How developmental toxicology is transforming from animal testing to human-relevant science
Every day, pregnant women worldwide use countless products, consume medications, and encounter environmental chemicals, relying on regulatory systems to ensure their safety. But how do scientists actually determine whether a substance might harm a developing fetus? For decades, the answer has involved extensive animal testing—but this field is undergoing a quiet revolution.
In 2009, leading toxicologists gathered for a pivotal workshop titled "Developmental Toxicology—New Directions," launching a fundamental rethink of how we assess chemical dangers to unborn children 13. Their mission: refine outdated methods, reduce animal testing, and embrace cutting-edge technologies that better predict human risks.
This article explores how developmental toxicology is transforming from a resource-intensive process into a more sophisticated, human-relevant science that protects the most vulnerable among us.
Developmental toxicology is the science dedicated to understanding how chemicals, drugs, or environmental exposures might cause harm to developing embryos or fetuses. These harmful effects, known as developmental toxicity, can include birth defects, growth retardation, functional deficits, or even loss of the pregnancy 35.
Unlike general toxicity that affects adults, developmental toxicity depends heavily on timing—exposure during critical windows of development, such as organ formation, can have devastating consequences that the same exposure would not cause later in pregnancy or in adulthood 8.
Testing substances in pregnant animals—typically rats and rabbits—following guidelines established over 40 years ago 3.
Resource-intensive, uses large numbers of animals, and doesn't always accurately predict human risk due to species differences 13.
The 2009 "Developmental Toxicology—New Directions" workshop emerged from growing recognition within the scientific community that while traditional methods were somewhat effective, they needed significant improvement 3. Two main drivers fueled this reevaluation:
Traditional animal testing approaches are incredibly resource-intensive, requiring significant time, specialized facilities, and large numbers of animals 1.
Legitimate concerns about how well results from animal studies translate to humans due to species differences in metabolism, placental structure, and embryonic development 3.
Rather than completely discarding established methods, scientists are working to refine them, enhancing both predictivity for human risk and animal welfare. Several key refinements emerged from the workshop discussions:
Toxicokinetics—the study of how chemicals move through living organisms—has become crucial for designing better studies 3. By understanding how a substance is absorbed, distributed, metabolized, and eliminated in different species, researchers can select the most appropriate animal models.
A compelling case study presented by Dr. Christopher Lau of the US EPA illustrated this principle perfectly. When studying perfluoroalkyl acids (PFAAs)—industrial chemicals found in human serum and wildlife—researchers discovered significant interspecies differences in how long these chemicals persisted in the body 3.
Another refinement involves using genetically modified animal models to understand how specific molecular pathways contribute to developmental toxicity 3. For example, if scientists know a drug targets a particular protein, they can study what happens when that protein is disabled in genetically engineered mice.
| Species | Implantation (Gestational Days) | Primitive Streak (Gestational Days) | Organogenesis Ends (Gestational Days) | Usual Parturition (Gestational Days) |
|---|---|---|---|---|
| Human | 6-7 | 13 | ~50-56 | 266 |
| Monkey | 9 | 17 | ~44-45 | 166 |
| Rabbit | 7.5 | 7.25 | 18 | 30-32 |
| Rat | 5-6 | 8.5 | 15 | 21-22 |
| Mouse | 5 | 6.5 | 15 | 19-20 |
One of the most compelling examples presented at the workshop illustrates how genetically modified models can predict developmental toxicity before human trials even begin 3.
Scientists studied α4-integrin knockout mice—animals genetically engineered to lack the gene responsible for producing α4-integrin, a protein involved in cell adhesion and signaling 3.
The experimental results confirmed the prediction: all three inhibitors caused developmental abnormalities in rabbit fetuses, with the severity correlating directly with the extent of α4-integrin inhibition 3.
This case demonstrated how understanding molecular mechanisms behind development can help predict toxicity of drugs targeting those mechanisms. The approach also shows how tiered testing—beginning with genetically modified models then moving to traditional animal studies—can provide more targeted, informative safety assessments 3.
| Testing Approach | Key Features | Advantages | Limitations |
|---|---|---|---|
| Traditional Animal Studies | Dosing during organogenesis; examination of near-term fetuses in two species 3 | Established regulatory acceptance; whole-organism complexity 3 | Resource-intensive; species differences; limited mechanistic insight 13 |
| Refined Animal Studies | Incorporation of toxicokinetics; use of genetically modified models; species selection based on relevance 3 | Improved human relevance; better dose selection; mechanistic understanding 3 | Still uses animals; requires specialized models and expertise 3 |
| New Approach Methodologies (NAMs) | Computational models; stem cell-based tests; zebrafish embryos; high-throughput screening 457 | Faster; less costly; reduced animal use; human biology-based 47 | Regulatory acceptance evolving; may not capture full complexity 4 |
Today's developmental toxicologists have access to an expanding arsenal of research tools that extend far beyond traditional animal models:
Animals engineered with specific gene deletions help identify whether molecular targets of drugs are essential for normal development 3.
Small, transparent vertebrates that develop rapidly, allowing real-time observation of developmental effects 5.
Advanced algorithms, including Graph Convolutional Networks, predict toxicity based on chemical structure 7.
Human pluripotent stem cells allow study of effects on human-specific developmental processes 4.
High-throughput screening platforms that rapidly test thousands of chemicals in automated assays 9.
| Tool/Model | Function in Research | Application in Developmental Toxicology |
|---|---|---|
| Knockout Mice 3 | Animals with specific genes disabled | Identify essential developmental pathways; predict toxicity of targeted drugs |
| Zebrafish Embryos 5 | Small, transparent vertebrate model | Medium-to-high throughput screening of chemical effects on development |
| Graph Convolutional Networks 7 | Deep learning algorithm | Predict toxicity from chemical structure without animal testing |
| Human Stem Cells 4 | Human pluripotent stem cells | Study effects on human-specific developmental processes |
| ToxCast/Tox21 Assays 9 | High-throughput in vitro screening | Rapid profiling of chemical effects on biological targets |
Perhaps the most transformative development in developmental toxicology is the emergence of New Approach Methodologies (NAMs)—an umbrella term for technologies that reduce or replace animal testing 469. The driving force behind NAMs includes both ethical concerns about animal use and the scientific limitation of traditional methods 4.
Computational methods, including quantitative structure-activity relationship (QSAR) models and machine learning algorithms, predict toxicity based on chemical structure and known properties 7.
Rather than relying on a single test, scientists combine multiple information sources—computational predictions, high-throughput screening data, and limited targeted animal testing 46.
This framework organizes knowledge about how molecular initiating events cascade through biological systems to eventually cause adverse outcomes like birth defects 4.
Regulatory agencies worldwide are increasingly accepting NAMs. The EPA's CompTox Chemicals Dashboard provides public access to computational toxicology data for thousands of chemicals, while initiatives like the Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) aim to standardize alternative models 59. Recent workshops, including those at the 2025 Society of Toxicology meeting, continue to build scientific confidence in these approaches 69.
The science of developmental toxicology has come a long way from simply dosing pregnant animals and examining their offspring. Today's approaches integrate toxicokinetics, species-specific biology, genetically engineered models, and cutting-edge computational methods to better predict risks to human development 37.
While traditional animal studies still play a role, the field is increasingly moving toward more sophisticated, human-relevant systems that use fewer animals while providing greater insight into mechanisms of toxicity 46.
This evolution matters far beyond scientific circles—it leads to safer products, more accurate risk assessments, and better protection for vulnerable populations like pregnant women and their developing children. As these new approaches continue to mature, we move closer to a future where we can confidently identify developmental hazards more quickly, cheaply, and humanely than ever before.