National Toxicology Program

1. What are nanoscale materials?
2. Why is NTP evaluating nanoscale materials?
3. How is NTP organized to address issues related to the safety of nanomaterials?
4. What research is NTP doing to address the possible human health risks associated with nanotechnology and nanoscale materials?
5. When will results from any NTP studies be available?
6. How is NTP coordinating its activities with other federal agencies and outside organizations?
7. What are the major challenges facing the NTP with regard to its nanotechnology safety assessment

What are nanoscale materials?

Nanoscale materials are a broadly defined set of substances that have at least one critical dimension less than 100 nanometers and possess unique optical, magnetic, or electrical properties. Ultrafine particulate matter is a well-known example of nanoscale particles found in the environment. The NTP's research program focuses on engineered nanoscale materials of current or projected commercial importance. Theoretically, nanoscale materials can be engineered from nearly any chemical substance; semiconductor nanocrystals, organic dendrimers, and carbon fullerenes and carbon nanotubes are a few of the many examples.

Why is NTP evaluating nanoscale materials?

Nanoscale materials are already appearing in commerce as additives or modifications to industrial and consumer products and as novel drug delivery formulations. Commercial applications that result in human exposure may differ substantially for nanoscale versus "bulk" manufactured base materials.

Currently, there is very little research focused on the potential toxicity of manufactured nanoscale materials. Published studies on the inhalation of ultrafine particles suggest that particle size can impact toxicity equally, if not more so, than chemical composition and hints at the complexity of the topic. The unique and diverse physico-chemical properties of nanoscale materials suggest that toxicological properties vary for materials of similar composition but differing size. There are indications in the literature that manufactured nanoscale materials may distribute in the body in unpredictable ways. Certain nanoscale materials have been observed to accumulate preferentially in particular cellular organelles. In 2003, the Rice University Center for Biological and Environmental Nanotechnology (CBEN) nominated nanoscale materials to the NTP toxicology testing program. The NTP initiated a research program evaluating nanoscale materials because of the intense current and anticipated future research and development focus on nanotechnology and the CBEN nomination.. The complexity of the issue requires the NTP to utilize both existing and new toxicological testing methods to adequately assess potential human health effects. Specific details on the nomination and study recommendations can be found at "Nominations to the Testing Program" for 2003.

How is NTP organized to address issues related to the safety of nanoscale materials?

NTP is an interagency program headquartered at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH). Three agencies, NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the Food and Drug Administration (NCTR/FDA), form the core of the NTP. The Director of the NIEHS/NIH also serves as the NTP Director.

NIEHS staff serve as principle coordinators of the NTP's nanotechnology safety initiative and work together with NCTR/FDA and NIOSH/CDC staff from a variety of scientific disciplines. At this stage, NTP research on nanoscale materials is being conducted primarily through government contracts with outside research organizations, by FDA staff at the NTP's Phototoxicology Center based at NCTR in Jefferson, AK and the Center for Food Safety and Applied Nutrition (CFSAN) in Washington, DC, and through collaborations with staff at the Center for Biological and Environmental Nanotechnology (CBEN) at Rice University.

What research is NTP doing to address the possible human health risks associated with nanotechnology and nanoscale materials?

The NTP intends to conduct studies that test hypotheses focused on the relationship of key physicochemical parameters of selected manufactured nanomaterials to their potential toxicity. Initial parameters of greatest concern are size, shape, surface chemistry, and composition. This strategy will be accomplished by developing a suite of analytical approaches to evaluate and characterize the physiochemical properties of nanoscale materials in their raw form and as formulated when given to animals or exposed to cells in culture. In addition, we will conduct animal toxicity studies of varying durations with specific nanomaterials using routes of administration that mimic possible human exposure. These studies will include evaluations of the absorption and handling of the materials by rodents. We also intend to develop a battery of in vitro models to evaluate the biological and toxicological effects of nanoscale materials. These models would be used to assess whether in vitro methods can predict which nanoscale materials might be a hazard for animals or people.

Based on these findings, the NTP will develop mathematical models (physiologically based pharmacokinetic models) to predict the absorption, distribution, metabolism, and elimination of nanoscale materials in humans. These models would be used to predict how modification of a given nanomaterial's physicochemical properties might reduce its absorption or increase its elimination, thereby reducing the probability that a toxic response would occur.
The NTP's nanotechnology safety initiative is focusing on 3 areas of research with respect to specific types or groups of nanoscale materials:

1. Non-medical, commercially relevant/available nanoscale materials to which humans are intentionally being exposed, e.g., cosmetics and sunscreens.
   
2. Nanoscale materials representing specific classes (e.g., fullerenes and metal oxides) so that information can be extrapolated to other members of those classes.
   
3. Subsets of nanomaterials to test specific hypotheses about a key physiochemical parameter (e.g., size, composition, shape, or surface chemistry) that might be related to biological activity.

Ongoing research activities are focusing initially on 4 classes of nanoscale materials: (1) metal oxides, (2) fluorescent crystalline semiconductors (quantum dots), (3) fullerenes, (4)carbon nanotubes.

• NTP scientists at the NCTR/NTP Center for Phototoxicity are examining the potential dermal toxicity of nanoscale materials available in non-medical, commercially available products. For example, nanoscale ceramics (nanoscale titanium dioxide or TiO2 and zinc oxide or ZnO) are already in use in certain cosmetics and sunscreens. These studies are addressing (1) the fate and distribution of nanoscale ceramics and quantum dots in the body following their dermal application to rodents with attention given to the role of surface coating, size, polarity, vehicle, and skin condition on the ability of nanoscale TiO2 to penetrate the skin; (2) whether nanoscale TiO2 and ZnO applied dermally to mice in combination with UVA-containing light affects cell signaling, and (3) the potential for TiO2 and ZnO applied dermally to haired and hairless mice in combination with UVA-containing light to cause skin cancer.

• NTP scientists at NIOSH/CDC are planning inhalation studies on single-walled nanotubes. They are interested in the potential toxicity of these nanoscale materials because of potential exposure to workers in occupational settings and because laboratory studies in rodents have reported potential toxicity of nanotubes in the lungs.

• Also in development are systemic studies on fullerenes (buckyballs) and related compounds because of the current, high mass production of these compounds, their increasing use in consumer products, and the use of derivatized fullerenes in drug delivery research. These studies are being led by NTP scientists at the NIEHS.

When will results from any NTP studies be available?

We anticipate the results from our studies being available in the next 1-5 years, depending on the type of study. Results from longer-term rodent studies will likely take several years.

How is NTP coordinating its activities with other federal agencies and outside organizations?

The NTP is coordinating and communicating its activities on nanotoxicology with other groups to aid the identification of areas where research is needed and avoid duplicative efforts.

• NIEHS/NTP staff are members of the Nanotechnology Environmental Health Implications (NEHI) Working Group of the Nanoscale Science, Engineering and Technology (NSET) Committee of the National Nanotechnology Initiative. This U.S. government, multi-agency workgroup meets monthly to discuss government activities focused on assessing the human health risks of nanotechnology.

• NIEHS/NTP staff have established regular meetings with staff at the National Cancer Institute (NCI) Nanotechnology Characterization Laboratory (NCL) to discuss research findings and exchange ideas to ensure that the physico-chemical characterizations and toxicological approaches being undertaken by both groups are coordinated and that activities are complementary and not duplicative.

• NTP staff has given numerous informational seminars at national and international meetings providing overviews of NTPs activities to assess the safety of nanoscale materials.

• Together with staff from the University of Florida, the NTP organized the first workshop to identify the critical issues in the development of effective strategies for evaluating the safety and toxicity of nanoscale materials. This workshop included current leaders in the field of nanotoxicology with representatives from multiple government agencies, academia, industry, and non governmental organizations and laid the groundwork for development of more detailed, specific strategies such as the recent International Life Sciences Institute (ILSI) -Risk Sciences Institutes screening strategies report. The report from the Florida workshop is available at "Meetings & Workshops."

• NTP staff from the NIEHS are advisors to the ILSI - Health and Environmental Sciences Institute (HESI) Nanomaterials Safety Subcommittee- an academic/government/industry consortium whose goals are to: (1) improve the science associated with developing toxicological and safety evaluations for engineered nanomaterials and (2) improve the fundamental understanding of the behavior of these materials in biological systems and the environment.

• The NTP established the NTP Board of Scientific Counselors Nanotechnology Working Group (NWG) as a mechanism to obtain input from non-government organizations (labor and environmental groups), industry, and other stakeholders on NTP nanotechnology activities. NWG meetings are open to the public and are advertised on the NTP website, through the NTP list-serve and in the Federal Register. Additional information on the NWG, including its charge, roster, and meeting schedule, can be found at "Advisory Board & Committees."

What are the major challenges facing the NTP with regard to its nanotechnology safety assessment?

Prioritizing and obtaining materials to evaluate are major challenges for the NTP. Specific nanomaterials with the highest exposure potentials are not well known, making it difficult to identify the most important materials to study. Obtaining materials is also an impediment. In many cases, information about the nanoscale material is proprietary. Consequently, the NTP may be unable to study those materials that pose the highest potential exposure to humans. In other cases, the material may be available, but not in sufficient quantities to allow an adequate hazard evaluation, particularly regarding long-term, repeated exposure studies.

Characterization of nanomaterials has proven to be more difficult than anticipated for several reasons. First, a standard nomenclature has not been developed. Second, biologists, physicists, and materials scientists working in this area often do not communicate effectively. In addition, an analytical infrastructure to allow characterization is not consistently available or well-located. The high degree of variability in size and surface chemistry of nanoscale materials and in the coatings, crystal structure, shape, and composition used in preparing these materials increase both their complexity and the multiple permutations that must be considered in their evaluation. Adequate methods to detect nanomaterials in cells and tissues also need further development.

Some of these impediments can be addressed by ensuring the availability of dedicated staff and resources. For example, development of a repository of well characterized model nanomaterials for use in both toxicological and biomedical research would significantly enhance the quality research investigating the heath effects of nanoscale materials. In addition, increased personnel, resources, and analytical capabilities could potentially enable the NTP nanotechnology safety assessment to move forward at a faster pace and/or broaden its scope.