How Meaningful are the Results of Nanotoxicity Studies in the Absence of Adequate Material Characterization?

Abstract

For the very few people who may not have an understanding of nanotechnology, here is a quick overview. Nanotechnology is an emerging multidisciplinary technology that involves the synthesis of molecules in the nanoscale (i.e., 10−9 m) size range. The origin of the term “nanotechnology” is derived from the Greek word “nano,” meaning ”dwarf.” From a chemistry and material science perspective, the development of new products using nanomaterials is exciting because, for a given particle-type, as one moves down the nanoscale (i.e., as the particle size is decreased within the nanoscale range), fundamental physical and chemical properties appear to change—often yielding completely new and different physical/chemical properties. For example, titanium dioxide particle-types, lose their white color and become colorless at decreasing size ranges < 50 nm. Other particle-types, known for electrical insulating properties, may become conductive at the nanoscale; or insoluble substances can become more soluble below 100 nm. Accordingly, these alterations in physical properties have generated great interest in this new technology (Colvin, 2003). Given the excitement associated with all of the nanotechnology applications, evaluating the potential hazards related to exposures to nanoscale materials and its products has become an emerging area in toxicology and health risk assessment. The development of a safety database for nanoscale particles is evolving as new particles, materials, and exposure methodologies are being developed (i.e., implications research). Nanoparticle-types (often defined as < 100 nm in one dimension) may have different health impacts when compared to fine-sized (bulk) particle-types of similar chemical composition. In this regard, data from some pulmonary toxicity studies in rats demonstrate that exposures to ultrafine/nanoparticles produce enhanced toxicity responses when compared with larger-sized particles of similar chemical composition (Donaldson et al., 2001; Oberdorster, 2000). Particle surface area and particle number determinations have been postulated to play significant roles in the development of nanoparticle-related lung toxicity. In particular, some reports indicate that inhaled ultrafine/nanoparticles, following deposition in the alveolar regions of the lung, largely escape alveolar macrophage surveillance and transmigrate to the pulmonary interstitium or the systemic circulation following deposition in the alveolar regions of the lung (Donaldson et al., 2001; Oberdorster, 2000). Alternatively, other recent studies indicate that the toxicity of some nanoparticulates may be related, in large part, to the surface reactivity of the particles, indicating that the particle surface–cellular interactions may take precedence over the core particle or particle size/surface area per se in influencing the development of inflammatory and cytotoxic responses in the lung (Warheit et al., 2007a,b). Particle surface and interfaces are important components of nanoscale materials. As the particle size is reduced, the proportion of atoms found at the surface is enhanced relative to the proportion inside its volume. This results in nanoscale particles, which are likely to be more reactive, thus generating more effective catalysts from an applications standpoint. However, from a health implications perspective, reactive groups on a particle surface are likely to modify the biological (potentially toxicological) effects. Therefore, changes in surface chemistry forming the “shell” on a (core) nanoparticle-type may be important and relevant for health effects. In addition, surface coatings can be utilized to alter surface properties of nanoparticles to prevent aggregation or agglomeration with different particle-types, and/or can serve to “passivate” the particle-type to mitigate the effects of ultraviolet radiation induced reactive oxidants. It is interesting to note that surface coatings, functioning to reduce aggregation and to facilitate particle dispersion, enhance the efficacy of the particle-type in its designed application, but may also accelerate translocation of the nanoparticle from the respiratory tract to the systemic circulation and thereby significantly increase nanoparticle distribution throughout the body (Borm et al., 2006; Oberdorster et al., 2005). To capture this concept of the importance of nanoparticle core-shell dynamics, it should be noted that from a toxicological perspective, two different nanoparticle-types containing titanium dioxide as their “core” may not be biologically equivalent. There can be differences in crystal structures (anatase vs. rutile), surface reactivity, aggregation status, particle size distribution, surface area, as well as surface coatings—including passivation and neutralization. These physicochemical differences are manifested in different pulmonary inflammatory and cytotoxic effects ranging from benign to more moderate health impacts (Warheit et al., 2007b).