The groundbreaking promise of cross-species extrapolation is transforming how we protect both human health and our natural environment
Imagine a world where a safety test conducted on a tiny zebrafish embryo could accurately predict chemical risks for humans, eagles, and even otters. This isn't science fiction—it's the groundbreaking promise of cross-species extrapolation, a revolutionary approach that's transforming how we protect both human health and our natural environment. At the forefront of this change is the International Consortium to Advance Cross-Species Extrapolation in Regulation (ICACSER), a global collaboration working to replace thousands of animal tests with sophisticated computer models and mechanistic biology 1 8 .
For decades, chemical safety evaluation has operated in silos: mammalian data (primarily from rats and mice) drove human health considerations, while studies on select fish, invertebrates, and algae informed environmental protection goals 1 . This divided approach not only required enormous numbers of laboratory animals but also missed crucial opportunities to share knowledge across species boundaries.
Today, with global efforts to reduce animal testing and new technological capabilities, scientists are pioneering methods that leverage existing data to protect all species more efficiently and humanely 1 2 .
Traditional toxicity testing has relied heavily on whole-animal studies that measure obvious "apical" endpoints like reproduction, growth, development, and mortality 1 . These tests have provided the backbone of chemical safety assessments for generations, but they come with significant limitations:
Time to complete testing for a single chemical
Cost per approved drug compound
Required to test unevaluated pharmaceuticals
Drugs lacking complete ecotoxicity data
The global regulatory landscape is rapidly evolving in response to these challenges. Europe banned marketing of cosmetics tested on animals in 2013, and the U.S. Environmental Protection Agency has committed to eliminating mammalian regulatory studies by 2035 1 . This regulatory shift has accelerated the development of alternative methods that can provide better protection with fewer animals.
At the heart of this scientific revolution lies the "One Health" approach—a collaborative effort to attain optimal health for people, animals, and the environment 1 2 . This perspective recognizes the fundamental interconnectedness between human health and ecosystem health, acknowledging that chemicals released into our environment don't respect species boundaries.
"The ultimate protection goal is the health of the planet and all its inhabitants," explain scientists behind ICACSER, emphasizing that focused efforts to advance methods for cross-species extrapolation can leverage existing toxicity data from both mammals and other model organisms to protect all species 1 .
This unified approach represents a paradigm shift in toxicology. Instead of seeing human and environmental health as separate domains, researchers now recognize that knowledge about chemical effects in one species can inform understanding of potential risks to others through conserved biological pathways.
The science of cross-species extrapolation relies on a fundamental biological insight: despite outward differences, many molecular pathways and physiological processes have been conserved through evolution across diverse species. The key framework enabling this approach is the Adverse Outcome Pathway (AOP), which organizes existing knowledge about how chemicals cause harm at different biological levels 1 8 .
An AOP creates a structured chain of events linking:
The initial interaction between a chemical and its biological target (e.g., a protein)
Cellular, tissue, and organ-level responses that follow the initial interaction
Effects relevant to risk assessment at the individual or population level 1
This framework allows scientists to determine the "taxonomic domain of applicability"—how broadly across different species a particular pathway is likely to operate based on conservation of the underlying biological components 1 8 . For example, if the molecular target of a chemical exists and functions similarly in both humans and fish, and the downstream cellular responses are also conserved, we can predict that similar adverse outcomes might occur in both species.
Modern cross-species extrapolation heavily depends on bioinformatics—the collection, organization, storage, analysis, and synthesis of biological information using computers 1 2 . Scientists have developed sophisticated tools that can analyze genetic and protein sequences across species to predict which organisms might be vulnerable to particular chemicals.
These computational approaches allow researchers to mine the vast amounts of existing toxicity data more effectively and make predictions without additional animal testing. When combined with New Approach Methodologies (NAMs)—including in silico, in chemico, and in vitro assays—these methods form a powerful toolbox for 21st-century chemical safety assessment 1 .
With thousands of chemicals in commerce and countless species in our environment, testing every chemical on every species is impossible. Scientists needed a way to quickly and accurately predict which organisms would be most vulnerable to specific chemicals based on conservation of molecular targets.
Researchers developed a bioinformatic tool called Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) to address this challenge 8 . The methodology follows a systematic process:
Researchers gather protein sequences for the chemical target of interest (e.g., a receptor, enzyme) from well-studied species where the chemical's mechanism is understood.
Using sophisticated algorithms, the tool compares sequences across multiple species, identifying conserved regions critical for chemical binding and protein function.
Each species receives a vulnerability score based on similarity of the chemical binding site, conservation of key functional domains, and presence of necessary structural features.
The tool generates predictions about which species are likely vulnerable to the chemical based on evolutionary conservation of the molecular target 8 .
| Species | Protein Sequence Identity (%) | Binding Site Conservation | Predicted Vulnerability |
|---|---|---|---|
| Human (reference) | 100 | High | High |
| Zebrafish | 85 | Moderate | Moderate |
| Fathead Minnow | 82 | Moderate | Moderate |
| Daphnia magna | 45 | Low | Low |
| Green Algae | 30 | Very Low | Very Low |
The SeqAPASS tool has demonstrated remarkable success in predicting cross-species susceptibility for various chemicals, including pharmaceuticals . In one large-scale analysis, researchers used this approach to evaluate the potential environmental risks of 975 approved drugs, revealing that a significant percentage posed potential concerns based on evolutionary conservation of their drug targets .
| Drug Class | Human Target | Fish Conservation | Invertebrate Conservation |
|---|---|---|---|
| Antidepressants | Serotonin transporter | High | Low |
| Anti-inflammatories | Cyclooxygenase | High | Moderate |
| Blood pressure medications | β-adrenergic receptor | High | Very Low |
| Hormone therapies | Estrogen receptor | High | Low |
The power of this approach lies in its ability to quickly prioritize chemicals and species of greatest concern. This allows regulators to focus limited testing resources where they're most needed and helps pharmaceutical companies design environmentally friendly drugs early in development.
The advancement of cross-species extrapolation relies on both computational tools and experimental reagents that enable researchers to study biological conservation and chemical effects. The following table highlights essential tools and methods used in this innovative field.
| Tool/Reagent | Type | Primary Function | Example Applications |
|---|---|---|---|
| SeqAPASS | Bioinformatics platform | Predicts species susceptibility based on sequence conservation | Initial screening of chemical risks across ecosystems 8 |
| ECODrug | Database | Assesses evolutionary conservation of drug targets | Identifying potentially eco-toxic pharmaceuticals |
| Adverse Outcome Pathway (AOP) Framework | Conceptual framework | Organizes knowledge about toxicity mechanisms | Structuring cross-species extrapolation hypotheses 1 |
| GEARs (Genetically Encoded Affinity Reagents) | Laboratory reagents | Visualize and manipulate endogenous proteins | Studying protein localization and function in model organisms 4 |
| Reporter Assays | Cell-based tests | Measure receptor activation and cellular responses | Screening chemical effects on specific pathways 7 |
These tools represent a blend of computational and experimental approaches that together form a comprehensive strategy for understanding and predicting chemical effects across species. As the field advances, these toolkits continue to evolve, incorporating new technologies like artificial intelligence and high-throughput screening methods 5 .
The science of cross-species extrapolation represents a fundamental shift in how we approach chemical safety—from reactive animal testing to proactive prediction, from isolated assessments to unified protection strategies. As we continue to develop more sophisticated tools and deeper biological understanding, we move closer to a future where we can effectively safeguard both human health and ecological systems with greater efficiency, reduced animal use, and improved predictive power.
"What worries me is that industry appears apprehensive that testing chemicals for their behavioral effects will lead to increased costs and potentially uncover effects they'd rather not have to address," says Professor Alex Ford from the University of Portsmouth 6 . "When we're talking about protecting human health and wildlife, surely using the most sensitive, and thereby most protective, data should take priority over profit margins."
As this field advances, it promises not only to transform toxicology but also to reflect our growing understanding of the profound connections between human wellbeing and the health of the planet we share. Through the innovative work of consortia like ICACSER, we're building a scientific foundation for a future where people and wildlife can thrive together in a healthier, safer environment.