Skip to main content
European Commission logo print header

Toward Precision Toxicology: New Approach Methodologies for Chemical Safety

Periodic Reporting for period 1 - PrecisionTox (Toward Precision Toxicology: New Approach Methodologies for Chemical Safety)

Reporting period: 2021-02-01 to 2022-07-31

Our society depends on a healthy environment. Yet the direct effects on human health of most industrial chemicals are largely unknown because the innovations in this important economic sector have historically outpaced our abilities to test their safety.

Part of this dilemma stems from a historical reliance on observing toxicological adverse health effects on mice or rats as surrogates for humans because of our shared mammalian biology. But these traditional approaches using models by “analogy” (i.e. mice are human) are notoriously unsustainable and unethical, and there is increasing evidence that no single species can reliably be used to predict the effects of harmful chemicals on humans.

PrecisionTox is unique in its concept to use a diversity of distantly related (more ethically acceptable) organisms as human surrogates by “homology” (i.e. toxicity by descent). Our main scientific objective is to demonstrate that toxicity to humans can be better deduced by a ‘comparative toxicology’ approach -- by exposing an evolutionarily diverse suite of model test species (fruit flies, nematodes, water fleas, and embryos of zebrafish and clawed frogs) and a human cell line to chemicals and by mapping the origins of toxicity pathways based on repeated measurements of genetic and metabolic changes indicative of adversity. The anticipated impact is the discovery of many concerved pathways to toxicity and their biomarkers that can be useful for both environmental and human health protection.

Work relating to the second objective has yet to officially begin. But a pilot study to detect why some individuals are more susceptible to toxicity than others is showing that fruit fly populations may also potentially serve as a ‘susceptibility model’ for human populations. This concept of "quantitative susceptibility" stems from statistical genetic evidence that the heritable basis for differences among individuals is often found in genes and pathways that are shared among species. The anticipated impact is a new method to set regulatory limits on the exposure to chemicals based on variation in people’s genetic susceptibility to their adverse outcomes.

The project’s final objective is to translate the research from PrecisionTox into a brighter future for chemical risk management. Our aim here is to work to resolve specific risk management problems by conducting case studies with regulators, and to build a model of how new approach methodologies (NAMs) made from the knowledge of conserved pathways to toxicity and their biomarkers will be incorporated into future chemical risk governance structures. Ultimately at its core, this is an exercise in overcoming ‘socio-technical barriers’ to the uptake of NAMs and of marketplace engineering.
The logistical and strategic work towards these objectives had begun with the successful launch of a uniquely integrated and multidisciplinary project. Some work was able to progress ahead of schedule because of unforeseen opportunities. Other work was delayed by unforeseen knock-on effects of the global pandemic. Yet this period also produced findings that are consistent with the concepts being espoused by the project. Our achievements include:

1. The implementation of a data management plan that is fitted towards (what will be) the world’s largest comparative molecular toxicology dataset in accordance with F.A.I.R. principles. This work is a shining example of how such plans should be produced, especially around the expectations of the regulatory community.
2. The implementation of computational strategies and methods to identify reliable biomarkers based on a machine learning workflow.
3. The launch of a central project database that includes workflows that enable real-time integration of new experimental data to help guide in-flight refinements to the experimental designs for comparative toxicology.
4. The implementation of an improved chemicals selection strategy based upon stakeholder-driven priorities.
5. The creation and use of key standard operational procedures (SOPs) that harmonises the experimental conditions for testing the first 50 chemicals across the five model species plus cell lines.
6. The implementation of novel automation procedures to more rapidly and robustly collect and process biomolecules for gene expression and metabolomics data.
7. Significant upgrades to the genomic and metabolomic resources of the model test species Daphnia (water flea) that will help unite human and eco-toxicology.
8. Accelerated actions and stakeholder engagements to promote the uptake of new approach methodologies in regulatory settings.
9. The implementation of project plans for Management, Communication, Dissemination, Exploitation, and a successful first annual meeting held in Barcelona and online.
10. A detailed Equality analysis across the consortium and a five-year plan for an overall aim to foster diversity, inclusion, and career opportunities for all participants of PrecisionTox and of ASPIS.

In addition to focusing on solving logistical and strategic challenges, some early findings are aligned with the expectations of the key concepts of toxicity by descent from (i) mining existing data, (ii) a pilot study for comparative toxicology, and (iii) a pilot study for detecting genetic associations with toxicological susceptibilities.
Progress beyond the state of the art during the first 18 months of PrecisionTox is primarily found in the incremental (trial by error) achievements at solving the real-world challenges at pursuing a project of this scale and complexity. These include pushing technical and technological boundaries in (i) automation for high throughput screening accounting for difference among species, (ii) advancing the detection and interpretation of molecular signals of toxicity, (iii) implementing computational methods for associating these signals to identifiable pathways to toxicity using machine learning, (iv) the theory and practice of F.A.I.R. data management, and (v) the theory and practice of breaking through techno-social barriers for the regulatory uptake of NAMs.

Although new knowledge from this increased capacity to produce large volumes of comparative molecular toxicology data will emerge only later, the validation of the key concepts underpinning this project and the utility of conserved biomolecular pathways to toxicity and their biomarkers has potential to substantially accelerate the pace and accuracy of chemical hazard assessment for the protection of both human health and the environment. Stakeholders of this project have expressed their wishes to see a more mechanistic and integrative approach to assessing and regulating chemicals. Given the interdisciplinarity of PrecisionTox by uniting science with law (and provided we succeed) we continue to expect (i) legal, political, and/or regulatory frameworks to take advantage of NAMs in chemical safety assessment, (ii) defined avenues for the early commercial adoption of NAMs across a wide range of mechanisms which depend upon the level of certainty of biomarkers at establishing causation between chemicals and their adverse health effects, and (iii) results that are relevant in the formulation of the next legislative tools for chemical safety.