No abstract

Carbon nanotubes (CNT) are an important new class of technological materials that have numerous novel and useful properties. The forecast increase in manufacture makes it likely that increasing human exposure will occur, and as a result, CNT are beginning to come under toxicological scrutiny. This review seeks to set out the toxicological paradigms applicable to the toxicity of inhaled CNT, building on the toxicological database on nanoparticles (NP) and fibers. Relevant workplace regulation regarding exposure is also considered in the light of our knowledge of CNT. CNT could have features of both NP and conventional fibers, and so the current paradigm for fiber toxicology, which is based on mineral fibers and synthetic vitreous fibers, is discussed. The NP toxicology paradigm is also discussed in relation to CNT. The available peer-reviewed literature suggests that CNT may have unusual toxicity properties. In particular, CNT seem to have a special ability to stimulate mesenchymal cell growth and to cause granuloma formation and fibrogenesis. In several studies, CNT have more adverse effects than the same mass of NP carbon and quartz, the latter a commonly used benchmark of particle toxicity. There is, however, no definitive inhalation study available that would avoid the potential for artifactual effects due to large mats and aggregates forming during instillation exposure procedures. Studies also show that CNT may exhibit some of their effects through oxidative stress and inflammation. CNT represent a group of particles that are growing in production and use, and therefore, research into their toxicology and safe use is warranted.

Ultrafine particles are a component of air pollution, derived from primary combustion sources, and so we have undertaken a programme of study on the mechanisms of lung injury caused by ultrafine particles. Ultrafine particles made of low-solubility, low-toxicity materials are more inflammogenic in the rat lung than fine respirable, particles made from the same material. Ultrafine particles can cause inflammation via processes independent of the release of transition metals, as shown by the fact that soluble products from ultrafine carbon black have no ability to cause inflammation. The property that drives the greater inflammogenicity of ultrafines is unknown but very likely relates to particle surface area and involves oxidative stress. Increases in intracellular Ca(++) may underlie the cellular effects of ultrafines, although the mechanism whereby ultrafines have this effect is not understood. However, increased influx of Ca(++) into macrophages occurs via the membrane Ca(++) channels following contact with ultrafine particles, and involves oxidative stress. Increased Ca(++) in macrophages exposed to ultrafines can lead to the transcription of key pro-inflammatory genes such as TNFalpha. Ultrafine particles can also impair the ability of macrophages to phagocytose and clear other particles, and this may be pro-inflammogenic.

This review considers the molecular toxicology of combustion-derived nanoparticles (CDNP) following inhalation exposure. CDNP originate from a number of sources and in this review we consider diesel soot, welding fume, carbon black and coal fly ash. A substantial literature demonstrates that these pose a hazard to the lungs through their potential to cause oxidative stress, inflammation and cancer; they also have the potential to redistribute to other organs following pulmonary deposition. These different CDNP show considerable heterogeneity in composition and solubility, meaning that oxidative stress may originate from different components depending on the particle under consideration. Key CDNP-associated properties of large surface area and the presence of metals and organics all have the potential to produce oxidative stress. CDNP may also exert genotoxic effects, depending on their composition. CDNP and their components also have the potential to translocate to the brain and also the blood, and thereby reach other targets such as the cardiovascular system, spleen and liver. CDNP therefore can be seen as a group of particulate toxins unified by a common mechanism of injury and properties of translocation which have the potential to mediate a range of adverse effects in the lungs and other organs and warrant further research.

Objective: Rats exposed to high airborne mass concentrations of low-solubility low-toxicity particles (LSLTP) have been reported to develop lung disease such as fibrosis and lung cancer. These particles are regulated on a mass basis in occupational settings, but mass might not be the appropriate metric as animal studies have shown that nanoparticles (ultrafine particles) produce a stronger adverse effect than fine particles when delivered on an equal mass basis. Methods: This study investigated whether the surface area is a better descriptor than mass of LSLTP of their ability to stimulate pro-inflammatory responses in vitro. In a human alveolar epithelial type II-like cell line, A549, we measured interleukin (IL)-8 mRNA, IL8 protein release and glutathione (GSH) depletion as markers of pro-inflammatory effects and oxidative stress after treatment with a range of LSLTP (fine and nanoparticles) and DQ12 quartz, a particle with a highly reactive surface. Results: In all the assays, nanoparticle preparations of titanium dioxide (TiO 2 -np) and of carbon black (CBnp) produced much stronger pro-inflammatory responses than the same mass dose of fine TiO 2 and CB. The results of the GSH assay confirmed that oxidative stress was involved in the response to all the particles, and two ultra-fine metal dusts (cobalt and nickel) produced GSH depletion similar to TiO 2 -np, for similar surfacearea dose. As expected, DQ12 quartz was more inflammatory than the low toxicity dusts, on both a mass and surface-area basis. Conclusion: Dose-response relationships observed in the in vitro assays appeared to be directly comparable with dose-response relationships in vivo when the doses were similarly standardised. Both sets of data suggested a threshold in dose measured as surface area of particles relative to the surface area of the exposed cells, at around 1-10 cm 2 /cm 2 . These findings are consistent with the hypothesis that surface area is a more appropriate dose metric than mass for the pro-inflammatory effects of LSLTP in vitro and in vivo, and consequently that the high surface area of nanoparticles is a key factor in their inflammogenicity.