Over 300,000 chemicals are thought to circulate in our food, consumer products and environment, and surprisingly little is known about their impact on human health for most of these substances.
The techniques used to assess toxicity have traditionally been unethical, involving extensive, slow, and costly animal testing on mammalian species such as mice and rats, and findings often translate poorly to human biology. Alternative testing on human-derived cells in a lab misses the systemic toxicity effects and cannot yet capture the complexity of human biology. Decades can elapse between a new chemical being produced and marketed and our understanding and regulation of its harm.
John Colbourne, Professor and Chair of Environmental Genomics at the University of Birmingham (UoB), says we are at the cusp of a revolution in toxicology driven by technology. By harnessing emerging insights from the so-called ‘-omics’ sciences, and using a broad array of testing platforms to measure impact of chemicals on biological processes, precision toxicology “will allow us to better prevent harm caused by chemicals based on knowing why toxicity happens and take action at the earliest stages of product development.”
The -omics revolution
Two decades since the first sequencing of the human genome, a cluster of scientific disciplines has developed to reveal far more details on the complexity and variability of biology. Genomics covers genes and genetic variations among individuals that indicate susceptibility to disease, while transcriptomics, proteomics and metabolomics help us understand the inner workings of cells.
“Modernising toxicology is based on the same idea that you can have a full view of what's happening within cells and organisms at the bio-molecular level,” says Professor Colbourne. “With these technologies you can comprehensively measure these molecules, and their responses to chemicals should indicate what we call the chemical modes of action – the process by which chemicals interfere with biology at the molecular level to be predictive of an outcome.”
Professor Colbourne and his colleagues are leading research to apply -omics science to a wide variety of distantly related species to humans that are used in biomedical research. PrecisionTox, an EU-funded project hosted at the University of Birmingham with 15 organisations across eight countries, is discovering toxicity that is shared with humans by evolutionary descent primarily focused on alternative animal models including invertebrates. These include Drosophila melanogaster (the fruit fly), C. elegans (the nematode worm), and Daphnia (the water flea). Daphnia is particularly useful because it is a premier model species for ecotoxicology, explains Professor Colbourne.
The team is also studying the embryos of Xenopus laevis, the clawed frog, and Danio rerio, zebrafish embryos, which are not sentient beings, avoiding the ethics of toxicity testing. The team is collecting transcriptomics and metabolomics and collecting data to discover the key events that lead to adversity at the molecular level.
Precision toxicology is not just impactful for humans but also the wider animal and natural environment. “Precision toxicology is funded to be applied in the realm of protecting human health but what's interesting about a mechanistic understanding is that it transcends the unnatural divide between human toxicology and ecotoxicology. The same data may be applied for the protection of all animals, including humans,” says Colbourne.
“Those biomolecular pathways that are critical for health are deeply rooted in the evolutionary history of animals. We are therefore attempting to map the evolutionary origins of pathways that are relevant to toxicity, which we call ‘toxicity by descent’. No one species is a good predictor of toxicity to humans, so we're using a panel of species to inform us on protective measures avoiding toxicity based on detailed knowledge of animal biology. In this realm, the toxicity data obtained on a mechanistic level becomes applicable for human, animal and environmental health.”
Regulators and toxicologists are looking to replace outdated and ineffective techniques to make decisions about chemical regulations that have required observing the harmful effects of toxicity, one chemical at a time.
Precision toxicology should empower regulators to make decisions instead on groups of chemicals that produce similar -omics data, for instance, that would indicate similar toxicological effects, especially for compounds that have similar physical chemical properties. That should allow regulators to group chemicals together based on their shared modes of action and limit animal testing to a much smaller number of substances that are representing the group to assess their adversity.
Because of the known limits of animal testing, risk assessors invoke ‘safety factors’ when deciding on limits on human exposure to chemicals. Typical safety factors for humans are arbitrarily set at 100 times lower than concentrations that are found to be harmful in rodents. The models are necessarily pragmatic given the need to decide on a safety value but are “not driven by any kind of science and therefore not very reassuring to the public”. Another emerging use of -omics data is the detection of what experts call the “point of departure” at which the concentration of a substance triggers biomolecular changes that signal a stress response.
“It is not in anybody's favour to have regulatory limits that are beyond safety, but it's also not to our advantage to unnecessarily set regulatory limits that hamper the economy and innovation as well. The more precise we can be in determining those safety limits, the more the process of regulating harmful substances becomes a win-win situation for both the public as well as the economic health of the UK and Europe,” says Colbourne.
Post-Brexit, the UK government is producing its own chemicals strategy, as it diverges from the European Union’s legislated programme, called REACH. While the UK’s departure from the EU has had a negative impact on many aspects of science, especially funding, a fresh canvas could bring dividends in areas like chemical regulation where science has advanced considerably since Europe’s rules were first developed. The UK could be a trend-setter, he says, an early adopter in using precision toxicology to inform its regulatory process.
Michabo Health Science Ltd, a University of Birmingham spinout co-founded by Professor Colbourne and Professor Mark Viant, provides services and awareness training specifically designed for the chemical regulators and industry on new approach methodologies. “There is a desire in the UK to learn more about it, to critically evaluate its potential. And hopefully that will translate to changes in the legal and the regulatory framework,” he comments.
There is, Professor Colbourne says, a will to move away from animal testing and harness the latest science to estimate toxicity through other techniques. But it’s a long process that will “require very strong dialogue among practitioners, the scientists, and the stakeholders, including regulators and industry, to refine what would be deemed to be acceptable data, to what degree we trust that these new methodologies are in fact, reliable indicators of safety.”
He says policy makers both in the UK and Europe are clearly supportive of evidence-based policies for the regulation of chemicals, but the pace of the -omics revolution for toxicology is rapid. “Many regulatory agencies are hiring new staff, especially in the UK which must now create its own rules and implement its own procedures to ensure safety. Many of these new recruits are graduates from our toxicology programme at UoB who are knowledgeable about the new science. There's a demand for this next generation of risk assessors and regulators that have this scientific background, which enables a smoother transition towards these approaches.”
One challenge to overcome is a perception that moving away from animal testing leads to greater uncertainty about safety. “One of the big challenges that new approach methodologies [like precision toxicology]face is that some people imagine that animal test results are the benchmarks. But in fact, the objective is to protect human health, not by replacing outcomes observed as toxicity to a rat. The critical evaluation of the new approach methodologies has spilled over to now finally questioning the uncertainty around traditional methods as well, which is a good thing.”
Progress also depends on collaborations that go much further than the lab. “How do you translate this into a change in practice? At the end of the day, it's about the governance structures including laws that reflect society's desires and the way that society functions that will pave the way for scientific impact,” says Colbourne.
The University of Birmingham embodies an interdisciplinary approach, spanning both mechanistic toxicology as well as areas like environmental law. The PrecisionTox project works across three colleges - life and environmental sciences, arts and law and the medical school. “We've torn down those academic silos and we interact a lot among colleges to deliver this new type of approach for protecting human and environmental health from chemicals. Although important, -omics is only a part of the revolution in toxicology.”
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