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Engineered nanomaterials (ENs) comprise a diverse suite of structures manufactured from a range of distinct components that are having an ever-increasing number of applications in industry, commerce and medicine (Figure 1). ENs reported to be produced in the largest quantities include TiO2, SiO2, ZnO, AlOx, FeOx, silver, carbon nanotubes, fullerenes and quantum dots, at levels ranging from 0.5 – 5,500 tonnes/year worldwide . The negative impact of ENs on the environment and human health due to off-target effects is of major concern and requires ongoing investigation. A recent database (NanoE-Tox), compiled from 224 articles published over the preceding decade, was created in order to obtain an overview of the environmental effects of eight chemically distinct ENs where toxicity toward crustaceans (Daphnia magna), fish, algae or bacteria was the primary readout . The purposes of such databases are to: 1) gain an understanding of the relative toxicities of various ENs and how these relate to their physicochemical properties, 2) decipher the mechanism(s) by which their toxicities occur and, 3) provide an alternative to ethically questionable, time consuming and costly animal studies, through the development of predictive models that derive from these databases. NanoE-Tox reported the most ecotoxic ENs to be made from silver, followed by ZnO and CuO, with the primary mechanism of toxicity of these ENs being dissolution of ions, however, direct cell membrane damage, oxidative stress and genotoxicity were also potentially contributing factors for Ag and ZnO ENs. A lack of sufficient information regarding the various physicochemical parameters (primary size, shape, surface charge, surface area) meant that their contributions to cytotoxicity could not be conclusively defined.
There is currently a dearth of empirical data published concerning the impact of ENs, and the influence of their various physicochemical parameters, on human health. Nevertheless, since the lungs are one of the primary routes of inadvertent entry of ENs there has been an increasing number of studies using human lung cells in vitro to determine the potential of ENs to cause inflammation, genotoxicity, oxidative stress or cytotoxicity. Although in vitro data often cannot substitute for results obtained in vivo, it has been shown to be feasible in specific circumstances. For example, an in vitro model assessing the pro-inflammatory potential of ultrafine particles on the bronchoalveolar adenocarcinoma-derived lung cell line, A549, generated findings strongly correlative with in vivo results . Additionally, in vitro studies assessing the cytotoxicity of CuO ENs (and ZnO ENs) on A549 cells were shown to correlate well with in vivo effects on lungs . At this stage the paucity of in vitro data assessing the impact of ENs on lung cells places limitations on the understanding of how EN mediate their cytotoxic effects. Whilst a picture is developing of these mechanisms, it is predominantly derived from studies of ENs using one cell line, A549 (Figure 2), and therefore more studies using other lung cell lines, preferably in parallel, are required (Figure 3). In lieu of waiting for exhaustive data on their effects on human health, certain ENs are surface modifiable such that their impact on human health could be significantly reduced. For instance, we have recently demonstrated that surface modifying amorphous silica nanoparticles (~50 nm diameter) with amine groups reduced their ability to promote inflammatory responses in mice lungs . This modification made no significant change in the size of these ENs and is believed to reduce their oxidative potential by decreasing the amount of exposed surface silanol groups.
It is becoming increasingly apparent that each EN formulation requires testing for potential harm to health as opposed to invoking generalized assumptions since the alteration of one physicochemical parameter within the formulation can have a significant impact on downstream biological processes. As an example, we have recently shown that CuO ENs (nanoparticles), physically and chemically similar in all respects apart from size (4 nm versus 24 nm) had significantly different impacts on viability of, and ROS production in, lung cells . The finding that 4 nm CuO NPs were less toxic than 24 nm CuO NP coincided with lower intracellular levels of Cu for the former suggesting that the smaller NPs (on a per weight basis) were less readily taken up by the lung cells in vitro. These results are in contrast with expectations based on findings with ENs made from other metals such as TiO2 (size range 14 – 196 nm), Au (1.4 nm versus 15 nm; 10 – 50 nm versus 100 – 200 nm) and Ag (15 – 55 nm) where smaller ENs correlated with higher cytotoxicity and highlights that each EN requires intensive analysis in regards to its potentially deleterious biological effects . Understanding the impact of EN on lung tissue function and health would also pave the way for potentially useful nanomedicines, particularly those aimed at local delivery of drugs to lung cancer patients. Currently, however, there is understandable reluctance in the medical community to use inhalation delivery of EN-based nanomedicines particularly for less life-threatening lung pathologies, such as asthma, and this is primarily due to the knowledge gap with respect to the harmful effects of these potential nanomedicines on patients as well as occupational health concerns. Recently, a promising EN-based vaccine was developed in our laboratory to prevent dust mite-induced asthma . The vaccine comprising a house dust mite antigen, Der p2, and the Toll-like receptor-9 agonist, CpG oligodeoxynucleotide, co-loaded into nanoparticles (300 nm) made from the biodegradable, non-toxic and FDA-approved polymer poly(lactic-co-glycolic acid), was administered subcutaneously rather than via the lungs and was shown to be effective in a mouse model of dust mite-induced asthma, demonstrating protection against Der p2-induced airway hyperresponsiveness and allergic airway inflammation. It is, however, evident that certain lung pathologies, such as lung cancer, will benefit from direct delivery of ENs to the lungs via, for example inhalation local delivery . In summation, with the inevitable role that nanomedicines are to play, combined with the increased production of ENs for consumer and industrial applications, there is an onus on the scientific community to vigilantly interrogate, in a considered and multidisciplinary fashion, the potential hazards of ENs to both human health and the environment.