After 54 months of H2020 support, PrecisionTox remains a uniquely interdisciplinary project by integrating comparative toxicology, population genetics, functional genomics, metabolomics, computational biology, and law. Its mission is to provide a new evolutionary perspective on chemical toxicity that harms humans and other animals, and to investigate how this shift in understanding can be incorporated into existing and future regulatory frameworks. For example, our science and policy research contributes to discussions that help shape Europe’s roadmap to phase out animal testing for chemical safety evaluations in response to the European Citizens’ Initiative “Commit to a Europe without Animal Testing”. Recommendations directly linked to our research include: (i) expanding the taxonomic scope of NAMs, (ii) proposing short-, medium-, and long-term strategies for integrating NAMs across regulatory sectors, and (iii) enhancing the use of relevant data and alternative model species to assess chemical risks, thereby supporting the protection of humans, animals, and ecosystems through ‘One Health’ governance of chemical safety.
While early reporting periods focused on project setup and knowledge generation, our achievements during months 37-54 include:
• Having completed all harmonised toxicity testing experiments measuring the relative toxicity, toxicokinetics, and baseline toxicity of 200 substances for all five model species and human hepatocytes, resulting in comparative toxicology findings and potential regulatory applications based on the results.
• Nearing completion of collecting phenotypic data for 200 substances on cellular and systemic toxicity outcomes across all models, including approximately 50 morphological descriptors and embryonic behaviours for Danio. This phenotypic data is made ready to anchor the biomolecular toxicity data.
• Nearing completion of experimental sampling for transcriptomics and metabolomics data production.
• Validating a third refinement of the methodology for RNA sequencing that contributes to a generalised protocol for reproducible results.
• Producing a quarter of the total metabolomics data using the project’s high-throughput sample processing protocols. Deep Metabolome Annotation (DMA) for Daphnia is completed.
• Uploading biomolecular data and results for 50 substances to the Data Commons, which benefits from an enhanced data processing pipeline (for RNA sequencing data) and can be accessed by exploring the results using a highly modular and adaptable PrecisionTox Data Explorer application.
• Producing early-stage discoveries on modes of action shared among all models.
• Genome-wide screening of genetic variation for toxicity in Drosophila and human cells is almost finished, revealing notable sex- and population-level differences that will assist in tailoring safer public health exposure thresholds.
• Obtaining single-cell resolution data on the toxicological effects on gene regulation for Daphnia, Drosophila, and Danio.
• Nearing completion of three case studies that demonstrate the use of comparative omics data for grouping substances based on chemical modes of action.
• Producing guidance on reporting, sampling, and utilising omics data for regulatory applications.
• Reporting on the solutions to overcome socio-technological barriers to the uptake of NAMs in chemical regulation, and on the capacity of EU legislative tools to incorporate NAMs.
• Helping to shape EU and UK policy via its active contributions to roadmap developments, high-profile events, and ongoing parliament engagement.
In its final phase, PrecisionTox will prioritise knowledge production and FAIR data stewardship, as its data legacy represents its most significant long-term asset. Impact will also be pursued through dissemination and regulatory engagement.
