Evaluating the safety of nanoscale materials and nanotechnology-enabled products

Nigel J. Walker

National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27705, USA

E-mail: walker3@niehs.nih.gov

ABSTRACT

The unique and diverse physico-chemical properties of engineered nanoscale materials suggest that their toxicological properties may differ from materials of similar composition but larger size. Studies also suggest that particle size, surface area and surface chemistry of engineered nanoscale materials can impact toxicity equally, if not more so, than chemical composition. Ongoing research is evaluating the toxicological properties of current major nanoscale materials classes that represent a cross-section of composition, size, surface coatings, and physico-chemical properties. The studies are designed to investigate fundamental questions concerning how nanoscale materials are absorbed and distributed in vivo and whether they can adversely impact biological systems. Some of these fundamental questions include: What are the appropriate methods for detection and quantification of nanoscale particles in tissues? How are nanoscale materials absorbed, distributed in the body and taken up by cells? Are there novel toxicological interactions? The National Toxicology Programs 's Nanotechnology Safety Initiative (http://ntp.niehs.nih.gov/go/nanotech ) is focusing research with respect to specific types or groups of nanoscale materials to address (1) the fate and distribution of nanoscale metal oxides 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 applied dermally to mice in combination with UV-containing light affects cell signaling, and (3) the potential for TiO2 applied dermally to haired and hairless mice in combination with UV-containing light to cause skin cancer.

Introduction

Nanotechnology is defined by the National Nanotechnology Initiative (NNI) as “the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications.” In theory, materials that can be manipulated by nanotechnology can be engineered from nearly any chemical substance. Nanoscale materials (nanomaterials, nanoparticles), 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. In contrast, fluorescent semiconductor nanocrystals (quantum dots), organic dendrimers, carbon fullerenes (“buckyballs”) and carbon nanotubes, and nanoscale metals oxides such as titanium dioxide are a few of the many examples of what are referred to as engineered nanoscale materials.

While nanomaterials are already appearing in commerce as additives or modifications to industrial and consumer products and as novel drug delivery agents, there has been only limited research on the potential toxicity of engineered nanoscale materials in vivo, mostly upon carbon nanotubes (Donaldson et al. 2006). As a result concern is growing that the promise of nanotechnology to address societal needs in energy, manufacturing, therapeutics and remediation will be impeded by our lagging knowledge about potential hazards from exposures to the diverse array of nanomaterials available (Maynard et al. 2006).

The same unusual chemical and physical properties that make nanomaterials so potentially useful also make their interactions with biological systems difficult to anticipate and study (Colvin, 2003). The unique and diverse physicochemical properties of nanoscale materials suggest that toxicological properties may differ from materials of similar composition but different size. 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 (Oberdorster et al. 2005). In part this is due to the fact that as particle size decreases, the surface area per unit mass increases. Surface properties can be changed by coating nanoscale particles with different materials, but surface chemistry also is influenced by the size of the particle.

This interaction of surface area and particle composition in eliciting biological responses adds an extra dimension of complexity in evaluating potential adverse events that may result from exposure to these materials. If biological and toxicological effects of a given nanoparticle are due to its surface then because of the greater surface area, the dose required to elicit a biological or toxicological response may be less than that of larger sized materials. In addition there are indications in the literature that engineered nanoscale materials may distribute in the body in unpredictable ways and that depending upon the surface coatings certain nanoscale materials have been observed to accumulate preferentially in particular tissues.

National Toxicology Program Nanotechnology Safety Initiative

The National Toxicology Program (NTP) is a multiagency program based at the National Institute of Environmental Health Sciences (NIEHS) that coordinates toxicology research and testing programs within the federal government and conducts research to provide information about potentially toxic chemicals to health, regulatory, and research agencies, scientific and medical communities, and the public. The NTP is engaged in a broad-based research program to address potential human health hazards associated with the manufacture and use of nanoscale materials. This initiative is driven by the intense current and anticipated future research and development focus on nanotechnology. The goal of this research program is to evaluate the toxicological properties of major nanoscale materials classes which represent a cross-section of composition, size, surface coatings, and physicochemical properties, and use these as model systems to investigate fundamental questions concerning if and how nanoscale materials can interact with biological systems.

The NTP, through its research contracts and collaborative interagency activities is conducting 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 is being 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, NTP is conducting whole animal-based studies of varying durations with specific nanomaterials using routes of administration that mimic possible human exposure. These studies include evaluations of the absorption and handling of the materials by rodents as well as the assessment of the development of adverse responses in vivo. NTP is also utilizing in vitro models to evaluate the biological and toxicological effects of nanoscale materials.

The NTP’s Nanotechnology Safety Initiative (http://ntp.niehs.nih.gov/go/nanotech) is focusing on 3 areas of research with respect to specific types or groups of nanoscale materials:

1. 1. Non-medical, commercially relevant/available nanoscale materials to which humans are intentionally being exposed, e.g., cosmetics, sunscreens and materials used in nanotechnology enabled consumer products.
2. 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. 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.

Initial research activities are focusing initially on severla classes of nanoscale materials: (1) titanium dioxide (2) fluorescent crystalline semiconductors (quantum dots), (3) fullerenes, and (4) carbon nanotubes. NTP scientists at the National Center for Toxicological Research (NCTR) NTP Center for Phototoxicity have been examining the potential dermal toxicity of nanoscale materials available in non- medical, commercially available products. For example, nanoscale titanium dioxide (TiO2) is 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 applied dermally to mice in combination with UVA- containing light affects cell signaling, and (3) the potential for TiO2 applied dermally to haired and hairless mice in combination with UVA-containing light to cause skin cancer. 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.

References

Colvin, V. L. 2003. The potential environmental impact of engineered nanomaterials. Nature Biotechnol. 21, 1166-70.

Donaldson K, Aitken R, Tran L, Stone V, Duffin R, Forrest G, Alexander A. 2006. Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety. Toxicol Sci. 92:5-22.

Maynard, A. D., Aitken, R. J., Butz, T., Colvin, V., Donaldson, K., Oberdorster, G., Philbert, M. A., Ryan, J., Seaton, A., Stone, V., Tinkle, S. S., Tran, L., Walker, N. J., and Warheit, D. B. 2006. Safe handling of nanotechnology. Nature 444, 267-9.

Oberdorster G, Oberdorster E, Oberdorster J. (2005). Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect,113, 823-39.