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

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)).