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Adverse outcome pathways: a concise introduction for toxicologists

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Abstract

Adverse outcome pathways (AOPs) are designed to provide a clear-cut mechanistic representation of critical toxicological effects that propagate over different layers of biological organization from the initial interaction of a chemical with a molecular target to an adverse outcome at the individual or population level. Adverse outcome pathways are currently gaining momentum, especially in view of their many potential applications as pragmatic tools in the fields of human toxicology, ecotoxicology, and risk assessment. A number of guidance documents, issued by the Organization for Economic Cooperation and Development, as well as landmark papers, outlining best practices to develop, assess and use AOPs, have been published in the last few years. The present paper provides a synopsis of the main principles related to the AOP framework for the toxicologist less familiar with this area, followed by two case studies relevant for human toxicology and ecotoxicology.

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Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

AEP:

Aggregate exposure pathway

AO(s):

Adverse outcome(s)

AOP(s):

Adverse outcome pathway(s)

AOP-KB:

Adverse outcome pathway knowledge base

ARE:

Anti-oxidant response element

DPRA:

Direct peptide reactivity assay

E2:

17-Beta-estradiol

EPA:

Environmental Protection Agency

FELS:

Fish early life-stage

GPMT:

Guinea pig maximization test

hCLAT:

Human cell line activation test

HPG:

Hypothalamic–pituitary–gonadal

IATA:

Integrated approaches to testing and assessment

JRC:

Joint Research Centre of the European Commission

Keap1/Nrf2:

Kelch-like ECH-associated protein 1/nuclear erythroid 2-related factor

KE(R):

Key event (relationship)

LLNA:

Local lymph node assay

MIE:

Molecular initiating event

MUSST:

Myeloid U937 skin sensitization test

OECD:

Organization for Economic Cooperation and Development

QSAR:

Quantitative structure–activity relationship

REACH:

Registration, Evaluation, Authorization, and Restriction of Chemicals

SETAC:

Society of Environmental Toxicology and Chemistry

VTG:

Vitellogenin

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Acknowledgements

This work was supported by the grants of the European Research Council (ERC Starting Grant 335476), the Fund for Scientific Research-Flanders (FWO Grants G009514N, G010214N, and G051117N), the University Hospital of the Vrije Universiteit Brussel-Belgium (Willy Gepts Fonds UZ-VUB) and the Cefic Long-range Research Initiative Project LRI-ECO20.2 with support of ECETOC. The authors would like to thank Dr. Steve Edwards, Dr. Dan Villeneuve and Dr. John Vandenberg for their technical peer review.

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Author notes

  1. Mathieu Vinken and Dries Knapen are equally contributing first authors.

Authors and Affiliations

  1. Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Mathieu Vinken

  2. Zebrafishlab, Veterinary Physiology and Biochemistry, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium

    Dries Knapen & Lucia Vergauwen

  3. Systemic Physiological and Ecotoxicological Research (SPHERE), Department of Biology, University of Antwerp, Groenenborgerlaan 171, 2020, Antwerp, Belgium

    Lucia Vergauwen

  4. Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, 44139, Dortmund, Germany

    Jan G. Hengstler

  5. National Center for Environmental Assessment, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC, 27709, USA

    Michelle Angrish

  6. European Commission, Joint Research Centre (JRC), Ispra, Italy

    Maurice Whelan

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  1. Mathieu Vinken
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Correspondence to Mathieu Vinken.

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The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the US Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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Vinken, M., Knapen, D., Vergauwen, L. et al. Adverse outcome pathways: a concise introduction for toxicologists. Arch Toxicol 91, 3697–3707 (2017). https://doi.org/10.1007/s00204-017-2020-z

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