chemical Safety (IPCS) (2002) In: Damstra T, Barlow S, Bergman A, Kavlock RJ, van der Kraak G (eds) Global assessment of the state-of-the-science of endocrine disruptors. World Health Organization, Geneva, p 2002

    Google Scholar 

  • International Programme on Chemical Safety (IPCS) (2005) Chemical-specific adjustment factors for interspecies differences and human variability: Guidance document for use of data in dose/concentration-response assessment. Harmonization Project document no. 2. World Health Organization, Geneva

    Google Scholar 

  • IPCS (2006) Concise international chemical assessment document 68: tetrachloroethylene. World Health Organization, International Programme on Chemical Safety. World Health Organization, Geneva, Geneva

    Google Scholar 

  • Iorio F, Bosotti R et al (2010) Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc Natl Acad Sci U S A 107:14621–142626

    Article  PubMed  PubMed Central  Google Scholar 

  • Jaworska J, Dancik Y et al (2013) Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice. J Appl Toxicol 33:1353–1364

    PubMed  CAS  Google Scholar 

  • Joint Meeting on Pesticide Residues (JMPR). 2006. Report of the joint meeting of the FAO panel of experts on pesticide residues in food and the environment and WHO the core assessment group. FAO plant production and protection paper 187 (Thiacloprid). Available via ftp://ftp.fao.org/docrep/fao/010/a0888e/a0888e00.pdf. Accessed 28 Nov 2015

  • Judson RS, Magpantay FM et al (2015) Integrated model of chemical perturbations of a biological pathway using 18 in vitro high-throughput screening assays for the estrogen receptor. Toxicol Sci 148(1):137–154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Knapen D, Vergauwen L et al (2015) The potential of AOP networks for reproductive and developmental toxicity assay development. Reprod Toxicol 56:52–55

    Article  PubMed  CAS  Google Scholar 

  • Langley GR (2011) Considering a new paradigm for Alzheimer’s disease research. Drug Discov Today 19:1114–1124

    Article  Google Scholar 

  • Langley G, Christopher P et al (2015) Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ Health Perspect 123:A268–A272

    Article  PubMed  PubMed Central  Google Scholar 

  • Liteplo RG, Meek ME (2003) Inhaled formaldehyde: exposure estimation, hazard characterization and exposure-response analysis. J Toxicol Environ Health B 6:85–114

    Article  CAS  Google Scholar 

  • MacKay C, Davies M et al (2013) From pathways to people: applying the adverse outcome pathway (AOP) for skin sensitization to risk assessment. ALTEX 30:473–486

    Article  PubMed  Google Scholar 

  • Maxwell G, Aeby P et al (2011) Skin sensitisation: the Colipa strategy for developing and evaluating non-animal test methods for risk assessment. ALTEX 28:50–55

    Article  PubMed  Google Scholar 

  • McKim JM Jr, Keller DJ 3rd et al (2012) An in vitro method for detecting chemical sensitization using human reconstructed skin models and its applicability to cosmetic, pharmaceutical, and medical device safety testing. Cutan Ocul Toxicol 31:292–305

    Article  PubMed  CAS  Google Scholar 

  • Meek ME, Renwick A et al (2002a) Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment. Toxicology 27:115–120

    Article  Google Scholar 

  • Meek B, Renwick A et al (2002b) Guidance for derivation of chemical-specific adjustment factors (CSAF). Dev implement Hum Ecol Risk Assess 8:769

    Article  CAS  Google Scholar 

  • Meek M, Bucher J et al (2003) A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol 33:591–653

    Article  PubMed  Google Scholar 

  • Meek ME, Berry C et al (2008) Mode of action frameworks: a critical analysis. J Toxicol Environ Health B 11:681–685

    Article  Google Scholar 

  • Meek ME, Klaunig JE (2010) Proposed mode of action of benzene-induced leukemia: Interpreting available data and identifying critical data gaps for risk assessment. Chem Biol Interact 184(1-2):279–285

    Article  PubMed  CAS  Google Scholar 

  • Meek ME, Boobis A et al (2014a) 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

    Article  PubMed  CAS  Google Scholar 

  • Meek ME, Palermo CM et al (2014b) Mode of action human relevance (species concordance) framework: evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. J Appl Toxicol 34:595–606

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • National Industrial Chemical Notification and Assessment Scheme (NICNAS) (2006) Priority existing chemical assessment report 21: Benzene. National Industrial Chemical Notification and Assessment Scheme, Commonwealth of Australia. Available via http://www.nicnas.gov.au/chemical-information/pec-assessments. Accessed 28 Nov 2015

  • National Research Council (2007) Toxicity testing in the 21st century: a vision and a strategy. National Academy of Sciences, Washington, DC

    Google Scholar 

  • Natsch A, Ryan CA et al (2013) A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation. J Appl Toxicol 33:1337–1352

    PubMed  CAS  Google Scholar 

  • Nukada Y, Miyazawa M et al (2013) Data integration of non-animal tests for the development of a test battery to predict the skin sensitizing potential and potency of chemicals. Toxicol In Vitro 27:609–618

    Article  PubMed  CAS  Google Scholar 

  • OECD (2007) Test guideline No. 440: uterotrophic bioassay in rodents A short-term screening test for oestrogenic properties. OECD, Paris, France. Available via http://www.oecd-ilibrary.org/environment/test-no-440-uterotrophic-bioassay-in-rodents_9789264067417-en. Accessed 28 Nov 2015

  • OECD (2008) Report of the second survey on available Omics tools. OECD environment, health and safety publications series on testing and assessment no. 100. OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • OECD (2009) Report of the expert consultation to evaluate an estrogen receptor binding affinity model for hazard identification. OECD series on testing and assessment no. 111 OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • OECD (2011) Report of the workshop on using mechanistic information on forming chemical categories. OECD series on testing and assessment no. 138. OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • 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. OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • OECD (2012b) Guidance document on standardized test guidelines for evaluating chemicals for endocrine disruption. Series on testing and assessment, no. 150. OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • OECD (2012c) 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. Series on testing and assessment, no.168. OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • OECD (2013a) Guidance document on developing and assessing adverse outcome pathways. Series on testing and assessment, no. 184. OECD, Paris, France. Available via http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono%282013%296&doclanguage=en. Accessed 28 Nov 2015

  • OECD (2013b) Test guideline no. 438: isolated chicken eye test method for identifying (i) Chemicals inducing serious eye damage and (ii) Chemicals not requiring classification for eye irritation or serious eye damage. OECD Paris, France. Available via 10.1787/9789264203860-en. Accessed 28 Nov 2015

  • OECD (2013c) Test guideline no. 437: bovine corneal opacity and permeability test method for identifying (i) Chemicals inducing serious eye damage and (ii) Chemicals not requiring classification for eye irritation or serious eye damage. OECD Paris, France. Available via 10.1787/9789264203846-en. Accessed 28 Nov 2015

  • OECD (2015a) Test guideline no. 442C: In Chemico skin sensitisation: Direct Peptide Reactivity Assay (DPRA). OECD Paris, France. Available via 10.1787/9789264229709-en. Accessed 28 Nov 2015

  • OECD (2015b) Test guideline no. 442D: in vitro skin sensitisation : ARE-Nrf2 Luciferase test method. OECD Paris, France. Available via 10.1787/9789264229822-en. Accessed 28 Nov 2015

  • OECD (2015c) Report of the workshop on a framework for the development and use of integrated approaches to testing and assessment. Series on testing and assessment no. 215. OECD Paris, France. Available via http://www.oecd.org/env/ehs/testing/reportoftheworkshoponaframeworkforthedevelopmentanduseofintegratedapproachestotestingandassessment.htm. Accessed 28 Nov 2015

  • OECD (2015d) Test no. 439: in vitro skin irritation: reconstructed human epidermis test method. OECD, Paris, France. Available via 10.1787/9789264242845-en. Accessed 28 Nov 2015

  • OECD (2015e) Test guideline no. 435: in vitro membrane barrier test method for skin corrosion, OECD. OECD, Paris, France. Available via 10.1787/9789264242791-en. Accessed 28 Nov 2015

  • OECD (2015f) Test guideline no. 431: in vitro skin corrosion: reconstructed human epidermis (RHE) test method. OECD, Paris, France. Available via 10.1787/9789264242753-en. Accessed 28 Nov 2015

  • OECD (2015g) Test guideline no. 430: in vitro skin corrosion: transcutaneous electrical resistance test method (TER). OECD, Paris, France. Available via 10.1787/9789264242739-en. Accessed 28 Nov 2015

  • OECD (2015h) Test guideline no. 492: reconstructed human Cornea-like Epithelium (RhCE) test method for identifying chemicals not requiring classification and labelling for eye irritation or serious eye damage. OECD, Paris, France. Available via 10.1787/9789264242548-en. Accessed 28 Nov 2015

  • OECD (2015i) Test guideline no. 491: short time exposure in vitro test method for identifying (i) Chemicals inducing serious eye damage and (ii) Chemicals not requiring classification for eye irritation or serious eye damage. OECD, Paris, France. Available via 10.1787/9789264242432-en. Accessed 28 Nov 2015

  • OECD (2016) User’s handbook supplement to the guidance document for developing and assessing AOPs. OECD Paris, France. Available via https://aopkb.org/common/AOP_Handbook.pdf. Accessed 28 Nov 2015

  • Organization for Economic Coordination and Development (OECD) (2002) Guidance notes for analysis and evaluation of chronic toxicity and carcinogenicity studies. OECD series on testing and assessment no. 35 OECD, Paris, France. Available via http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm. Accessed 28 Nov 2015

  • Patlewicz G, Kuseva C et al (2014) Towards AOP application – implementation of an integrated approach to testing and assessment (IATA) into a pipeline tool for skin sensitization. Reg Toxicol Pharmacol 69:529–545

    Article  CAS  Google Scholar 

  • Patlewicz G, Simon TW et al (2015) Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes. Regul Toxicol Pharmacol 71:463–477

    Article  PubMed  Google Scholar 

  • Perkins EJ, Antczak P et al (2015) Adverse outcome pathways for regulatory applications: examination of four case studies with different degrees of completeness and scientific confidence. Toxicol Sci 148:14–25

    Article  PubMed  CAS  Google Scholar 

  • Reif DM, Martin MT et al (2010) Endocrine profile and prioritization of environmental chemicals using ToxCast data. Environ Health Perspect 118:1714–1720

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Richard A (2014) Mining the ToxCast chemical-data landscape for green chemical design: an SAR-Chem-Informed approach (GCE18). Presented at: the 18th annual green chemistry & engineering conference (June 17–19, 2014). Available via http://presentations.acs.org/common/media-player.aspx/GCE2014/GCESC/GCE004/GCE18. Accessed 28 Nov 2015

  • Rotroff DM, Dix DJ et al (2013) Using in vitro high throughput screening assays to identify potential endocrine disrupting chemicals. Environ Health Perspect 121:7–14

    PubMed  Google Scholar 

  • Sanderson K (2011) It’s not easy being green. Nature 469:18–20

    Article  PubMed  CAS  Google Scholar 

  • Seed J, Carney EW et al (2005) Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Crit Rev Toxicol 35(8-9):664–672

    Article  PubMed  CAS  Google Scholar 

  • Schultz TW, Yarbrough JW et al (2005) Structure–activity relationships for reactivity of carbonyl compounds with glutathione. SAR QSAR Environ Res 16:313–322

    Article  PubMed  CAS  Google Scholar 

  • Schadt EE, Lum PY (2006) Reverse engineering gene networks to identify key drivers of complex disease phenotypes. J Lipid Res 47:2601–2613

    Article  PubMed  CAS  Google Scholar 

  • SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing) (2014) Alternative testing strategies: towards the replacement of in vivo repeated dose systemic toxicity testing, annual report volume 4. Available via http://www.seurat-1.eu/pages/library/seurat-1-annual-reports.php. Accessed 28 Nov 2015

  • Tollefsen KE, Scholz S et al (2014) Applying Adverse Outcome Pathways (AOPs) to support integrated approaches to testing and assessment (IATA). Reg Toxicol Pharmacol 70:629–640

    Article  Google Scholar 

  • Tsujita-Inoue K, Hirota M et al (2014) Skin sensitization risk assessment model using artificial neural network analysis of data from multiple in vitro assays. Toxicol In Vitro 28:626–639

    Article  PubMed  CAS  Google Scholar 

  • United Nations Economic Commission for Europe (UNECE) (2007) Amendments to the globally harmonized system of classification and labelling of chemicals (GHS). Available via http://www.unece.org/trans/danger/publi/ghs/ghs_rev02/02files_e.html. Accessed 28 Nov 2015

  • United Nations Environment Programme (UNEP)/World Health Organization (WHO) (2012) State of the science of endocrine disrupting chemicals. Available via http://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/. Accessed 28 Nov 2015

  • Urbisch D, Mehling A et al (2015) Assessing skin sensitization hazard in mice and men using non-animal test methods. Regul Toxicol Pharmacol 71:337–351

    Article  PubMed  CAS  Google Scholar 

  • US Environmental Protection Agency (EPA) (1999) Minutes of the chloroform risk assessment review subcommittee meeting, October 27–28, 1999, U.S. Environmental protection agency, science advisory board. U.S. Environmental Protection Agency, Washington, DC. Available via http://yosemite.epa.gov/sab/sabproduct.nsf/ec0009.pdf. Accessed 28 Nov 2015

  • US EPA (2000) Scientific advisory panel report no. 2000–05: atrazine: hazard and dose-response assessment and characterization. Office of pesticide programs, U.S. Environmental Protection Agency, Washington, DC. Available via www.thecre.com/pdf/finalatrazine.pdf. Accessed 28 Nov 2015

    Google Scholar 

  • US EPA (2005a) Guidelines for carcinogen risk assessment office of pesticide programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www3.epa.gov/airtoxics/cancer_guidelines_final_3-25-05.pdf. Accessed 28 Nov 2015

  • US EPA (2005b) Science issue paper: mode of carcinogenic action for cacodylic acid (dimethylarsinic acid, DMAV) and recommendations for dose response extrapolation. July 26. Health Effects Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://users.physics.harvard.edu/~wilson/arsenic/EPA%20DMA%20mode.pdf. Accessed 28 Nov 2015

  • US EPA (2007a) Scientific advisory panel report: advisory on EPA’s assessments of carcinogenic effects of organic and inorganic arsenic: report of the US EPA science advisory board. U.S. Environmental Protection Agency, Washington, DC. Available via http://yosemite.epa.gov/sab/sabproduct.nsf/EPA-SAB-07-008.pdf. Accessed 28 Nov 2015

  • US EPA (2007b) Framework for determining a mutagenic mode of action for carcinogenicity: using EPA’s 2005 cancer guidelines and supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. Available via http://www3.epa.gov/airtoxics/childrens_supplement_final.pdf. Accessed 28 Nov 2015

  • US EPA (2009a) The U.S. Environmental protection agency’s strategic plan for evaluating the toxicity of chemicals. U.S. Environmental Protection Agency, Washington, DC. Available via http://nepis.epa.gov/Exe/ZyPDF.cgi/P1003351.PDF?Dockey=P1003351.PDF. Accessed 28 Nov 2015

  • US EPA (2009b) Integrated bioactivity and exposure ranking: a computational approach for the prioritization and screening of chemicals in the endocrine disruptor screening program. December 2014. Docket ID No. EPA–HQ–OPP–2014–0614–0003. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www.regulations.gov. Accessed 28 Nov 2015

  • US EPA (2009c) The use of structure activity relationships of estrogen binding affinity to support prioritization of pesticide inert ingredients and antimicrobial pesticides for screening and testing, Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://archive.epa.gov/scipoly/sap/meetings/web/pdf/082509minutes.pdf. Accessed 28 Nov 2015

  • 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. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://yosemite.epa.gov/sab/sabproduct.nsf/373C1DB0E0591296852579F2005BECB3/$File/OPP+SAP+document-May2011.pdf. Accessed 28 Nov 2015

  • US EPA (2012a) Guidance for waiving or bridging of mammalian acute toxicity tests for pesticides and pesticide products (acute oral, acute dermal, acute inhalation, primary eye, primary dermal, and dermal sensitization). Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www2.epa.gov/sites/production/files/documents/acute-data-waiver-guidance.pdf. Accessed 28 Nov 2015

  • US EPA (2012b) Universe of chemicals and general validation principles. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www2.epa.gov/sites/production/files/2015-07/documents/edsp_chemical_universe_and_general_validations_white_paper_11_12.pdf. Accessed 28 Nov 2015

  • US EPA (2014) Integrated bioactivity and exposure ranking: a computational approach for the prioritization and screening of chemicals in the endocrine disruptor screening program. Docket ID Number EPA-HQ-OPP-2014-0614-0003Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www.regulations.gov. Accessed 28 Nov 2015

  • US EPA (2015) Use of an alternate testing framework for classification of eye irritation potential of EPA pesticide products. Office of Pesticide Programs, U.S. Environmental Protection Agency, Washington, DC. Available via http://www2.epa.gov/sites/production/files/2015-05/documents/eye_policy2015update.pdf. Accessed 28 Nov 2015

  • Van der Veen JW, Rorije E et al (2014) Evaluating the performance of integrated approaches for hazard identification of skin sensitizing chemicals. Regul Toxicol Pharmacol 69:371–379

    Article  PubMed  CAS  Google Scholar 

  • Villeneuve DL, Crump D et al (2014a) Adverse Outcome Pathway (AOP) development I: strategies and principles. Toxicol Sci 142:312–320

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Villeneuve DL, Crump D et al (2014b) Adverse Outcome Pathway (AOP) development II: best practices. Toxicol Sci 142:321–330

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wambaugh J, Wang A et al (2014) High throughput heuristics for prioritizing human exposure to environmental chemicals. Environ Sci Technol 48:12760–12767

    Article  PubMed  CAS  Google Scholar 

  • Willett C, Bishop P et al (2011) Application of an integrated testing strategy to the US EPA endocrine disruptor screening program. Toxicol Sci 123:15–25

    Article  PubMed  CAS  Google Scholar 

  • Willett C, Rae JC et al (2014a) Pathway-based toxicity: history, current approaches and liver fibrosis and steatosis as prototypes. ALTEX 31:407–421

    PubMed  Google Scholar 

  • Willett C, Rae JC et al (2014b) Building shared experience to advance practical application of pathway – based toxicology: liver toxicity mode-of-action. ALTEX 31:500–519

    PubMed  PubMed Central  Google Scholar 

  • Wilson VS, Bobseine K et al (2004) Development and characterization of a cell line that stably expresses an estrogen-responsive luciferase reporter for the detection of estrogen receptor agonist and antagonists. Toxicol Sci 81(1):69–77

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. The Humane Society of the United States, Washington, DC, 20037, USA

    Catherine Willett

  2. Center for Food Safety and Applied Nutrition, Food and Drug Administration, College Park, MD, 20740–3835, USA

    Suzanne Fitzpatrick

  3. McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, ON, Canada, K1N

    Bette Meek

  4. Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK, MK44 1LQ

    Carl Westmoreland

Authors
  1. Catherine Willett
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  2. Suzanne Fitzpatrick
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  3. Bette Meek
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  4. Carl Westmoreland
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Corresponding author

Correspondence to Catherine Willett .

Editor information

Editors and Affiliations

  1. Environmental Laboratory, US Army Engineer Research & Development Center, Vicksburg, Mississippi, USA

    Natàlia Garcia-Reyero

  2. Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan, USA

    Cheryl A. Murphy

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Willett, C., Fitzpatrick, S., Meek, B., Westmoreland, C. (2018). Use of Adverse Outcome Pathways in Human Risk Assessment and Toxicology. In: Garcia-Reyero, N., Murphy, C. (eds) A Systems Biology Approach to Advancing Adverse Outcome Pathways for Risk Assessment. Springer, Cham. https://doi.org/10.1007/978-3-319-66084-4_17

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