Cefic-lri Programme | European Chemical Industry Council

C8 – Assessing the Repeatability of Metabolomics Within a Regulatory Context Through a Multi-laboratory Ring-trial

Principal Investigator

Prof. Mark Viant
School of Biosciences, University of Birmingham
Edgbaston, Birmingham, B15 2TT, UK
Tel  +44 121 414 2219
Email: m.viant@bham.ac.uk

Collaborators

Hennicke Kamp
BASF SE, Carl-Bosch-Str 38, 67056 Ludwigshafen, Germany
hennicke.kamp@basf.com

Tilmann Walk
BASF Metabolome Solutions GmbH, Tegeler Weg 33, 10589 Berlin, Germany
tilmann.walk@basf.com

Richard Beger and Jinchun Sun
Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
Richard.Beger@fda.hhs.gov
Jinchun.Sun@fda.hhs.gov

Timothy Ebbels and Toby Athersuch
Imperial College London, South Kensington, London, SW7 2AZ, UK
t.ebbels@imperial.ac.uk
toby.athersuch@imperial.ac.uk

David Crizer
National Toxicology Program, National Institute of Environmental Health Sciences, 111 TW Alexander Drive, Research Triangle Park, NC 27713, USA
david.crizer@nih.gov

Aniko Kende
Syngenta, Jealott’s Hill International Research Centre, Bracknell, RG42 6EY, UK
aniko.kende@syngenta.com

Ralf Weber
University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
r.j.weber@bham.ac.uk

Pim Leonards 
Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam, The Netherlands
pim.leonards@vu.nl

Description

Background:

Metabolomics has reached a critical point in determining its value to regulatory toxicology. Building on 20 years of metabolomics research in toxicology, during 2018-19 the first metabolomics data in a registration dossier was submitted to ECHA; metabolomics best-practice and reporting guidelines for regulatory toxicology were published in Nature Communications 1 by the MEtabolomics standaRds Initiative in Toxicology (MERIT) consortium; and an OECD project to develop a Metabolomics Reporting Framework (MRF) was launched. Recognising its potential importance as a New Approach Methodology (NAM), and needing to better understand its capabilities, ECHA procured ‘services related to metabolomics measurements and multi-omics data interpretation’ in 2018. Given this increase in regulatory activity, an assessment of the reproducibility of metabolomics findings of regulatory relevance – across multiple laboratories – is now required. The overarching aim of this ring-trial is to determine whether this technology is fit-for-regulatory-purpose immediately, or whether refinements in analytical or data analysis practices are needed.

Unlike earlier ring-trials in metabolomics, this project assesses metabolomics reproducibility in terms of the consistency of the findings and conclusion of regulatory relevance, specifically the conclusions drawn on group membership derived from the similarities (and differences) of the metabolic responses to multiple chemicals. This will be the first ring-trial based on chemical grouping in a regulatory context. Ultimately, a demonstration of high reproducibility of the conclusion of regulatory relevance should help to facilitate the uptake of metabolomics by the chemical industry.

Objectives of the C8 project:

  1. Prepare a set of quality-checked plasma samples for the metabolomics ring-trial, derived from 28-day rodent tests using eight chemicals that were selected from the MetaMap®Tox database by the European Chemicals Agency.
  2. Conduct a blinded ring-trial comprising of seven experienced metabolomics labs (spanning industrial, government and academic) and report the findings and conclusions of regulatory relevance, using MERIT/MRF guidelines, to the European Chemicals Agency.
  3. Collate and evaluate all ring-trial findings and conclusions, review all statistical analyses and the reporting template used, recommend amendments to the OECD Metabolomics Reporting Framework, and disseminate project outcomes to regulators and industry.

(1 – Viant, M.R., Ebbels, T.M.D., Beger, R.D. et al. Use cases, best practice and reporting standards for metabolomics in regulatory toxicology. Nat Commun 10, 3041 (2019)). 

Related Publications

Publications

Demonstrating the reliability of in vivo metabolomics-based chemical grouping: towards best practice Mark R. Viant E. Amstalden T. Athersuch  M. Bouhifd  S. Camuzeaux  D. M. Crizer  P. Driemert T. Ebbels D. Ekman  B. Flick V. Giri M. Gómez‑Romero V. Haake M. Herold A. Kende F. Lai P. E. G. Leonards  P. P. Lim10 · G. R. Lloyd  J. Mosley  C. Namini J. R. Rice S. Romano  C. Sands M. J. Smith T. Sobanski A. D. Southam L. Swindale B. van Ravenzwaay· T. Walk R. J. M. Weber
· F. M. Zickgraf H. Kamp

 

Timeline: July 2020 > June 2022

LRI funding: € 454,530

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