The objective of this scoping review was to ascertain the distribution of the current literature on the human and environmental impacts of nanoparticles. Specifically, in this review, we synthesised evidence regarding the exposure pathways and types of nanoparticles that have been researched and the ones that have not, as well as the biomarkers that have been used in assessing human and environmental impact of exposure to nanoparticles.
While the majority of studies originated from Europe and Central Asia, the United States of America (USA) alone recorded the highest number of publications. This finding is not surprising, as the USA has continuously fostered the development of nanotechnology through significant investments in research and development in this area. In 2016, the USA was projected to account for almost one-third of total global nanotechnology research funding [136]. Moreover, the USA and the European Union have over the years taken a committed approach towards enhancing the health and safety of nanoparticles [137]. As part of this commitment, annual meetings are held, where researchers discuss topics relating to nano-safety, as well as funding priorities and research needs.
While there have been some investments in nanotechnology research in African countries (including Egypt and South Africa), a recent publication by the United Nations Economic Commission for Africa (UNECA) indicates that the African continent, relative to other continents, is lagging behind with regards to nanotechnology research [138]. This assertion is consistent with the findings of this review, which found only one study originating from North Africa (Egypt), with no study conducted in Sub-Saharan Africa.
Over the past two decades, there have been increasing public awareness of nanotechnology and a growing concern about its commercial applications [139]. This has led to rapidly increasing scientific publications in this field, especially from early 2000s [140]. It is, therefore, not surprising that the studies included in this scoping review were published from the year 2006. Indeed, a literature search of nanotechnology publications by Huang et al. [140] revealed over 50,000 publications for the year 2006.
Although the included studies investigated a wide range of nanoparticles, most of them focused on inorganic-based nanoparticles (e.g., zinc oxide, titanium dioxide, copper oxide, and silica), followed by carbon-based nanoparticles (e.g., carbon-nanotubes, fullerenes, and graphene) (Table 3). This finding is consistent with previous reviews that have reported extensive investigation into the impact of inorganic-based and/or carbon-based nanoparticles [141, 142]. These nanoparticles may have gained attention due to their extensive production and usage. In addition to their use for cancer treatment, inorganic and carbon-based nanoparticles provide significant benefits in photothermal therapy, diagnosis, tissue engineering, imaging contrast agents, and sensing applications [143]. This is due to their unique physical and chemical properties (such as electrical, thermal, structural, mechanical, and optical diversity), which make them stronger, flexible, and more electrically conductible towards several biological entities [141, 144]. The advantages of, for example inorganic-based nanoparticles, including their high reactivity, small size and good capacity have been found to induce adverse harmful effects in both humans and the environment.
In this review, a number of approaches were used by included studies to assess the toxicity of nanoparticles. However, the majority of the studies applied the in vitro method, perhaps because in vitro studies are time saving and cost-effective. Nonetheless, the in vitro approach has been criticised by researchers (e.g., Bahadar et al. [145]) for producing varying results in different laboratories.
The included studies used differing methods in assessing cytotoxicity and genotoxicity: cell membrane integrity was assessed with Lactate dehydrogenase (LDH) assays [44, 57, 116]; cell viability was assessed using tetrazolium reduction assays [82, 83, 90, 116]; apoptosis was assessed using immunohistochemistry biomarkers [60, 65, 86]; electron microscopy was used to assess intracellular localisation of nanoparticles [34, 106]; and cell inflammation was estimated using chemokines biomarkers (i.e., IL-8, TNF- α, and IL-6) [146]. Compounds such as MTT, XTT, MTS, and WST-1 are used to detect viable cells [147]. However, in the current review, most of the studies employed MTT tetrazolium assays for investigating cell toxicity [47, 49, 50, 58, 116]. Similar findings have been reported by Bahadar et al. [145] who conducted a review on the toxicity of nanoparticles.
Most of the studies in this review focused on assessing the characteristics of nanoparticles, as well as the impact of nanoparticles on, particularly, human health. In recent years, there have been promising results from the application of nanoparticles to human health, especially in cancer treatment. This is due to the potential of nanoparticles to provide innovative solutions to curb the limitations of traditional treatment methods, including radiotherapy and chemotherapy [148]. Relative to conventional cancer treatment methods, nanoparticle-based drug delivery systems have been shown to have significant advantages in a) drug resistance, b) correctly targeting tumour cells, c) having good pharmacokinetics, and d) reduction of treatment side effects [149]. Notwithstanding these benefits, however, nanoparticles have potential harmful effects, and there are controversies about their safe use in humans [139]. This has undoubtedly led to the rapidly growing number of studies investigating the human health impact of nanoparticles, as was revealed in this review.
The majority of the studies (n = 90) in this review used immortalised cell lines as the biomarker for assessing human health impact of nanoparticles, and only 22 studies used primary cells as biomarkers. Immortalised cell lines have mostly been used for nano-safety studies because, relative to primary cells, they are generally less expensive, readily accessible, and easier to cultivate [150]. However, the type of cell that is used as biomarker for nano-safety studies is of great importance since this may have an impact on the general outcome of studies [151]. Cancer cell lines, for example, have a disturbed anti-apoptotic balance, and have undergone transformation in metabolism, which impacts their ability to sustain their high rate of proliferation [152]. As such, using these cells may have an impact on study findings. Nonetheless, the use of primary cells in nano-safety studies, are not without limitations. Primary cells have limited lifespan in vitro and can suffer from clonal changes.
In using immortalised cell lines, several studies [153, 154]) have reported variations in findings regarding nanoparticle-induced effects in cell lines obtained from different species or tissues. For example, Zhang et al. [153] and Mukherjee et al. [154] investigated the effect of exposure to silver nanoparticle on mammalian cells. Zhang et al. [153] used epithelial cells and microphages, and Mukherjee et al. [154] used the human dermal and cervical cell lines as biomarkers. Mukherjee et al. [154] reported nanoparticle-induced cytotoxicity such as elevated levels of oxidative stress, cell membrane damage, and glutathione depletion, whereas Zhang et al. [153] reported effects including changes in antioxidant defence and metallothionein. Moreover, while Ekstrand-Hammarstrom et al. [155] and Kermanizadeh et al. [156] have compared the effect of nanoparticles on immortalised cell lines versus primary cells of the same species and tissues, available data regarding the relative effectiveness of these two types of cells are unclear. Therefore, it is difficult to make explicit conclusions as to which of these two types of cells can be used as a reliable biomarker for nano-safety studies.
This review has revealed that humans are exposed to nanoparticles through inhalation, ingestion, or dermal route. After their exposure, nanoparticles induce toxic effects such as production of oxidative stress at the exposure site, inflammation, DNA damage, and cell death [87, 88]. For instance, exposure of human neuroblastoma (Sh-sy5y) cells to inorganic nanoparticles, such as titanium dioxide, silica dioxide, and silver are associated with induction of neurotoxicity, membrane damage, reaction oxygen specie formation, decrease in cell viability, and autophagy dysfunction [40]. Similarly, exposure to carbon-based nanoparticles such as single and multi-walled carbon nanotubes reduce cell viability, as well as induce changes in cell structure, cell cycle, and cell-to-cell interactions in human lung epithelial cells (BEAS-2B) [107].
The findings of this scoping review indicate a gap in the literature regarding environmental impact of nanoparticles. Out of the 117 included studies, only 5 had assessed the environmental impact of exposure to nanoparticles. This significant gap in the scientific literature has been highlighted by authors such as Bundschuh et al. [157]. The growing production and usage of nanoparticles has undoubtedly led to a diversification of emission sources into both the aquatic and soil environment. Nanoparticles enter the environment mainly through three emission scenarios: a) released during production of nano-enabled products and raw materials, b) during application, and c) following disposal of products containing nanoparticles [158]. These emissions occur either indirectly through systems such as landfills or wastewater treatment plants, or directly to the environment. Nonetheless, nanoparticles are mostly released during the application phase and following disposal [159]. Indeed, during production, only about 2% of the production volume is emitted [160]. The studies in this review used biomarkers such as soil samples and soybean seeds, zebrafish larvae, fish, and Daphnia magna neonates. This finding is in line with a previous review by Bundschuh et al. [157], which explored the effects of nanoparticles on the environment.
In this review, every effort was made to reduce bias. The search strategy was developed by experts of the review team with many years of experience in conducting systematic/scoping reviews. A comprehensive search of multiple relevant databases and other resources was conducted by one review author (EAK) and a rerun of the searches was done after 4 weeks of the initial search. Two authors (EAK and RF or PB and SH) independently screened the search results, and disagreements between reviewers were resolved by FVZ or TP.
The main limitation of this review is that the searches were limited to studies published in the English language. This may have led to the exclusion of potentially relevant papers published in other languages. Also, searches were restricted to studies published from the year 2000, which may have led to the omission of potentially relevant papers.
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