Toxicity nanomaterials-induced

The mechanisms of engineered photoactive nanomaterials-induced toxicity apply only partially to amorphous silica nanoparticles, mainly because their composition and structure differ from those of quantum dots, metal nanoparticles, carbon nanotubes and quartz nanoparticles. The amorphous structure and nontoxic composition provide amorphous siUca nanoparticles with a significant advantage-that is, the nanoparticle has a relatively low toxicity compared to the above-mentioned photoactive nanomaterials. Until now, studies on the toxicity of siUca nanopartides have been reported both in vitro and in vivo, as discussed below. 

In Vitro Studies of Silica Nanomaterials-induced Toxicity... 

Although the toxidties of silica nanomaterials have been investigated widely in vitro, these studies may not reflect the true scenario, as would occur with in vivo exposure. For example, a low efficiency of endocytosis might lead to a low cyto-toxidty in vitro, while severe chronic toxicity may be induced in the evacuation process. Therefore, in vivo studies are necessary in order to evaluate silica nanomaterials-induced toxicity. 

Pulmonary exposure is the most popular route for in vivo investigations of nanomaterials-induced toxidty. In order to better understand the toxic effect of amorphous silica nanomaterials, the nanomaterials were instilled into the respiratory tract [38, 44—46, 100] and, after a period of treatmenf the acute and subacute pulmonary toxic effects were monitored. However, this phenomenon was an induced transient toxicity, and pulmonary function was fully recovered after several days post-exposure. Compared to the persistent pulmonary inflammation caused by crystalline silica nanomaterials, the negative effect of amorphous silica nanomaterials was considered insignificant. 

The duration of treatment with nanomaterials in living systems is another important factor that affects silica nanomaterial-induced toxicity. Whilst for in vitro studies a greater toxicity was observed with a prolonged treatment (several days)... 

The size of the nanomaterial greatly influences its toxicity particularly as the nanomaterial s size decreases, certain of its parameters changed [3, 11, 118, 119]. Many studies have shown that variations in the size of nanomaterials account for the different toxicity levels between nanosized and micrometer-sized materials [97, 99,100,103], It is known that a reduction in size can increase the rate of uptake and translocation of silica nanomaterials in vitro and in vivo, thereby inducing a more severe and transient toxicity [56]. 

However, the exceptional size-specific behavior of nanomaterials in combination with their relatively large surface-to-volume ratio might result in potential risk for human health and the environment [26-28]. For example, fullerene (C60) particles suspended in water are characterized by antibacterial activity against Escherichia coli and Bacillus subtilis [29] and by cytotoxicity to human cell lines [30]. Single- and multiwalled carbon nanotubes (CWCNTs and MWCNTs) are toxic to human cells as well [31, 32]. Nano-sized silicon oxide (Si02), anatase (Ti02), and zinc oxide (ZnO) can induce pulmonary inflammation in rodents and humans [33-35],... 

Mesenchymal stem cells isolated from murine bone marrow were applied in a study designed to evaluate the molecular toxicity of hydroxyapatite nanoparticles (Remya et al., 2014). Hydroxyapatite nanoparticles (50 nm) were used to study the cytotoxicity, nanoparticle uptake, effect on cytoskeletal arrangement, oxidative stress response and apoptotic behaviour with the confluent cells as per standard protocols. The results of the MTT assay indicated that hydroxyapatite nanoparticles do not induce cytotoxicity up to 800 pg ml-1. It was also observed that apoptosis related to oxidative stress and reactive oxygen species (ROS) production following nanoparticle treatment was comparable to that of the control (cells without treatment). Hence, it can be concluded that mesenchymal stem cell in vitro cultures can be used as a model to evaluate the potential toxicity of nanomaterials. 

Markers for cytotoxicity not measured from the BAL include cytokines. Cytokines are proteins that indicate specific types of cellular responses. Monitoring various cytokine levels in exposure studies can provide information about cells that are targeted because each cytokine possesses a specific function. There are more than 18 cytokines that have been identified, and cytokines commonly examined in toxicity studies can be grouped into pro-inflammatory, anti-inflammatory, and cell proliferation and differentiation stimuli subsets (47). Measuring cytokine levels along with BAL fluid markers allows a better understanding of the types of cells being activated and the types of injuries induced by the introduction of the nanomaterial. 

Evidence indicates exposure to nanoparticles can induce an inflammatory response in the CNS. For example, when a sample of mice were exposed to airborne particle matter, increased levels of pro-inflammatory cytokines (TNF-a IL-la), transcription factor, and nuclear factor-kappa beta (NF-k/3) were observed (114). TNF-a serves a neuroprotective function (115), but given certain pathogens TNF-a can be neurotoxic (116-120). IL-a activates cyclooxygenase (COX)-2, phospholipase A2, and inducible nitric oxide synthase (iNOS) activity, which are all associated with inflammation and immune response (121). IL-a is also partially responsible for increasing the permeability of the blood-brain barrier (122, 123). Thus, there is great interest in better understanding how nanoparticles enter the body and translocate as this will impact all organs and thus the toxicity of nanomaterials. 

A great number of opposing results have been reported for the cytotoxicity of both bare and surface-modified iron oxide nanoparticles, and the well-known debate on whether iron oxide nanoparticles are biocompatible or toxic at a variety of doses still remains [29]. Similarly, many smdies support that SiO nanoparticles with a size range from the nanometer to submicron are not toxic and SiO has been used as a nontoxic, negative control in cytotoxicity smdies of other nanomaterials [30]. But there are also smdies showing that SiO nanoparticles of 21 and 48 nm can induce oxidative stress, cell damage, and eventually apoptosis in hepatic and myocardial cells [31,32]. 

Cellular uptake is an important process by which cells internalize substances such as nutrients, proteins and foreign materials, and therefore plays an important role in ceU-nanomaterial interactions. The endocytic pathways for the internalization of substance include phagocytosis, macropinocytosis, clathrin-mediated endocytosis, and non-clathrin-mediated endocytosis [54,55], all of which are closely related to the host responses addressed in the previous section. However, cellular uptake of a material does not necessarily implicate toxicity. But due to exceptionally small size and large surface area, cellular uptake of nanomaterials is different from that of conventional micron materials, which probably induce altered toxicological effects and, thus, needs to be studied. 

In in vivo studies, the induced toxicity of silica nanomaterials is transient, with the level of apoptosis, neutrophil and macrophage counts andcytokine/chemokine expressions returning to normal between one week and one month of recovery. 

Dopants may also leak from the silica matrix, and if this occurs then the toxicity of the silica nanomaterials will be altered. However, under certain circumstances, leakage can be deliberately induced, an example being in the case of drug delivery. Here, anticancer drugs can be doped inside a siUca matrix and then delivered to target cells [15, 21, 26] the subsequent intracellular release of the drug molecules would then result in death of the cancer cells. 

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