VOXLAB

The PrecisionTox podcast

The VOXLAB podcast series takes you on a journey towards precision toxicology. Listen to the voices of scientists across the globe working to advance life sciences and provide faster and more accurate solutions to understand the mechanisms of action of toxicants on human health.
Discover what the Theory of Evolution teaches us about fruit flies, round worms, water flea, zebrafishes and frogs and how we can harvest this knowledge to better protect all animals, including humans, and the ecosystems from the adverse effects of chemicals thanks to the power of phylogenetics and toxicology.
The content of this programme only reflects the authors’ view, the EU cannot be held responsible for any use of the information contained therein.

Episode #1:

What Drosophila can bring to toxicology and human health?

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Did you know that 60% of the Drosophila melanogaster (or fruit fly) genome is 60% homologous to that of humans? And that 75% of these genes were inherited from a common ancestors? That makes a valuable argument to use flies as a relevant model to study human health.
Dr. Trudy Mackay, Director of Clemson University Centre for Human Genetics, explains how the theory of evolution and the advancement of genetics have led the PrecisionTox project to select Drosophila as one organism models to develop methods to accelerate chemical risk assessment to better protect humans and the environment and ultimately replace mammalian models.

Towards Precision Toxicology

PrecisionTox

Project info

Precision Tox

Grant agreement ID : 965406

Coordinated by

The University of Birgmingham UK

Status

Ongoing project

Funded under

H2020-EU.3.1.5

Start date

01 February 2021

End date

31 January 2026

Overall budget

€ 19 305 583,75

EU contribution

€ 19 305 583,75

“PrecisionTox aims to transform regulatory toxicology by simultaneously deploying five biomedical model species and human cell lines to uncover molecular toxicity pathways shared across the animal kingdom, enabling chemicals to be classified according to their precise effects on human health.”

Scientific innovations identifying genes connected to disease have already transformed health care by delivering ‘precision medicine’. Yet it is well known that disease results not from genes alone but from the interaction between genes and the environment. Precision toxicology therefore builds toward the ultimate goal of safeguarding health by understanding how environmental factors such as pollution contribute to illness and premature death.

“We do not rely on the strength of the science alone to engineer change.”

Precision Toxicology is based on three core concepts. PhyloToxicology replaces traditional animal testing with an Evolutionarily Diverse Model Suite of organisms from multiple branches of the tree of life. Variation in Susceptibility determines safe levels of exposure to chemicals based on genetic variation. Embedded Translation engages directly with regulators and other key stakeholders in project planning, selection of chemicals for investigation, and case studies for applying Precision Toxicology in policy and law.

Phylogenetic Toxicology (Phylotoxicology)

Problem: Whole-organism toxicity testing is crucial but no single model is a perfect human surrogate.

Although mammals such as rats are considered the ‘gold standard’ for toxicology research, ample evidence demonstrates that these animals are not perfect predictors of human response to chemical exposure. Indeed, no animal is a perfect human substitute. This limitation — along with the desire to reduce expenses, improve the pace of testing, and reduce experimentation on animals — have driven recent toxicology efforts to instead use human-derived cell-lines. Unfortunately, focusing on cells has major drawbacks as toxic response often involves multiple cell and organ systems. The biological processes governing health cannot be fully observed by looking at isolated strains of cells.

Solution: Evolutionarily diverse model organisms plus human cell lines (Phylotoxicology).

Our consortium’s approach overcomes these limitations by leveraging the power of the phylogenetic tree, also known as the tree of life. All animals share the same genetic ancestry and, despite having branched off into diverse forms through evolution, animals continue to share much of the same DNA. Importantly, genes that govern disease response are among the most likely to be shared among different animals. As a result, instead of using traditional mammal models like rats, greater accuracy can be achieved by using a diverse range of biomedical model species — fruit flies, water fleas, round worms, and embryos of frogs and zebrafish — along with human cell lines to observe what happens when organisms are exposed to chemicals. Moreover, by using advanced approaches to analyzing activity at the molecular level, we can identify the fundamental biological mechanisms by which these organisms — and humans — respond to toxic chemical exposure.

Variation in Susceptibility

Problem: Exposure limits are set through guesswork.

Current methods for establishing safe exposure levels to toxic chemicals begin with quantities known to cause harm to one specific breed of mammal – usually a type of rat – and then apply some factor of 10 as a safety buffer. For example, if the presence of 5 parts per million of a chemical in water causes cancer in the specific rat strain used in the experiment, then the safe exposure level might be set at 0.05 parts per million for a human water supply (applying 102 as the ‘adjustment factor’). This guesswork not only risks putting people in harm’s way, but also might overestimate potential harm, leading to unnecessary anxiety and regulation. Additionally, this arbitrary approach fails to take into account that some people (and animals) will be more vulnerable to harm from a given toxic chemical than others due to genetic variation in susceptibility.

Solution: Study markers of susceptibility.

PrecisionTox addresses this challenge by conducting a detailed study of population variation with respect to the genes governing toxic response. Susceptibility to harm from exposure to a given chemical is a trait and, like any other trait, varies among individuals. By identifying gene sequences modulating molecular toxicity pathways, and by evaluating linkages between the genetic targets and individual susceptibility using unique genetically diverse model systems and human cell lines, informed estimates of safe exposure become possible.

Embedded Translation

Problem: Scientific answers are not sufficient; change requires buy-in from decision makers. 

Although there is broad interest in moving away from traditional animal testing, replacing old standards with new ones is a difficult task. Change often produces anxiety, and decision makers can be reluctant to promote approaches with which they are unfamiliar.

Solution: Co-produce PrecisionTox with key decision makers.

Rather than push scientific findings towards regulators and private companies at the end of the project, PrecisionTox instead works directly with a Stakeholder Advisory Group to gain insight, guidance, and feedback on producing results that can be used in the real world. This group of experienced regulators and private sector experts actively participates in shaping project activities — including selecting chemicals for testing, identifying and addressing challenges to uptake of new testing methods, participating in case studies for integrating findings into regulation, and helping to spread the word about project results.

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