Use cases, best practice and reporting standards for metabolomics in regulatory toxicology

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Abstract

Metabolomics is a widely used technology in academic research, yet its application to regulatory science has been limited. The most commonly cited barrier to its translation is lack of performance and reporting standards. The MEtabolomics standaRds Initiative in Toxicology (MERIT) project brings together international experts from multiple sectors to address this need. Here, we identify the most relevant applications for metabolomics in regulatory toxicology and develop best practice guidelines, performance and reporting standards for acquiring and analysing untargeted metabolomics and targeted metabolite data. We recommend that these guidelines are evaluated and implemented for several regulatory use cases.

Abstract

Lack of best practice guidelines currently limits the application of metabolomics in the regulatory sciences. Here, the MEtabolomics standaRds Initiative in Toxicology (MERIT) proposes methods and reporting standards for several important applications of metabolomics in regulatory toxicology.

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Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment.

Gerald Ankley, Richard S. Bennett, Russell Erickson … (2010)

Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk-effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework.

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Adverse outcome pathway (AOP) development I: strategies and principles.

Daniel Villeneuve, Doug Crump, Natàlia Garcia-Reyero … (2014)

An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

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Update: use of the benchmark dose approach in risk assessment

Anthony Hardy, Diane Benford, Thorhallur Halldorsson … (2017)

Abstract The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the NOAEL approach for deriving a Reference Point (RP). Most of the modifications made to the SC guidance of 2009 concern the section providing guidance on how to apply the BMD approach. Model averaging is recommended as the preferred method for calculating the BMD confidence interval, while acknowledging that the respective tools are still under development and may not be easily accessible to all. Therefore, selecting or rejecting models is still considered as a suboptimal alternative. The set of default models to be used for BMD analysis has been reviewed, and the Akaike information criterion (AIC) has been introduced instead of the log‐likelihood to characterise the goodness of fit of different mathematical models to a dose–response data set. A flowchart has also been inserted in this update to guide the reader step‐by‐step when performing a BMD analysis, as well as a chapter on the distributional part of dose–response models and a template for reporting a BMD analysis in a complete and transparent manner. Finally, it is recommended to always report the BMD confidence interval rather than the value of the BMD. The lower bound (BMDL) is needed as a potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL per ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re‐evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 SC guidance was used, in particular when the exposure is clearly smaller (e.g. more than one order of magnitude) than the health‐based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the expected wide application of the BMD approach.

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Author and article information

Contributors

Mark R. Viant:

ORCID: http://orcid.org/0000-0001-5898-4119

m.viant@bham.ac.uk

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 10 July 2019

Publication date PMC-release: 10 July 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 3041

Affiliations

[1 ]ISNI 0000 0004 1936 7486, GRID grid.6572.6, School of Biosciences and Phenome Centre Birmingham, , University of Birmingham, ; Edgbaston, Birmingham, B15 2TT UK

[2 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Imperial College London, ; London, SW7 2AZ UK

[3 ]ISNI 0000 0001 2158 7187, GRID grid.483504.e, US FDA, , NCTR, ; Jefferson, AR 72079 USA

[4 ]ISNI 0000 0001 2146 2763, GRID grid.418698.a, US EPA, ; Athens, GA 30605 USA

[5 ]ISNI 0000 0001 1551 0781, GRID grid.3319.8, BASF SE, ; 67063 Ludwigshafen, Germany

[6 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Vrije Universiteit Amsterdam, ; Amsterdam, Netherlands

[7 ]ISNI 0000 0004 1769 7123, GRID grid.420622.0, Health and Safety Executive, ; Buxton, UK

[8 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, The Francis Crick Institute, ; London, NW1 1AT UK

[9 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Oxford e-Research Centre, Department of Engineering Science, , University of Oxford, ; Oxford, OX1 3QG UK

[10 ]ISNI 0000000405980095, GRID grid.17703.32, International Agency for Research on Cancer, ; Lyon, France

[11 ]BASF Metabolome Solutions, 10589 Berlin, Germany

Author information

Mark R. Viant http://orcid.org/0000-0001-5898-4119

Timothy M. D. Ebbels http://orcid.org/0000-0002-3372-8423

Richard D. Beger http://orcid.org/0000-0003-4380-2356

Drew R. Ekman http://orcid.org/0000-0002-1649-379X

Hennicke Kamp http://orcid.org/0000-0002-1316-8756

Pim E. G. Leonards http://orcid.org/0000-0002-3052-8848

George D. Loizou http://orcid.org/0000-0002-9376-9243

James I. MacRae http://orcid.org/0000-0002-1464-8583

Philippe Rocca-Serra http://orcid.org/0000-0001-9853-5668

Reza M. Salek http://orcid.org/0000-0001-8604-1732

Tilmann Walk http://orcid.org/0000-0002-6341-3107

Ralf J. M. Weber http://orcid.org/0000-0002-8796-4771

Article

Publisher ID: 10900

DOI: 10.1038/s41467-019-10900-y

PMC ID: 6620295

PubMed ID: 31292445

SO-VID: 5b095acf-5d77-4876-a4fa-16bcd5cb66a5

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 10 January 2019

Date accepted : 7 June 2019

Funding

Funded by: European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) http://www.ecetoc.org/

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ScienceOpen disciplines: Uncategorized

Keywords: metabolomics,mass spectrometry,nmr spectroscopy,toxicology

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ScienceOpen disciplines: Uncategorized

Keywords: metabolomics, mass spectrometry, nmr spectroscopy, toxicology

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Use cases, best practice and reporting standards for metabolomics in regulatory toxicology

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Most cited references 65

Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment.

Adverse outcome pathway (AOP) development I: strategies and principles.

Update: use of the benchmark dose approach in risk assessment

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Cited by 53

Most referenced authors 1,815