Nanotoxicology

Metal based nanoparticles (NPs) are a prominent class of NPs synthesized for their functions as semiconductors, electroluminescents, and thermoelectric materials.[12] Biomedically, these antibacterial NPs have been utilized in drug delivery systems to access areas previously inaccessible to conventional medicine. With the recent increase in interest and development of nanotechnology, many studies have been performed to assess whether the unique characteristics of these NPs, namely their large surface area to volume ratio, might negatively impact the environment upon which they were introduced.[13] Researchers have found that some metal and metal oxide NPs may affect cells inducing DNA breakage and oxidation, mutations, reduced cell viability, warped morphology, induced apoptosis and necrosis, and decreased proliferation.[12] Moreover, metal nanoparticles may persist in the organisms after administration if not carefully engineered.[14]

The latest toxicology studies on mice as of 2013 involving exposure to carbon nanotubes (CNT) showed a limited pulmonary inflammatory potential of MWCNT at levels corresponding to the average inhalable elemental carbon concentrations observed in U.S.-based CNT facilities. The study estimated that considerable years of exposure are necessary for significant pathology to occur.[15]

One review concludes that the evidence gathered since the discovery of fullerenes overwhelmingly points to C₆₀ being non-toxic. As is the case for toxicity profile with any chemical modification of a structural moiety, the authors suggest that individual molecules be assessed individually.[16]

Other classes of nanomaterials include polymers such as nanocellulose, and dendrimers.

There are many ways that size can affect the toxicity of a nanoparticle. For example, particles of different sizes can deposit in different places in the lungs, and are cleared from the lungs at different rates. Size can also affect the particles' reactivity and the specific mechanism by which they are toxic.[17]

Nanomaterials present in aerosol particles are often in an agglomerated or aggregated state, which affects their toxicological properties. The examples shown here are silver nanoparticles, nickel nanoparticles, and multiwalled carbon nanotubes.

Many nanoparticles agglomerate or aggregate when they are placed in environmental or biological fluids. The terms agglomeration and aggregation have distinct definitions according to the standards organizations ISO and ASTM, where agglomeration signifies more loosely bound particles and aggregation signifies very tightly bound or fused particles (typically occurring during synthesis or drying). Nanoparticles frequently agglomerate due to the high ionic strength of environmental and biological fluids, which shields the repulsion due to charges on the nanoparticles. Unfortunately, agglomeration has frequently been ignored in nanotoxicity studies, even though agglomeration would be expected to affect nanotoxicity since it changes the size, surface area, and sedimentation properties of the nanoparticles. In addition, many nanoparticles will agglomerate to some extent in the environment or in the body before they reach their target, so it is desirable to study how toxicity is affected by agglomeration.

The agglomeration/deagglomeration (mechanical stability) potentials of airborne engineered nanoparticle clusters also have significant influences on their size distribution profiles at the end-point of their environmental transport routes. Different aerosolization and deagglomeration systems have been established to test stability of nanoparticle agglomerates.

NPs, in their implementation, are covered with coatings and sometimes given positive or negative charges depending upon the intended function. Studies have found that these external factors affect the degree of toxicity of NPs.

A scanning electron microscope image of bundles of multiwalled carbon nanotube piercing an alveolar epithelial cell.

Inhalation exposure is the most common route of exposure to airborne particles in the workplace. The deposition of nanoparticles in the respiratory tract is determined by the shape and size of particles or their agglomerates, and they are deposited in the lungs to a greater extent than larger respirable particles. Based on animal studies, nanoparticles may enter the bloodstream from the lungs and translocate to other organs, including the brain.[18] The inhalation risk is affected by the dustiness of the material, the tendency of particles to become airborne in response to a stimulus. Dust generation is affected by the particle shape, size, bulk density, and inherent electrostatic forces, and whether the nanomaterial is a dry powder or incorporated into a slurry or liquid suspension.[19]

Animal studies indicate that carbon nanotubes and carbon nanofibers can cause pulmonary effects including inflammation, granulomas, and pulmonary fibrosis, which were of similar or greater potency when compared with other known fibrogenic materials such as silica, asbestos, and ultrafine carbon black. Some studies in cells or animals have shown genotoxic or carcinogenic effects, or systemic cardiovascular effects from pulmonary exposure. Although the extent to which animal data may predict clinically significant lung effects in workers is not known, the toxicity seen in the short-term animal studies indicate a need for protective action for workers exposed to these nanomaterials. As of 2013, further research was needed in long-term animal studies and epidemiologic studies in workers. No reports of actual adverse health effects in workers using or producing these nanomaterials were known as of 2013.[20] Titanium dioxide (TiO₂) dust is considered a lung tumor risk, with ultrafine (nanoscale) particles having an increased mass-based potency relative to fine TiO₂, through a secondary genotoxicity mechanism that is not specific to TiO₂ but primarily related to particle size and surface area.[21]

Some studies suggest that nanomaterials could potentially enter the body through intact skin during occupational exposure. Studies have shown that particles smaller than 1 μm in diameter may penetrate into mechanically flexed skin samples, and that nanoparticles with varying physicochemical properties were able to penetrate the intact skin of pigs. Factors such as size, shape, water solubility, and surface coating directly affect a nanoparticle's potential to penetrate the skin. At this time, it is not fully known whether skin penetration of nanoparticles would result in adverse effects in animal models, although topical application of raw SWCNT to nude mice has been shown to cause dermal irritation, and in vitro studies using primary or cultured human skin cells have shown that carbon nanotubes can enter cells and cause release of pro-inflammatory cytokines, oxidative stress, and decreased viability. It remains unclear, however, how these findings may be extrapolated to a potential occupational risk.[18][20] In addition, nanoparticles may enter the body through wounds, with particles migrating into the blood and lymph nodes.[22]

Ingestion can occur from unintentional hand-to-mouth transfer of materials; this has been found to happen with traditional materials, and it is scientifically reasonable to assume that it also could happen during handling of nanomaterials. Ingestion may also accompany inhalation exposure because particles that are cleared from the respiratory tract via the mucociliary escalator may be swallowed.[18]

For some types of particles, the smaller they are, the greater their surface area to volume ratio and the higher their chemical reactivity and biological activity. The greater chemical reactivity of nanomaterials can result in increased production of reactive oxygen species (ROS), including free radicals. ROS production has been found in a diverse range of nanomaterials including carbon fullerenes, carbon nanotubes and nanoparticle metal oxides. ROS and free radical production is one of the primary mechanisms of nanoparticle toxicity; it may result in oxidative stress, inflammation, and consequent damage to proteins, membranes and DNA.[11] For example, the application of nanoparticle metal oxide with magnetic fields that modulate ROS leading to enhanced tumor growth.[2]

A primary marker for the damaging effects of NPs has been cell viability as determined by state and exposed surface area of the cell membrane. Cells exposed to metallic NPs have, in the case of copper oxide, had up to 60% of their cells rendered unviable. When diluted, the positively charged metal ions often experience an electrostatic attraction to the cell membrane of nearby cells, covering the membrane and preventing it from permeating the necessary fuels and wastes.[12] With less exposed membrane for transportation and communication, the cells are often rendered inactive.

NPs have been found to induce apoptosis in certain cells primarily due to the mitochondrial damage and oxidative stress brought on by the foreign NPs electrostatic reactions.[12]

Metal and metal oxide NPs such as silver, zinc, copper oxide, uraninite, and cobalt oxide have also been found to cause DNA damage.[12] The damage done to the DNA will often result in mutated cells and colonies as found with the HPRT gene test.