The same extraordinary property that makes a nanomaterial useful can also make it dangerous.
Imagine a material that is stronger than steel, capable of delivering life-saving drugs directly to cancer cells, and can make our electronics infinitely more powerful. Now, imagine that this very same material, due to its incredibly small size, might behave in unpredictable and potentially hazardous ways inside the human body. This is the central paradox of nanotechnology. For decades, regulators have used a tried-and-tested playbook to ensure chemical safety. But when it comes to nanomaterials, that playbook is proving dangerously outdated, forcing scientists to rewrite the rules of risk assessment from the ground up.
The traditional risk assessment framework, used for decades to evaluate everything from industrial solvents to pesticides, is built on a straightforward principle: understand the hazard and the exposure to determine the risk. This process has served us well with conventional chemicals. However, when applied to engineered nanomaterials (ENMs), this model begins to crumble under the weight of nanoscale complexity 1 3 .
A change in a physical property, like size or shape, can be as significant as changing its chemical formula.
The fundamental issue is that a nanomaterial's risk is not defined by chemistry alone. For instance, titanium dioxide in its bulk form is considered so safe it's used in toothpaste and sunscreen. Yet, when reduced to nano-size, the same substance can cause inflammatory responses in the lungs 7 . This is because at the nanoscale, materials often exhibit unique properties not seen in their larger counterparts.
There aren't just a handful of nanomaterials. Each base material can come in dozens of different "nanoforms" — varying in size, shape, surface charge, and aggregation state — each with its own potential biological effects 2 .
Scientific literature is often filled with conflicting results about a nanomaterial's toxicity. These discrepancies often stem from a lack of standardized testing methods 2 .
For traditional chemicals, dose is often measured in mass. For nanomaterials, is the relevant metric mass, surface area, or the number of particles? Science has not yet settled this debate 5 .
One analysis estimated that testing existing nanoparticles in the U.S. alone could take 34–53 years to complete using traditional methods 3 .
As one analysis concluded, "science is at present not advanced enough to fully substantiate decision criteria and specific protocols" needed for efficient nanomaterial risk assessment 1 .
Faced with these challenges, scientists are developing a new, more adaptive toolkit for nanomaterial risk assessment. These "New Approach Methodologies" (NAMs) aim to be faster, more efficient, and more insightful than the old models 2 .
Advanced in vitro (cell-based) tests and in silico (computer modeling) methods that reduce reliance on animal testing 2 .
Sophisticated models to understand how nanoparticles travel in the body and reach target organs 5 .
Using probability distributions to represent uncertainties in hazard and exposure data 4 .
A pivotal 2024 study published in Particle and Fibre Toxicology perfectly illustrates the modern approach to nanomaterial hazard assessment 2 . The research team set out to systematically address the challenges of discordant data and the applicability of New Approach Methodologies.
The researchers selected nine different nanoforms of three common materials: cerium dioxide (CeO₂), titanium dioxide (TiO₂), and silver (Ag). This included highly dispersed nanoparticles, controlled aggregates, and specially shaped materials like nanorods and nanowires.
Each nanomaterial was extensively characterized for its physico-chemical properties—size, shape, surface charge, and aggregation state—both in their stock bottles and in the cell culture medium where testing occurred.
The team assessed cytotoxicity using three different laboratory methods: Alamar Blue, Colony Forming Efficiency, and Electric Cell-Substrate Impedance Sensing to ensure reliable results.
The data was fed into computer models to analyze the similarities and differences between the nanoforms based on their properties and biological effects.
The experiment yielded clear results. The biological responses varied significantly among the different nanoforms, even for those with the same chemical composition 2 . For example:
This study underscores a fundamental truth in nanotoxicology: it is not just what a material is made of, but how it is built at the nanoscale that determines its biological activity. It successfully demonstrated how a rigorous, standardized approach can cut through conflicting data and provide a clearer picture of nanomaterial hazards.
| Property | What It Is | Why It Matters |
|---|---|---|
| Size | The primary particle size (e.g., diameter) | Determines ability to enter cells, cross biological barriers, and where it deposits in the lungs |
| Shape | The morphology (e.g., spherical, rod, fiber) | Fiber-like shapes can resemble asbestos, leading to prolonged persistence in lungs |
| Surface Charge | The electrical charge on the particle's surface | Influences how the particle interacts with cell membranes and proteins |
| Agglomeration State | Whether particles are single or clumped | Affects deposition in the body and cellular uptake; agglomerates may be less reactive |
| Aspect | Traditional Chemical RA | Next-Generation RA |
|---|---|---|
| Core Approach | Case-by-case testing of each substance | Grouping and read-across based on properties |
| Key Data | Mass-based dose and chronic animal studies | Multiple metrics, NAMs, and computational models |
| Timeframe | Decades per substance | Rapid screening and prioritization |
| Uncertainty Handling | Generic "safety factors" | Explicitly models uncertainty using probabilistic methods |
What does it take to run these cutting-edge experiments? Here are some of the key tools and reagents that are fundamental to modern nanomaterial risk assessment.
| Tool/Reagent | Function in Research |
|---|---|
| Stable Colloidal Dispersions | Provides a uniform, well-characterized starting material for testing, avoiding artifacts from poorly dispersed powders |
| Cell Culture Lines | Used in in vitro NAMs to screen for cytotoxicity (e.g., in lung or liver cells) without using live animals |
| Alamar Blue Assay | A common reagent used to measure cell viability; a change in color indicates metabolic activity of living cells |
| Comet Assay Reagents | A kit used to detect genotoxicity (DNA damage) in individual cells, a key endpoint for cancer risk |
| Dispersants (e.g., Serum) | Added to culture media to mimic physiological conditions and maintain nanomaterial stability during testing |
| Transmission Electron Microscope (TEM) | Not a reagent, but a crucial tool for visualizing and precisely measuring the size and shape of nanoparticles |
The path forward for nanomaterial risk assessment is not simply about generating more data. It is about generating the right kind of data and developing pragmatic, internationally accepted frameworks to use it 1 . The goal is to move away from a purely reactive, case-by-case approach to a more proactive and efficient system.
Widespread adoption of standardized methods for nanomaterial characterization and toxicity testing 2 .
Building open-access databases to consolidate global knowledge 5 .
A concerted effort to fully characterize and report nanomaterial properties, including negative results .
The conceptual questions surrounding nanomaterial risk are profound, challenging the very foundations of traditional toxicology. Yet, by embracing complexity and innovation, science is building a smarter, more efficient safety paradigm—one that can protect human health and the environment without stifling the incredible potential of the nanoscale world.