Metabolomics study heralds change in animal testing

The University of Birmingham is leading an international collaboration that has used metabolomics as a robust method to assess safety of chemicals, which is also raising hopes for a reduction in animal testing procedures.

Grouping and read-across, an EU-approved approach, allows toxicology information from already approved chemicals to be copied across to new structurally similar substances, enabling them to be brought forward for market approval. However, because this process is unreliable, the majority of new chemical grouping and read-across submissions are rejected by the European Chemicals Agency (ECHA).

The study from the MATCHING consortium, funded by the European Chemical Industry Council’s Long-Range Research Initiative (Cefic-LRI) was carried out in partnership with BASF, BASF Metabolome Solutions, ECHA, Imperial College London, Syngenta, Vrije Universiteit Amsterdam and the US Environmental Protection Agency.

Mark Viant, Professor of Metabolomics at the University of Birmingham explained: “Chemicals fall into three categories of drugs, pesticides and industrial chemicals and we are exposed to some of these every single day of our lives. Industrial chemicals are not intended for direct exposure to humans or the environment, but inevitably this will happen, so the toxicology information must be accurate.

“Instead of only measuring the structural similarity of the chemicals to form groups, we have found that by using metabolomics to measure the biological responses of the chemicals, we can make the grouping and read across more reliable.”

To test the effectiveness of metabolomics, six independent laboratories were sent common plasma samples from rats which had been tested with eight chemicals. The teams did not know what the chemicals were and had to correctly group them by looking for diagnostic metabolic biomarkers. By using a ‘shotgun approach’ like metabolomics, scientists could measure thousands of markers like amino acids and lipids, using mass spectrometry. This helped the labs group the eight chemicals into two groups of three and one of two chemicals.

All results were then sent to the European Chemicals Agency who compiled them before the findings were revealed to the whole consortium. The five labs whose data passed quality control all discovered the same grouping. This is the first time that the use of metabolomics for grouping has been proven to be a reproducible method.

Katherine Santizo from Cefic-LRI: “This is a massive step forward to improve the existing grouping and read-across approach. The fact that five labs from different countries all got the same, correct results while using different methods and instruments, their own procedures and statistical analysis shows that metabolomics is a reliable method.”

Professor Viant added that rats were ‘not good models for humans’ with reproducibility of results also ‘not great’ and that even without the ethical considerations, this approach was both a costly and slow process. “So, by making the grouping and read-across approach more robust by using metabolomics, the number of lab rats being tested could be dramatically cut,” he added.

Tomasz Sobanski, Team Leader for Alternative Methods in the Computational Assessment and Alternative Methods Unit, ECHA said: “The need to demonstrate the reliability of metabolomics was first identified during one of our workshops in 2016. We are very impressed with the results of this research and we believe that they will improve the grouping and read-across. We hope that learnings from this research will be included in new guidance for the chemical industry to allow commercial laboratories to provide these services widely.”

The study was published in Archives in Toxicology

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