Beyond Lab Rats: How Scientists Are Revolutionizing Chemical Safety Testing Across Species
A new approach to chemical safety assessment that protects both human and environmental health through innovative cross-species extrapolation methods.
The 300,000 Fish Problem
Imagine trying to protect every species on Earth from chemical harm without testing on most of them. That's the monumental challenge facing environmental scientists today. Traditional chemical safety assessment has relied heavily on animal testing—mammals for human health concerns, and select fish, invertebrates, and algae for environmental protection. These two streams rarely converged, creating silos of knowledge and duplication of effort.
of approved small-molecule drugs lack complete ecotoxicity data
pharmaceuticals on the market without adequate environmental safety profiles
fish that would be needed for traditional testing of these pharmaceuticals
The scale of this challenge is staggering: recent analyses reveal that approximately 88% of approved small-molecule drugs lack complete ecotoxicity data. For the estimated 1,700 pharmaceuticals currently on the market without adequate environmental safety profiles, generating this information using traditional methods would require testing with over 300,000 fish and decades of work 1 .
In response to this crisis, a global scientific consortium is pioneering innovative approaches that could revolutionize how we assess chemical safety. The International Consortium to Advance Cross-Species Extrapolation in Regulation (ICACSER) represents a paradigm shift from traditional animal testing to sophisticated computational and mechanistic methods that protect both human and environmental health through a unified framework 2 .
The Science of Reading Across Species: Key Concepts
One Health: An Interconnected Vision
At the heart of this scientific revolution lies the One Health principle—the recognition that human, animal, and environmental health are fundamentally interconnected. This collaborative approach works "locally, nationally, and globally to attain optimal health for people, animals, and the environment" 2 . The historical separation between human and ecological toxicology represented a critical barrier to achieving this vision, a gap that cross-species extrapolation aims to bridge.
New Approach Methodologies (NAMs)
NAMs represent an umbrella term for innovative strategies that reduce reliance on animal testing while improving our understanding of chemical toxicity. These include:
- In silico approaches: Computer simulations and modeling
- In chemico and in vitro assays: Tests in test tubes and cell cultures
- Omics technologies: Genomic, proteomic, and metabolomic analyses
- Toxicokinetic and exposure prediction: Modeling how chemicals move through and affect organisms 2
The Adverse Outcome Pathway Framework
A critical conceptual framework enabling cross-species extrapolation is the Adverse Outcome Pathway (AOP). An AOP is "a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment" 2 . In simpler terms, it maps the chain of events from initial chemical exposure to eventual harmful effects.
The power of AOPs lies in their ability to identify which steps in toxicity pathways are conserved across species. This helps scientists determine when data from one species can reliably predict effects in another 3 .
Bioinformatics: The Computational Engine
Bioinformatics—"the collection, organization, storage, analysis, and synthesis of biological information using computers"—provides the computational power driving this revolution 2 . By analyzing vast datasets of genetic, protein, and toxicity information, scientists can now predict how chemicals might affect diverse species without testing each one individually.
Molecular Initiating Event (MIE)
Chemical interacts with biological target at molecular level
Cellular Responses
Early cellular changes and signaling pathway alterations
Organ Responses
Tissue and organ-level effects
Organism Responses
Individual-level adverse outcomes
Population Responses
Effects on population sustainability
AOP framework helps identify conserved pathways across species for reliable extrapolation 3 .
A Closer Look: The GEARs Experiment—A Toolkit for Cross-Species Protein Tracking
To understand how cutting-edge science enables cross-species extrapolation, let's examine a groundbreaking 2025 study that developed a revolutionary protein tagging system called GEARs (Genetically Encoded Affinity Reagents) 4 .
The Experimental Challenge
Understanding exactly where proteins localize and how they function in living organisms has long been challenging. Traditional antibody methods work only in fixed (dead) samples, while GFP tagging requires inserting relatively large genetic sequences that can disrupt normal protein function. Scientists needed a versatile, minimal-interference system that could work across species boundaries.
Methodology: A Step-by-Step Breakdown
The research team developed and validated their GEARs system through a sophisticated multi-stage process:
- Toolkit Development: Researchers assembled a collection of small epitopes and their corresponding binding partners.
- Temperature Compatibility Testing: Verified functionality at zebrafish physiological temperatures.
- In Vivo Validation: Tested recognition and binding in live zebrafish embryos.
- Cross-Species Verification: Confirmed system worked in both zebrafish and mouse embryos.
- Degradation Application: Adapted GEARs to target tagged proteins for destruction.
GEARs system enables protein tracking across species with minimal disruption to normal function 4 .
Results and Significance: Breaking New Ground
The GEARs experiment yielded impressive results with far-reaching implications:
Tests with Nanog revealed that certain binders, particularly NbALFA and NbMoon, showed strong nuclear translocation with minimal background fluorescence, indicating highly specific binding 4 .
| GEAR Binder | Nuclear Translocation | Performance |
|---|---|---|
| NbALFA | High | Excellent |
| NbMoon | High | Excellent |
| FbSun | Moderate | Good |
| NbVHH05 | Moderate | Good |
| FbHA | Low | Limited |
| Nb127d01 | Minimal | Poor |
- Membrane localization tests with Vangl2 confirmed precise targeting
- Multifunctionality - binders can be linked to various functional modules
- Cross-species compatibility - works in zebrafish and mouse embryos
- Minimal disruption - small epitopes don't interfere with protein function
- Versatile applications - visualization, labeling, and degradation capabilities
The GEARs toolkit represents a significant advancement because it enables scientists to track and manipulate endogenous proteins in their natural contexts with minimal disruption to normal function. This has profound implications for cross-species toxicology, as it allows researchers to compare exactly how the same protein responds to chemical exposure across different organisms, providing crucial data for extrapolating toxic effects while reducing animal testing.
The Scientist's Toolkit: Key Resources in Cross-Species Extrapolation
The field of cross-species extrapolation relies on both experimental models and computational resources. Here are the essential tools powering this research:
Bioinformatics Tool
Assesses conservation of protein sequences and susceptibility across species to predict whether chemical targets are conserved across species 3 .
Database
Provides evolutionary conservation of drug targets to help identify which non-target species might be sensitive to human pharmaceuticals 1 .
Experimental System
Liver-on-a-chip technology that mimics human and animal liver responses, enabling direct comparison of drug toxicity between human, rat, and dog models without animal testing 5 .
Experimental Method
Multifunctional protein tagging using short epitopes that enables visualization and manipulation of endogenous proteins across vertebrate species 4 .
Computational Resource
Provides access to chemistry, toxicity, and exposure data for thousands of chemicals, centralizing data needed for predicting chemical effects across species 6 .
From Bench to Regulation: The Future of Chemical Safety Assessment
The regulatory landscape is gradually evolving to accommodate these innovative approaches. Recent legislation, such as the European ban on animal testing for cosmetics, has underscored authorities' willingness to consider NAMs for regulatory safety evaluation 2 . However, significant challenges remain.
Translating comparative toxicology research into real-world applications faces several obstacles:
- Technical Complexity: Successfully navigating cross-species extrapolation requires expertise spanning multiple disciplines.
- Validation Requirements: Regulatory acceptance demands rigorous demonstration that new methods are as reliable as traditional approaches.
- Data Integration: Effectively combining information from mammalian toxicology studies with ecotoxicological observations remains challenging 1 .
Despite these challenges, the field is advancing rapidly. The integration of high-throughput screening, computational modeling, and mechanistic toxicology is creating a more efficient and humane pathway for chemical safety assessment. As these approaches mature, we're moving toward a future where:
- Environmental risk can be accurately predicted from known human drug effects
- Chemical safety testing becomes faster, cheaper, and more predictive
- Far fewer animals are required for meaningful safety assessments
- Human and environmental health are protected through integrated approaches
Conclusion: Toward a Unified Vision of Planetary Health
The work of ICACSER and the researchers developing innovative tools like GEARs represents more than technical advancement—it embodies a fundamental shift in how we conceptualize chemical safety. By recognizing the interconnectedness of all species and leveraging cutting-edge science, we're developing the capability to protect both human and environmental health simultaneously.
As Dr. Carlie LaLone, one of the leaders of ICACSER, and her colleagues note, focused efforts to "advance cross-species extrapolation that leverage existing toxicity data from both mammals and other model organisms can be used to protect all species" 2 . In an era of increasing chemical innovation and environmental concern, this work has never been more critical.
The vision is clear: a future where we can accurately assess chemical safety for all species using sophisticated, humane methods that respect both scientific complexity and our planetary interconnectedness. Through the integration of computational power, mechanistic understanding, and cross-species frameworks, that future is coming into view.