NTRC Marks 20 Years of Studying Nanotoxicology: Highlights from the Toxicology and Internal Dose Team

Where It Started

As the Nanotechnology Research Center (NTRC) marks its 20th anniversary, we reflect on our achievements in the field of nanotoxicology.

Within the National Institute for Occupational Safety and Health (NIOSH), one NTRC goal is to understand possible harm from nanomaterials in workplaces. Our work has its origins in earlier research. We started by researching the tiniest components of air pollution, known as ultrafine particles. These are incredibly small particles measuring less than 100 nanometers across. To grasp this scale, consider that a sheet of paper’s thickness is a thousand times larger (about 100,000 nanometers).

Our early work laid the foundation for our current efforts to assess two types of nanoparticles found in workplaces. These are engineered nanomaterials (purposely created for various applications) and process-derived nanoparticles (unintentionally produced during industrial processes). The nano-scale size and related properties of ultrafine particles can make them more toxic than larger particles. Nanomaterials can travel farther into the body, interacting uniquely with cells and potentially causing health effects distinct from larger particles.

Earlier studies of ultrafine particles informed concerns about potential health risks as nanotechnology rapidly advanced. The small size and unique properties of engineered nanomaterials sparked worries about new or greater health effects. Researchers realized that workers could face the most extensive exposures, primarily through inhalation and skin contact.¹

In the early 2000s, a surge of nanotoxicology research began. Scientists anticipated potential hazards of nanomaterials and acted proactively. This new field of study often began its work before manufacturing and workplace handling of these materials were commonplace.^2–5 The field of nanotoxicology often worked in reverse of traditional worker health and epidemiology studies. Instead of investigating health effects after worker exposures, toxicologists strived to predict possible worker harm before exposures happened.²

Where We Are

NIOSH researchers have studied the toxicity of many engineered nanomaterials throughout their lifecycles. These include materials based on metals, carbon, clay, and cellulose in various forms. The research covers primary manufactured forms (such as carbon nanotubes, nanoscale titanium dioxide, and silver nanoparticles). It also covers modified versions for specific applications (like silica-coated iron oxide, heat-treated carbon nanotubes, and reduced graphene oxide).

The studies look at particles that are part of nanotechnology-enhanced materials, such as concretes and spray coatings. They also look at process-derived nanoparticles from activities like welding, thermal spraying, and 3D printing.^6–8  The images below illustrate some of these materials.

The major priorities in the toxicology research at NIOSH include the following:

• Assess acute (short-term) and chronic (long-term) toxicity from different exposure routes, focusing on inhalation and skin contact.
• Map how nanomaterials spread through the body and affect specific organs.
• Uncover the mechanisms by which exposure causes disease.
• Identify which material properties (such as size, shape, chemistry) contribute most to toxicity.
• Create biomarkers (measurable indicators in the body) to detect exposure and related health effects.
• Develop alternative models that predict toxicity in vivo (in living organisms).
• Build predictive toxicity models using bioinformatics (analyzing biological data) and computational approaches (simulating biological systems with computer algorithms).

Working Together

NIOSH established the Nanotechnology Research Center in 2004 to coordinate nanotechnology research across the institute. Ten critical areas of research have at least one key scientist assigned to each, serving as a coordinator:

1. Toxicity and internal dose
2. Measurement methods
3. Exposure assessment
4. Epidemiology and surveillance
5. Risk assessment
6. Engineering controls and personal protective equipment [PPE]
7. Fire and explosion safety
8. Recommendations and guidance
9. Global collaborations
10. Applications and informatics

Our progress depends on partnerships. These have extended across government agencies, occupationally based research consortiums, trades unions, and industry.

The Toxicology and Internal Dose Team in the NTRC benefits from working with these groups. Those studying material properties, conducting field research, and examining health patterns in populations are especially important. These partnerships help the team do the following:

• Assess materials that workers actually encounter.
• Develop lab tests that mimic how workers come into contact with materials over time.
• Measure exposure levels accurately.
• Use advanced tools to determine which material properties make substances toxic.

NIOSH’s body of research on carbon nanotubes is a model for assessing materials. Toxicology research began with primary materials using carbon nanotubes being developed before upscale production. Researchers used doses based on knowing larger counterpart materials received through partnerships with government and industry. Studies suggested carbon nanotubes could cause lung fibrosis, promote tumor development, and might move from lungs to other organs.^9–13

The growing nanotechnology industry led to closer teamwork with field researchers. This partnership brought actual materials from U.S. facilities to the lab to assess toxicity and identify key properties. This approach helped researchers measure exposure more accurately, which they then applied to earlier toxicity studies.^14,15 These partnerships also led researchers to study the toxicity of carbon nanotubes at later stages of their industrial use, including in coated materials and composites.¹⁶

Using samples from the worker health effects studies, researchers developed toxicology studies to determine biomarkers of exposure and disease.¹⁷ Seeking safer designs, studies explored how these materials cause harm and how modifying particle surfaces affects toxicity. The studies also investigated how their hazards compare with other fiber-like materials.^18–21

Together, these studies offer valuable data for understanding workplace hazards and risks. The images below illustrate some of the key findings from the carbon nanotube studies.

Modeling Workplace Exposure to Assess Toxicity

To assess toxicity, we need test systems that mimic real-world worker exposures. NIOSH engineers tackled this by modifying an acoustical generator and creating a wet aerosol generation system. These tools produce breathable nanomaterial aerosols for studying toxicity in living organisms.^9,22,23 They’ve also built a robotic welder, a spot-welder, and a thermal spray system. To simulate worker exposure, they adapted a 3D-printer to produce airborne nanoscale particles for real-time studies in living organisms.^6,24,25

Outside the inhalation facility, researchers constructed test chambers. These measure controlled processes (such as sanding, sawing, and cutting) using products containing nano- and advanced materials. The chambers control all aspects of the operation and environment, and they collect aerosols and particles for toxicity studies.^26,27 Some illustration of these systems are shown below.

Global efforts are also focusing on reducing animal testing. In this spirit, NIOSH investigators use new alternative methods and predictive models to estimate how substances affect living organisms. These predictions come from lab tests using cell cultures, which scientists then apply to living organisms. The following systems better simulate worker exposure than traditional cell culture approaches:

• Low-dose sub-chronic cell culture models (exposing cells to small amounts of substances over extended periods).
• Cell culture at the air-liquid interface (growing cells with air on one side, liquid on the other, mimicking lung tissue).
• Human precision-cut lung tissue sections (thin slices of human lung tissue kept alive in the lab).
• Three-dimensional tissue models of lung and skin (lab-grown structures that resemble real organs more closely than flat cell cultures).

Looking Forward

The NTRC’s toxicology research evolves as information emerges about advanced materials, their lifecycle, and processes using them. We are expanding our focus to study a broader range of advanced materials. This includes unique materials, including engineered nanoparticles and products from advanced material science, designed for specific physical and chemical functions.

As we move forward in finding how new materials and exposures might harm workers, our overall goal remains the same. We conduct research that provides the necessary knowledge for understanding workplace hazards and risks. This research seeks to help prevent work-related illness and disease.

Jenny R. Roberts, PhD, is the coordinator of the NTRC Toxicology and Internal Dose Team in the NIOSH Health Effects Laboratory Division

References

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