Toxicology of carbon nanomaterials

Fullerenes

A comprehensive and recent review on fullerene toxicity is given by Lalwani et al. These authors review the works on fullerene toxicity beginning in the early 1990s to present, and conclude that very little evidence gathered since the discovery of fullerenes indicate that C₆₀ is toxic. The toxicity of these carbon nanoparticles is not only dose and time-dependent, but also depends on a number of other factors such as: type (e.g., C₆₀, C₇₀, M@C₆₀, M@C₈₂, functional groups used to water solubilize these nanoparticles (e.g., OH, COOH), and method of administration (e.g., intravenous, intraperitoneal). The authors therefore recommend that pharmacology of every new fullerene- or metallofullerene-based complex must be assessed individually as a different compound.

Moussa et al. (1996–97) studied the in vivo toxicity of C₆₀ after intra-peritoneal administration of large doses. No evidence of toxicity was found and the mice tolerated a dose of 5 g/kg of body weight. Mori et al. (2006) could not find toxicity in rodents for C₆₀ and C₇₀ mixtures after oral administration of a dose of 2 g/kg body weight and did not observe evidence of genotoxic or mutagenic potential in vitro. Other studies could not establish the toxicity of fullerenes: on the contrary, the work of Gharbi et al. (2005) suggested that aqueous C₆₀ suspensions failing to produce acute or subacute toxicity in rodents could also protect their livers in a dose-dependent manner against free-radical damage. In a 2012 primary study of an olive oil / C₆₀ suspension administered to rats by intra-peritoneal administration or oral gavage, a prolonged lifespan to almost double the normal lifespan of the rats was seen and significant toxicity was not observed. An investigator for this study, Professor Moussa, generalized from its findings in a video interview and stated that pure C₆₀ is not toxic.

When considering toxicological data, care must be taken to distinguish as necessary between what are normally referred to as fullerenes: (C₆₀, C₇₀, ...); fullerene derivatives: C₆₀ or other fullerenes with covalently bonded chemical groups; fullerene complexes (e.g., water-solubilized with surfactants, such as C₆₀-PVP; host-guest complexes, such as with cyclodextrin), where the fullerene is supermolecular bound to another molecule; C₆₀ nanoparticles, which are extended solid-phase aggregates of C₆₀ crystallites; and nanotubes, which are generally much larger (in terms of molecular weight and size) molecules, and are different in shape to the spheroidal fullerenes C₆₀ and C₇₀, as well as having different chemical and physical properties.

The above different molecules span the range from insoluble materials in either hydrophilic or lipophilic media, to hydrophilic, lipophilic, or even amphiphilic molecules, and with other varying physical and chemical properties. Therefore, any broad generalization extrapolating for example results from C₆₀ to nanotubes or vice versa is not possible, though technically all are fullerenes, as the term is defined as a close-caged all-carbon molecule. Any extrapolation of results from one molecule to other molecules must take into account considerations based on a quantitative structural analysis relationship study (QSARS), which mostly depends on how close the molecules under consideration are in physical and chemical properties.

Carbon nanotubes

With reference to nanotubes, a 2008 study on carbon nanotubes introduced into the abdominal cavity of mice led the authors to suggest comparisons to "asbestos-like pathogenicity". It should be noted that this was not an inhalation study, though there have been several performed in the past, therefore it is premature to conclude that nanotubes should be considered to have a toxicological profile similar to asbestos. Conversely, and perhaps illustrative of how the various classes of molecules which fall under the general term fullerene cover a wide range of properties, Sayes et al. found that in vivo inhalation of C₆₀(OH)₂₄ and nano-C₆₀ in rats gave no effect, whereas in comparison quartz particles produced an inflammatory response under the same conditions. As stated above, nanotubes are quite different in chemical and physical properties to C₆₀, i.e., molecular weight, shape, size, physical properties (such as solubility) all are very different, so from a toxicological standpoint, different results for C₆₀ and nanotubes are not suggestive of any discrepancy in the findings.

Toxicity

The toxicity of carbon nanotubes has been an important question in nanotechnology. As of 2007, such research had just begun. The data is still fragmentary and subject to criticism. Preliminary results highlight the difficulties in evaluating the toxicity of this heterogeneous material. Parameters such as structure, size distribution, surface area, surface chemistry, surface charge, and agglomeration state as well as purity of the samples, have considerable impact on the reactivity of carbon nanotubes. However, available data clearly show that, under some conditions, nanotubes can cross membrane barriers, which suggests that, if raw materials reach the organs, they can induce harmful effects such as inflammatory and fibrotic reactions.

Under certain conditions CNTs can enter human cells and accumulate in the cytoplasm, causing cell death.

Results of rodent studies collectively show that regardless of the process by which CNTs were synthesized and the types and amounts of metals they contained, CNTs were capable of producing inflammation, epithelioid granulomas (microscopic nodules), fibrosis, and biochemical/toxicological changes in the lungs. Comparative toxicity studies in which mice were given equal weights of test materials showed that SWCNTs were more toxic than quartz, which is considered a serious occupational health hazard when chronically inhaled. As a control, ultrafine carbon black was shown to produce minimal lung responses.

Carbon nanotubes deposit in the alveolar ducts by aligning lengthwise with the airways; the nanotubes will often combine with metals. The needle-like fiber shape of CNTs is similar to asbestos fibers. This raises the idea that widespread use of carbon nanotubes may lead to pleural mesothelioma, a cancer of the lining of the lungs, or peritoneal mesothelioma, a cancer of the lining of the abdomen (both caused by exposure to asbestos). A recently published pilot study supports this prediction. Scientists exposed the mesothelial lining of the body cavity of mice to long multiwalled carbon nanotubes and observed asbestos-like, length-dependent, pathogenic behavior that included inflammation and formation of lesions known as granulomas. Authors of the study conclude:

This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products under the assumption that they are no more hazardous than graphite. Our results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided.

Although further research is required, the available data suggest that under certain conditions, especially those involving chronic exposure, carbon nanotubes can pose a serious risk to human health.

In 2014, experts from the International Agency for Research on Cancer (IARC) assessed the carcinogenicity of CNTs, including SWCNTs and MWCNTs. No human epidemiologic or cancer data was available to the IARC Working Group at the time, so the evaluation focused on the results of in vivo animal studies assessing the carcinogenicity of SWCNTs and MWCNTs in rodents.

The Working Group concluded that there was sufficient evidence for the specific MWCNT type “MWCNT-7”, limited evidence for the two other types of MWCNTs with dimensions similar to MWCNT-7, and inadequate evidence for SWCNTs. Therefore, it was agreed to specifically classify MWCNT-7 as possibly carcinogenic to humans (Group 2B) while the other forms of CNT, namely SWCNT and other types of MWCNT, excluding MWCNT-7, were considered not classifiable as to their carcinogenicity to humans (Group 3) due to a lack of coherent evidence.

Epidemiology and Risk Management

Currently, there is a lack of epidemiological evidence linking exposure to CNT to human health effects. To date, there have been only a handful of published epidemiological studies that have solely examined the health effects related to the exposure of CNT, while several other studies are currently underway and yet to be published. With the limited amount of human data, scientists are more reliant on the results of current animal toxicity studies to predict adverse health effects, as well as applying what is already known about exposures to other fibrous materials such as asbestos or fine and ultra-fine particulates. This limitation of human data has led to the use of the precautionary principle, which urges workplaces to limit exposure levels to CNT as low as possibly achievable in the absence of known health effects data.

To date, several international government agencies, as well as individual authors, have developed occupational exposure limits (OEL) to reduce the risk of any possible human health effects associated with workplace exposures to CNT. The National Institute for Occupational Safety and Health (NIOSH) conducted a risk assessment using animal and other toxicological data relevant to assessing the potential non-malignant adverse respiratory effects of CNT and proposed an OEL of 1 μg/m³ elemental carbon as a respirable mass 8-hour time-weighted average (TWA) concentration. Several individual authors have also performed similar risk assessments using animal toxicity data and have established inhalation exposure limits ranging from 2.5 to 50 ug/m³.

Safety and Exposure Prevention

Occupational exposures that could potentially allow the inhalation of CNT is of the greatest concern, especially in situations where the CNT is handled in powder form which can easily be aerosolized and inhaled. Also of concern are any high-energy processes that are applied to various CNT preparations such as the mixing or sonication of CNT in liquids as well as processes that cut or drill into CNT based composites in downstream products. These types of high-energy processes will aerosolize CNT which can then be inhaled.

Guidance for minimizing exposure and risk to CNT have been published by several international agencies which includes several documents from the British Health and Safety Executive titled "Using nanomaterials at work Including carbon nanotubes and other bio-persistent high aspect ratio nanomaterials" and the "Risk Management of Carbon Nanotubes" Safe Work Australia has also published guidance titled "Safe Handling and use of Carbon Nanotubes" which describes two approaches to managing the risks that include risk management with detailed hazard analysis and exposure assessment as well as risk management by using Control Banding. The National Institute for Occupational Safety and Health has also published a document titled "Current Intelligence Bulletin 65: Occupational Exposure to Carbon Nanotubes and Nanofibers" describes strategies for controlling workplace exposures and implementing a medical surveillance program.

These guidance documents generally advocate instituting the principles of the Hierarchy of Hazard Control which is a system used in industry to minimize or eliminate exposure to hazards. The hazard controls in the hierarchy are, in order of decreasing effectiveness:

• Elimination
• Substitution
• Engineering Controls
• Administrative Controls
• Personal Protective Equipment