Abstract
Nanotoxicology is a branch of toxicology that is related to potential effects of nanoparticles of diameter less than 100 nm. Due to relatively small size, they are reported to enter through biological tissue barriers and cellular membranes leading to toxic effects. Release of nanoparticles on the target surface also induces high level of toxicity in target cells. The nanoparticles are usually cationic and are easily attracted to the anionic biological membrane, resulting in the destruction of the membrane and interaction with proteins, DNA, and enzymes of the host cell. The carcinogenicity of some multiwall carbon nanotubes and nanoparticles are also reported in recent researches. Various concerns about the usage of nanoparticles including systemic translocation, direct effects on the central nervous system, intestinal tract involvement, biocompatibility, deposition, and clearing are reported till date. In this book chapter, we will review the potent role of nanomaterials to confer their toxicity at cellular and subcellular levels. Efforts have been made to summarize the new aspects of interactions with other toxicants either by reducing or enhancing health risks and the potent negative effects associated with nanomaterial pollution.
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22.1 Introduction
Increasing demand for high-quality water fit for consumption calls for effective strategies to treat wastewater (Rajasulochana and Preethy 2016). The growing use of pesticides and heavy metals pollutes the water bodies (Ayangbenro and Babalola 2017). The use of nanoparticles can help to solve this problem and would address the consequences of pesticides and heavy metals present in water (Cicek and Nadaroglu 2015). However, despite the progress made, use of these emerging sustainable technologies has been limited, largely due to limitation of the material’s properties, including cost (Lim 2017).
Nanoparticles possess useful characteristics such as direct band gap, high optical absorption coefficient, layered structure, and tunable band edges for optimized catalysis (Khan et al. 2017). Conversion of single-component nanomaterials to hybrid materials such as nanocomposites involves integration of synergistically different components in a controlled fashion (Camargo et al. 2009). Hybrid nanostructures have many advantages over single component nanomaterials such as multi-functionality, highly efficient charge separation at the interface and tunable band gap (Li et al. 2016). The use of nanoparticles for photocatalytic degradation will result in appreciable reduction in the pesticide amount in the water (Das et al. 2017). The combination of nanoparticles with bio-adsorbents to form nanocomposites is expected to show improved performance in terms of high efficiency of photoinduced charge separation and photostability (Hasija et al. 2019). The surface modification of the nanoparticles will facilitate the interaction of heavy metal ions with the particle’s surface and hence would result in better adsorption and improved performance of the photocatalyst (Upadhyay et al. 2014). Use of hybrid nanostructures is also expected to be advantageous over the single-component and pure systems. Better performance in terms of material stability, efficiency, and cost is expected over the existing systems (Sanchez et al. 2011). Recent advancement in nanotechnology industry has shown remarkable revolution over the last few decades, which progressively and hopefully will continue in future. Nanotechnology has shown significant contribution for the future of health science and medicine care (Fakruddin et al. 2012). In gene delivery, immunotherapy, and drug delivery systems, the ideal nanomaterials can achieve biocompatibility, high payload, low immunogenicity, efficient penetration and selective targeting to get timely arrival at tissues of interest (Singh and Lillard Jr 2009). Regular exponential growth in nanotechnology has led to consider new challenges to manage, predict, and understand the potential negative health effects followed by exposure (Setyawati et al. 2015). Different nanomaterials of different surface topographies, sizes, and compositions and various other properties need to be scrutinized to build the safety and efficacy for their use in human population (Jeevanandam et al. 2018). Nanotoxicology basically deals with the toxic nature of nanoparticles and elucidating their toxic effect on living systems (Taghavi et al. 2013). Most of the inert element becomes more active at nanoscale dimensions. Most of the nanoparticles are benign, and they may distribute throughout the body causing inflammation, oxidative stress, and other serious adverse effects (Buzea et al. 2007). High doses of nanoparticles represent realistic exposure and should be interpreted with caution which might result in toxico-kinetics and exposure assessment (Laux et al. 2018).
Multiwall carbon nanoparticles are discovered to cause asbestos-related serious health effects which prompted nanotoxicologists to cautiously check the release of nanoparticles at drug delivery sites (Yildirimer et al. 2011). Adverse effects of nanoparticles are evidenced in epidemiological, in vitro, and in vivo studies. However, data related to low dose exposures and chronic abnormalities still need to be explored (Gwinn and Vallyathan 2006). In most of the cases, these emerging engineered nanoparticles are directly linked to adverse health risks. New areas in toxicology includes the binding of nanoparticles with other contaminants either by reducing or enhancing various health issues and various adverse environmental effects related to nanomaterials pollution (Gupta and Xie 2018).
The purpose of this book chapter was to review the potential harmful effects of nanoparticles on the immune system with new approaches in nano-science. Efforts also have been made to scale up various biomarkers to monitor toxicity of nanoparticles at cell system.
22.2 Properties and Application of Nanomaterials
Nanomaterials exhibit various properties such as electronic, chemical, magnetic, optical, physical, thermal, and elastic properties. The nanoparticles find their application in a variety of fields such as medical field for drug delivery in vivo and in vitro, agriculture, and treatment of wastewater (Singh et al. 2019a, b; Kumar et al. 2019a, b), pesticide degradation (Singh et al. 2019c; Bhati et al. 2019; Kapoor et al. 2019), solar sensitizers, nanosensors, and photocatalysis because of their small size and physicochemical properties (size, shape, surface area, phase, and composition) (Sidhu et al. 2019; Kumar et al. 2019c).
Nanomaterials found their vast applications in different fields such as nanoscale carriers, nano-herbicides, nano-fertilizers, nano-pesticides, nanosensors, veterinary care, etc. (Kumar and Singh 2018a, b). Murphy (2008) and Tarafdar (2015) developed clay nanotubes (Halloysite) to reduce the concentration of pesticides by more than 70%, hence reducing its effectiveness impact on water streams. Panyam and Labhasetwar (2003) developed poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles for localized/targeted delivery of different agents including peptides, plasmid DNA, and proteins.
Recently, a titanium-based nanomaterial was found to have numerous applications such as in water splitting and degradation of organic compounds and as solar sensitizers. Titanium dioxide (TiO2) has various features such as polymorphs, low cost, good stability, environmentally friendly, and having good optical and electronic properties. Li et al. (2018) investigated that core–shell-structured TiO2 composites show tunable optical and electrical properties, even new functions, which are originated from the unique core–shell structures. The small size of Fe2O3 nanoparticles, changes their magnetic properties from paramagnetic to ferromagnetic and superparamagnetic and are used as contrast agents in intravenously injectable T2 MRI (Lee et al. 2014). The effective photocatalyst derived from TiO2 nanoparticles are also reported to enhance photocatalytic degradation of triazine pesticides such as atrazine (Yola et al. 2014). Chitosan-based zinc oxide nanoparticles (CZNP) are spherical in shape and are used in the treatment of cervical cancer cells (Wu and Zhang 2018). Gold nanoparticles (GNPs) along with TiO2 nanoparticles are used for fabricating conformal nanocomposite (NC) films of TiO2–Au (Chander et al. 2014). Yuan et al. (2010) investigated the synthesis of ZnO quantum dots (QDs) combined with chitosan (N-acetylglucosamine) for its effectiveness against tumor-targeted drug delivery. It was observed that stability of the ZnO quantum dots is dependent on chitosan due to its cationic charge and hydrophilicity. Qiu et al. (2014) have developed a composite having core shell structure of ZnO interlayer and magnetic Fe3O4 core. Based on its properties, it has been shown to be effective against targeted delivery of anticancer drugs.
22.3 Hazardous Effect of Nanomaterials
The nanomaterials have a small size, i.e., few nanometers, and possess high reactivity to interact with organisms. They pose potential human health and environmental hazards when released directly into the environment and gets interacted with water, air, and soil (Elsaesser and Howard 2012). When the dust and air pollution consist of ultrafine particles of size <100 nm, it indicates possible long-term hazardous effects of man-made nanoparticles on humans. They can enter via oral, pulmonary (lungs), nasal, intraocular, and various other routes. Nanomaterials are found in aquatic and terrestrial environments by runoff and eventually reach into the food chain and accumulate in the body and other metabolic pathways. They are somehow toxic to various species including invertebrates, algae, bacteria, crustaceans, nematodes, mammals, fishes, rats, etc. (Landa et al. 2012; Exbrayat et al. 2015). Warheit et al. (2008) assessed the hazardous effects of several fine or nanoparticle types such as carbonyl iron, amorphous silica, crystalline silica, and nano zinc oxide in rats. They observed that silica nanoparticles sustain cytotoxic and inflammation effects.
Karimi et al. (2018) used colloidal nanoparticles of fumed silica (f-SiO2), silica (c-SiO2), alumina (Al2O3), and ceria (CeO2) as corrode in chemical and mechanical planarization (CMP) processes. The CMP slurries of CeO2 and Al2O3 reduced reproduction in Daphnia magna upon chronic exposure which have negative consequences to water bodies. Jeng & Swanson (2006) investigated the effect of metal oxide nanoparticles ZnO, Al2O3, Fe3O4, TiO2, and CrO3 on apoptosis, cellular morphology, membrane leakage of lactate dehydrogenase (LDH mitochondrial function), and permeability of the plasma membrane, out of which ZnO nanoparticles were highly toxic, Al2O3 nanoparticles were moderately toxic, and TiO2 and Fe3O4 exhibited low toxicity. It also results in the decreased mitochondrial function in the cells treated with ZnO nanoparticles ranging from 50 to 100 μg/mL.
Ghodake et al. (2011) reported the phytotoxicity of zinc and cobalt oxide NPs by Allium cepa test using onion bulbs as an indicator organism to check their effects on cell morphology, root elongation, adsorption potential, and root morphology of a plant. Zinc oxide NPs accumulate in the chromosomal and cellular modules, thus causing phytotoxic damage. Landa et al. (2012) studied the effect of titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles using microarrays on gene expression in roots of Arabidopsis thaliana. ZnO nanoparticles elicit stress response in phenotype and gene expression of A. thaliana.
22.4 Effects of Nano-based Products on the Immune System
Any alteration in the properties of nanoparticles transforms them either to a valuable or hazardous product (Jeevanandam et al. 2018). The deposition of nanoparticles in the human system acts as a foreign material that led to the emergence of a new branch, i.e., nanotoxicology (Suh et al. 2009). This field aims to cross verify the negative and harmful effects of nanoparticles on the environment as well as on human health (Table 22.1) (Singh 2009). This will aid in understanding how these nanoparticles cross the different barriers and enter into the blood system as well as interact with other tissues. Moreover, it will provide an insight into how the aggregation of these nanoparticles affects the normal functioning of the organ and induce ailments like fibrosis, inflammation, etc. (Barua and Mitragotri 2014). Nanoparticles induce biological toxicity by various possible routes in the human body via endocytosis and penetration into cell membrane and through the cell membrane channel (Manke et al. 2013). Most of the nanoparticles produces oxygen radicals and induces apoptosis and mitochondrial perturbation followed by toxicity (Behzadi et al. 2017). Nanoparticles react with biological fluids and body proteins and results in the generation of oxidative stress (Dayem et al. 2017). Nanoparticles such as silver NPs (AgNPs), titanium dioxide (TiO2), NPs, and gold NPs (AuNPs) result in various immune-related disorders in mononuclear phagocytic system cells of the spleen and liver (Giannakou et al. 2016). Most of the immune cells such as macrophages, dendritic cells, leukocytes, platelets, monocytes, etc. recognize and uptake nanoparticles when they are in the tissue or in circulation process (Lameijer et al. 2013). Immune cells uptake nanoparticles from the bloodstream by adsorption process through opsonization. They remain in the body for a long term and cause various exposures. They also enhance intense manifestations that cause several disorders such as activation of complement system and acute inflammation (Look et al. 2010). It also has adverse effects on innate and specific immune responses. Acute inflammation is induced by activation of NF-κB pathway which results in enhanced production of chemokines and cytokines (Liu et al. 2017). Innate immune system results in the generation of ROS after exposure to metal oxide particles. Further, ROS lead to alterations in DNA and proteins which further causes inflammatory damage (Fu et al. 2014).
Gold nanoparticles are reported to induce various immunomodulatory effects by secreting inflammatory cytokines (IL-8 and TNFα) which activate NF-κB pathway when THP1 cells were exposed to AuNPs coated with negatively charged poly(acrylic acid) (Deng et al. 2011). In a similar study, Sharma et al. (2013) also confirmed that when B-lymphocytes were exposed to AuNPs stabilized with citrate, it induces NF-κB pathway and structural changes in cellular function of cells are registered. Another example of immunomodulatory effects by single and multiwall carbon nanotubes on various cell types was also reported in which they induce unregulated antigen-presenting cell maturation (He et al. 2013). CNT is also testified to enhance ROS production which causes alterations in fibrosis in lungs of rats and neoplastic damage. They also increased high risk against cardiopulmonary diseases in lungs by generating pro-oxidant and pro-inflammatory milieu (Dong and Ma 2016).
22.5 Mechanism of Toxicity of Nanomaterials
Recent studies have revealed that reactivity of the nanoparticles triggers the formation of ROS (especially, hydroxyl radicals and superoxide radical anions) due to activation of oxidative enzymes leading to the formation of oxidative stress (Kim et al. 2015). There are various reasons for the initiation of oxidative stress, such as (1) nanoparticles have the property to trigger the ROS production as the cellular response, (2) transition metal-based nanoparticles serve as the catalyst during the formation of non-metal nanoparticles, (3) formation of reactive molecules on the surface of nanoparticles, and (4) induction or activation of redox groups on nanoparticles (Fu et al. 2014).
Moreover, particle size is also considered to be the factor responsible for cellular cytotoxicity. As small particles provide the large surface area, it increases the chances of the interaction of nanoparticles with cellular components like carbohydrates, fatty acids, nucleic acids, and proteins (Wang et al. 2017). Further, nanosized particles have additional benefits as it readily enters the cell and leads to cellular damage (Wang and Wang 2013). Apart from this, the surface charge of particle also contributes to cytotoxicity as it controls the cellular uptake of particles and interaction among the biomolecules and cell organelles. This phenomenon can be understood by the context that positively charged nanoparticles interact with DNA (negatively charged), resulting in DNA damage (Fröhlich 2012). Additionally, the shape of nanoparticles has been considered to affect the toxicity level (Sukhanova et al. 2018). Although the TiO2 (amorphous) is known to have surface defects, this serves as evidence that active site stimulates the ROS production (Cheng et al. 2018). Besides, Fe2O3 nanoparticles (rod-shaped) were found to trigger high cytotoxic responses in comparison to Fe2O3 nanoparticles (sphere-shaped) in macrophage cell lines of RAW 264.7 of murine (Lee et al. 2014). Hence, it has become essential to understand the cellular as well as the molecular mechanism of nanoparticle toxicity and their effect on the biological system to develop a safe and precise assay of engineered nanoparticles for risk evaluation.
22.6 Biomarkers to Monitor Nanotoxicology
The advent of nanoparticles has gained significant attention in short period of time due to its widespread functionality in different fields. But the biggest challenge remains the same, i.e., their effect on the biological system (Riehemann et al. 2009). The outmost reasons are their applicability of nanotechnology in different industries and increase in the number of nanomaterials for different purposes in industries, increasing their chances of interaction with our body (Dowling 2004). Nowadays, researchers are focusing on understanding the potent effects of these nanoparticles on cells and tissues on the basic route, which can be due to dermal penetration, ingestion, injection, or inhalation. Moreover, studies have also been conducted to discover biomarkers involved during bio-interfaces, facilitating in creating the biomarkers database to monitor nanotoxicity (Della Rocca et al. 2011).
Biomarkers are stated to be characteristic which measure as well as work as an indicator to assess the biological process, pharmacologic response, or pathogenic process. Hence, it can be anything which can measure the change in antigens, cytokine concentration, genes, and even proteins (Wagner and Atkinson Jr 2015). Because of a wide range of biomarkers, we are focusing on the two groups of biomarkers pro-oxidative and pro-inflammatory because the primary responses induced by toxic nanoparticles in various tissues and cells are oxidative stresses and inflammation (Khanna et al. 2015). The outcomes of these two responses are impairment of tissue function and cell damage. Therefore, these biomarkers can serve as primary detection tool to measure the effect of nanoparticles on health and can also be used for early detection of the adverse effects (Iavicoli et al. 2012).
Pro-inflammatory biomarkers are commonly used to assess the variation in responses due to inflammation and oxidative stress in particular organs like the cardiovascular, immune, and respiratory systems (Bergamaschi 2012). Inflammatory immunological biomarkers are used to define any change in the immune system on the introduction of nanomaterial in the biological system which elicits inflammation. In these antigens, antibodies, chemokines, cytokines, and phagocyte congregation are measured and interrelated with the inflammation response (Xu et al. 2016). These biomarkers are effective in diagnosis of various diseases, but during nanotoxicological studies, its efficacy decreases. Hence, extensive care is taken while identifying the cause of inflammatory response via nanoparticles (Gendelman et al. 2015). This supports and provides evidence as to why the immune system synthesizes different types of antibodies, cytokines, and chemokines, after encountering with pathogen or external agent causing stress (Gamucci et al. 2014). The major advantage of nanoparticles is its size, which allows them to penetrate directly through the cell wall, accumulate protein on their surface, and even translocate themselves through blood–brain barrier (Sonvico et al. 2018). The mobile nature of nanoparticles and their ability to aggregate themselves in various tissues elicit the immune response and make correlation between the immune response and presence of nanoparticles, which form the basis of biomarker analysis (Dobrovolskaia et al. 2016). At this point of time, major researchers are focusing on determining the toxic dosage which triggers immune response and how to prevent the toxic exposure of nanoparticles. Till date, numerous biomolecules have been identified which play a key role in inflammation (Elsabahy and Wooley 2013).
Numerous studies have highlighted metal oxide nanoparticles like iron oxide (Fe3O4), as it elicits immunogenic response in cell and can be used for biomarker studies for assessing potential toxicity (Arias et al. 2018). Joo with his colleague (2013) investigated the adverse effect of Fe3O4 on rodents. The results obtained were quite similar with Srinivas et al. (2012), as there was an increase in level of pro-inflammatory cytokines such as transforming growth factor beta (TGF-β TNF-α), interleukin-1 (IL-1,2,4,6,12), and immunoglobulin-E (IgE) which can serve as the biomarker for detecting various ailments (Srinivas et al. 2012). Additionally, tissue damage and inflammation have also reported to increase the expression of few genes encoding for different proteins like tissue-inhibiting metalloproteinase, serum amyloid A (SAA), and heat shock protein. The gene SAA is usually expressed in the liver which elicits the synthesis of TNF-α IL-1 and IL-6 which are also produced as a response to metal oxide nanoparticles (Skovgaard et al. 2009). The discussed biomarkers have recorded to involve in various situation when cell experiences stress. Moreover, they are also reported to be produced by the body in response to cold (Buzea et al. 2007). Biomarkers also serve as parameter for analysis in experimental design and aid in interpreting the result of biomarker assessment. Hence, studies focusing on the assessment of nanomaterial only triggering the inflammatory response enable us to discover the true biomarkers of nanotoxicity (Oberdörster 2010).
On the other hand, pro-oxidative biomarkers are the ones having response to various metal oxide nanoparticles, generally by generating the ROS stress. Therefore, it is essential to observe the ROS level induced by interaction of nanoparticles as ROS generation has been linked with different cardiovascular and respiratory ailments like atherosclerosis, asthma exacerbation, thrombosis, and inflammation (Fu et al. 2014). CuO (copper oxide), TiO2 (titanium oxide), ZnO (zinc oxide), and Fe3O4 (iron oxide) are the metal oxide nanoparticles which have shown to cause the overproduction of ROS, as they allow the propagation of free radicals on their surface during their interaction with enzymes, oligomers, and proteins (Karlsson et al. 2008). Due to distinctive electrical surface properties, these nanoparticles generate substantial amount of ROS, which can be used as nanotoxicity biomarker. These are the two important types of biomarkers that are employed for nanotoxicological assessment.
22.7 Conclusion
There cannot be a second opinion that nano-sized materials have widespread applications in various fields of science and technology. However, there are numerous reports that depict the side effects of the nanomaterials on biological systems and cellular levels. Although they are relatively small sized, yet they have an enormous effect on human life and ecosystem. The elevated use of nanotechnology poses a risk not only to consumers but also firsthand to the workers. Their physicochemical parameters in addition to production of toxic ions, generation of free radical species, and high surface charge ratio result in cytotoxicity by nanoparticles which may include quantum dots, gold and silver nanoparticles, titanium dioxides, CNTs, etc. Both in vivo and in vitro assays require a better knowledge of toxicity mechanism so as to avoid side effects and exploit the benefits that nanotechnology has to offer. The information will further help to formulate the measures able to reduce the potential hazards of nanomaterials. Nanomaterials causing oxidative stress could be replaced with nanomaterials that are relatively less harmful. Further proper administration of antioxidants and other therapies to the occupational workers should also be taken into consideration to check their immune-related disorders. Also, the incorporation of nanomaterials should be considered effectively because the method of incorporation of nanomaterials in a product strongly influences its release in the environment. Thus, knowledge of pathogenic mechanisms of the nanomaterials is very crucial.
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Singh, S. et al. (2020). Challenges and Future Perspectives of Nanotoxicology. In: Siddhardha, B., Dyavaiah, M., Kasinathan, K. (eds) Model Organisms to Study Biological Activities and Toxicity of Nanoparticles. Springer, Singapore. https://doi.org/10.1007/978-981-15-1702-0_22
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