Deciphering the pathways for evaluation of nanotoxicity: Stumbling block in nanotechnology

1. Cutting edge nanotechnology: need of the hour

Skepticism concerning peril and jeopardize of nanoscale materials on the environment and human health may impede the oppression and utilization of these new-fangled materials. The stipulation in ginormous pace concerning nanotechnology requires attaining knowledge of not only the fringe benefits but also the venomous properties of nanoscale materials. The recent evolution in manufacturing and technology-assisted the proliferation in the utilization of engineered nanomaterials. Pioneering in nanotechnology elucidates inherent properties and comprehensive applications work as a magic bullet to the biota. Hitherto, the nanotechnology field has created substantial contemplation amidst researchers' attributes to its phenomenal applications extended to robotics, biotechnology, electronics, computer, and aerospace industry. Latterly, nanotechnology is also employed to the myriad of nanomedicine which embeds nanotechnology derived treatment, diagnosis, and impedes human diseases like cancer as presented by (Wagner et al., 2006). They can be categorized into several sections such as metallic nanoparticles, inorganic nanoparticles, and polymers depending on their physio-chemical properties. The fate of nanomaterials in living cells has been investigated for prolonged duration nevertheless there exists a specified paucity of the fundamental cognizance of toxicity and constructing a common principle to analyze all the materials under a general domain. Presently, the absolute cognizance of composition, solubility, charge, shape, size, crystallinity, surface functionalization, and interaction of nanoparticles agglomerates with the biological systems is vague as highlighted by (Colvin, 2003). Therefore, it is ambiguous whether nanoparticles exposure to living beings could foster detrimental biological responses. It is captivating to note how usual it is for researchers to use the locution “facile” when they are illustrating a novel approach for the synthesis of a nanomaterial. In contrast, it is not deftly attained or accomplished to conduct toxicological testing on all these novel materials.

The major bone of contention associated with nanotoxicological research is that scientists are outlying too frequently contemplating the characteristics and applications of nanomaterials as highlighted by (Das et al., 2021) However, the exponential growth of nanomaterials would lead to acute implications related to noxious impacts on environment and human health. We pretend to delineate the conventional principles of toxicological functioning of nanoparticles; when we are in actuality only investigating solitary examples of nanoscale materials stipulated randomly and a boundless cosmos of various synthetic nanoparticles. What we need to effectuate is to backpedal the reasoning of toxicity. We should evaluate various nanoscale materials in a synchronized and meticulous manner to reckon whether an ordinary biological response prevails or only the comprehension in toxicity of nanoscale materials transfigured into a vaticinated science as studied by (Gupta and Xie, 2018) and (Jeevanandam et al., 2018). One of the key challenge is to assess precise characterization and experimental methods encompassing toxicological investigation of nanomaterials.

2. Nanotoxicology

The locution nanotoxicology may upheave an alarm amidst the general populace; howbeit it is somewhat an avant-garde bough of toxicology that addresses the gap in the proficiency of toxicity incites by nanomaterials. Nanotoxicology is an emerging domain that is apprehensive with efficient noxious impacts of nanoscale materials (size less than 100 nm) studied by (Ray et al., 2009). Ordinarily, the steady aggrandized toxicity of some nanosized materials contrary to other conventional bulk materials transpired due to high aspect ratio which makes them exceptionally reactive. Nanotoxicology includes various aspects of science from quantum physics and chemistry to molecular biology and bestows the framework for obliterating the probabilities related to the manufacturing of nanoscale materials and their applications. The precedence of the small size of nanomaterials is hypothesized to perforate into tissues, biological barriers, and cellular membranes more efficiently in contrary to other prodigious materials as presented by (Gidwani and Singh, 2013). Therefore, the progression in nanotechnology should address the implications of nanomaterials which could be serious commination to the mankind and ecosystem as presented by (Coussens and Goldman, 2005). One of the challenging contrivances in the province of nanotechnology is to evaluate the characteristics of nanoscale material which leads to baneful effects which was investigated by (Fleischer and Grunwald, 2008) and by (Sheetz et al., 2005). Undeniably, substantial indagation is presently being stimulated to evaluate the toxicity of different nanomaterials in a range of environments and to address risk factors associated with it which was presented by (Fojt\uu et al., 2017). Ample exploration has been regulated worldwide on the range of nanomaterials to ameliorate the behaviour of nanoscale materials chemically, optically, or morphologically. Nonetheless, the empirical perception of their effects on living beings left out. A single discrepancy in nanomaterial can steer to an absolute alteration in the behavior and so does its methodology to impact living cells. Therefore, a coherent understanding of nanotoxicity can assist researchers to select materials that are environmentally benign and pre-eminent research to mitigate viable risks correlated with the human health and environment as presented by (DeLoid et al., 2017) and also studied by (Pietroiusti et al., 2018). Fig. 1 presents an overview of the scope of life cycle assessment of nanomaterials and the ecological or human health risk assessment.

Undeniably, apprehension has been elevated to the pertinence of a trivial number of investigations of nanotoxicity that have been produced over the past decade. Therefore, conjecture for discrete ethos concerning the safety assessment of nanomaterials should turn up. We entail heading away from the present engrossment with unassailable cornerstone and challenges instead of the substantial progress that has been constructed over recent years as novel and cultivated strategies have been employed for safe nano research.

With the forethought of analogizing, this anatomization delineates the nanosafety, emerging trends in nanotoxicity as it has been conferred that the locution “nano” in some way implicitly concomitant to breakneck which was studied by (Singh et al., 2019). Nanotoxicity is not just encircling environmental assessment and exposure of health welfare levels. Nonetheless, several factors need to be addressed into an experimental analysis to attain more efficient and reproducible experimental data as presented by (Bueno, 2020). Thus, herein, we revisit the critically ignored parameters of nanoscale materials to identify opportunities for toxicity prevention and reduction in resource consumption while taking the enire life cycle of nanoparticles into consideration. Furthermore, factors affecting the toxicology of nanomaterials, their management along with strategies for high throughput screening and biology system techniques to generate a mechanistic comprehension of hazards of nanomaterials for the environment and human health are assessed to permit a vital leap forward in material design. We require a paradigmatic breakthrough in the manner in which assessment of nanosafety is governed to amputate the Gordian knot and the objective is to cast light on the evolving tools for the exploration of nanotoxicity.

2.1. Mechanism and corroborations of nanoparticles toxicity

Researchers and technologists are proffering heed on nanoscale materials with exorbitant monodispersity and reproducibility. These new-fangled materials could inflict numerous plausible causes of toxicity; (a) nanoscale materials are involved in various oxidative and catalytic reactions, if these processes induce cytotoxicity, the pestilential could be higher due to high aspect ratio in contrary to conventional bulk materials, (b) nanoscale materials bespeaks excellent physical dimensions like magnetic, optical and electronic properties and the disintegration of nanoparticles could assist in peculiar obnoxious impact which is arduous to predict, and (c) some nanoscale materials contain compounds with well-known toxicity and therefore fragments of these materials could trigger similar obnoxious responses to the components. Despite attaining prevalence in the province of nanotechnology in the medicinal area, their implementations have been impeded attributes to their prolonged secondary severe impacts and potential toxicity as highlighted by (Lanone and Boczkowski, 2006).

Nanoparticles propound numerous advantages contrary to other traditional bulk materials and suitable for applications in biomedical devices, diagnostics, fuel additives, agricultural and pharmaceutical products, industrial utilization, etc (Shekhar, 2020, Shekhar, 2021). Consequently, the quantity of manufactured goods possessing nanoparticles is unabating escalated. With the emerging utilization of nanoparticles in the aforementioned applications, auxiliary perils of exposure subsist covering household products and traditional occupational settings. Nanoparticles exist in our atmosphere which is referred to as efficient resources of air, soil, and water “contaminants” as presented by (Eckelman et al., 2012). Furthermore, nanoparticles have been manifested not only for enhanced specificity of targeting howbeit; it also facilitates adsorption, stability, and solubility of the drug which was studied by (Gaiser et al., 2009). The small size of particle results in high surface area to volume ratio, therefore higher biological and chemical reactivity. Hence, size is a major factor in evaluating the potential toxicity of a particle. The increased reactivity of nanoparticles culminates enhanced production of free radicals and oxygen species which are highly reactive. Other factors enticing toxicity includes composition, shape, surface charge, structure, solubility, and aggregation. Emphatically, nanoparticles are extremely mobile in contrary to large-sized particles. They may be transported into the cells and taken by cell nucleus, mitochondria, which can cause cell mutation and death of cells. Crucially, the existing evinced that not all nanoparticles are venomous. The proliferation in oxidative stress, lung inflammation, obstructive impact on organs, and damage to cardiovascular systems attributes to the exposure of various engineered nanoparticles illustrated in Table 1. It has been investigated that a high level of exposure to some specific nanoparticles could lead to severe diseases like cancer and fibrosis.

Table 1. Delineates the utilization of various nanoparticles and their concomitant toxicity in medicine.

SL. No	Nanoparticles	Toxicity	Applications	References
1.	Carbon (nanotubes and fullerenes)	Interstitial inflammation and pulmonary toxicity	Drug delivery	Morimoto et al. (2013)
2.	Silver	ER stress response	Antibacterial agents	Huo et al. (2015)
3.	Gold	Splenic and hepatic toxicity	Therapeutics and biomedical imaging	Alkilany & Murphy (2010)
4.	Titanium dioxide	Central nervous system toxicity	Cancer therapeutics	Younes et al. (2015)
5.	Iron Oxide	Disruption in iron homeostasis and oxidative stress	Cancer drug carrier systems, immunoassays and magnetic resonance imaging contrast	Laurent et al. (2014)
6.	Ceramic	Cytotoxic activity and oxidative stress in the heart, brain, liver, and lungs	Cancer drug delivery	(Singh et al., 2016)
7.	Silica	Aggregation in platelets, reproductive and physiological toxicity	Diagnostic imaging and drug delivery	Nemmar et al. (2015)
8.	Poly (lactic-co-glycolic acid)	–	Drug delivery and cancer therapy	Fornaguera et al. (2015)
9.	Chitosan	–	Drug delivery	Agnihotri et al. (2004)
10.	Reduced graphene Oxide grafted Poly (ethylene glycol)	The decrement in the viability of cells	Potential photo-thermal therapy of tumor	Robinson et al. (2011)
11.	Oxidized graphene	Cell viability decreases with increasing concentration	Cervical cancer applications	Chowdhury et al. (2013)
12.	Titanium dioxide	Decease in mast cells of serotonin exocytosis	Immune cell applications	Maurer-Jones et al. (2010)

Imbalance in the production of reactive oxygen or nitrogen species and the ability of a cell to detoxify the reactive intermediates or to restore the damage resulted is defined as oxidative stress. Ordinarily, reactive oxygen species are deduced into the water in ambient conditions through a network of interacting enzymes. In the detoxification pathway, a range of enzymes protects the cells against oxidative stress. Obstruction in the regular redox state of tissues can cause noxious effects attributes to the formation of free radicals and peroxides results in detrimental impacts on cells via a direct attack on membrane lipids, proteins, and DNA. These aforementioned oxidative damages lead to cellular death. In process of oxidative stress, electroactive species can be directly regulated at bare carbon or surface of the platinum electrode by utilizing proper potential value which is appropriately positioned over living cells at micrometers distance. By implementing this approach, single living cells can be regulated. Direct evaluation of reduction reaction due to the existence of oxygen in the measurement medium becomes very challenging and is ordinarily conducted only in an indirect scheme by using electrochemical mediators. The extent of oxidative stress can be influenced by size, shape, type, and surface coating.

An investigation elucidated that exposure of single-walled carbon nanotubes to workers at present permissible exposure limit can cause burgeoning of some lung lesions as investigated by (Chalupa et al., 2004). Carbon nanotubes have been manifested to trigger kidney cell death and to impede further growth of cells by reducing the ability of cellular adhesive which was studied by (Handy et al., 2008). The nanoparticle exposure can be categorized into two categories: primary and secondary depending upon the extent. In primary impacts, the toxicity of nanoparticles emerged out from direct cellular contact results in inflammation, oxidative stress, and DNA damage. Attributes to their small size, nanoparticles may transform into the blood via tissue barriers where they can deposit and circulate in other organs consequently fostering into secondary nanoparticle exposure. The impact of secondary exposure may contain toxicity in the region of nanoparticle deposition in various organs like spleen, liver, kidney, and stimulations in systematic functions presented by (Nel et al., 2009). Ordinarily, nanoparticles are released into the environment and exposed to humans via the pulmonary route by taking in airborne nanoparticles during breathing as highlighted by (Schrand et al., 2012).

3. Assessment of nanotoxicity

The bone of contention tormenting congruous toxicity may be the utilization of biochemical evaluation which can be affected by nanoparticles themselves, leading to statistics and ensuing incompatible assessment of toxicity. To establish procedures and guidelines for production and utilization of nanomaterial, such erroneous and incongruent data will make it arduous for regulators, consequently obstructing the propensity to speculate how nanomaterials will impact organism in the biota. Fig. 2 attributes to the distinct physiochemical properties and enhanced reactivity of nanoparticles, there is extortionate potential for the aforementioned materials to meddlesome with spectrofluorometric and spectrophotometric analysis. Sales et al elucidated three categories of characterization of materials; (a) In the primary, characterization has been carried out when the material is received or synthesize in powder form, (c) Secondary analysis includes investigation of material in the wet state as suspension or solution form for instance in cell culture and water medium, (c) Tertiary characterizations are conducted on particles via biological systems in vitro or in vivo followed by characterization in lung fluids or blood as studied by (Warheit et al., 2009). Mainly, the tertiary analysis is an actual test to be carried out for nanoparticle toxicity certainly non-trivial but most appurtenant for investigation of toxicological data.

Ordinarily, some specific tests which are normally reported for various nanoparticles are MTS, MTT (tetrazolium based assays), Alamar blue, and LDH (lactate dehydrogenase cytotoxicity test) which was investigated by (Han et al., 2011) and also investigated by (Holder et al., 2012). Innumerable in-vitro and in-vivo nanotoxicology investigations include analogous assays that are outlined to coherently and swiftly analyze the toxicity. Protocols which are umpteen counts on several stages in biochemical reactions elicit in altering the fluorescence or absorbance, which are further quantified to give information on biological or physiological endpoints. Some authors propounded that selection of appropriate in vitro screening assay and their affirmation should be proficient within the upcoming years as presented by (Maynard and Aitken, 2016). In vitro assays of high content integrated with genome-wide expression investigation of unprotected cells have also been implemented to assess the toxicity of non-coated quantum dots coated with polyethylene glycol which was investigated by (Zhang et al., 2006). Comparably, authors reported screening of high content to evaluate the toxicity of quantum dots grafted with gold nanoparticles which was studied by (Jan et al., 2008). Another researcher implemented the utilization of multiparameter cytotoxicity assay which evaluates oxidative stress in contrary to the impact of metal oxide-based nanoparticles in bronchial macrophage and epithelial cell lines which was investigated by (George et al., 2010).

The precise measurement and amount of a nanomaterial which comes in proximity of biological target are of utmost importance (Lison et al., 2014). Investigated the details about the toxicity mechanism, deduce experimentally or evaluated by analogy with identical nanomaterials, is mandatory to direct researchers while selecting the most admissible amount to analyze the effect of dose-response relationship (Zhang et al., 2019). implemented the utilization of electron microscopes in the assessment of nanotoxicity to evaluate interactions of bio-nano, morphology, ultrastructural changes by exposure of nanomaterials, size, localization of tissues and cells. Recently, electrochemical methods were utilized to evaluate critical mechanisms for nanoparticle toxicity as studied by (Özel et al., 2014). Electrochemical investigations can be executed in a range of sample types and environments such as in vitro and in vivo. The most efficient mechanism of toxicity is attributed to the excess production of reactive species which leads to oxidative stress. Initiation in molecular events leads to activation in the toxicity of signaling pathways, utilization of electroanalytical techniques directly which also enhances the sensitivity and selectivity of measures implemented in biosensors which was presented by (Li et al., 2018). (Erofeev et al., 2018) fabricated a platinized based carbon nanoelectrode having a cavity on the tip merged on a micro-manipulator and an upright microscope to analyze levels of intracellular reactive oxygen species estimated in the range of cancer cells before and after exposure to iron oxide nanoparticles of size 10 nm. Less than 30 min was required to evaluate the toxicity of nanoparticles by regulating the production of reactive oxygen species in the proposed methodology. Some specific nanomaterials can destruct cellular DNA and some can be utilized to investigate genotoxicity induced by nanomaterials. Fibroblasts cell in human lungs and epithelial cells, when exposed to gold and silver nanoparticles, cadmium oxide nanoparticles, and single-walled carbon nanotubes examined by multiplexed impedimetric chip. Amidst these nanoparticles, cadmium nanoparticles displayed the swift rate of cytotoxicity which was studied by (Hondroulis et al., 2010). Monitoring system impedance-based evaluated the cytotoxicity of fibroblasts utilized titanium dioxide nanoparticles which was investigated by (Cimpan et al., 2013). An efficient method derives by (Moe et al., 2013) profiling the cytotoxicity of silver and titanium dioxide nanoparticles on three cell lines which are one mammalian cell line and two human carcinoma cell lines. The cytotoxicity obtained was cell, particle, and concentration-dependent. The limitation of this method is that they accord cellular response to toxicants without elucidating its effects. Assessment of nanotoxicity could get fringe benefits from another cutting edge electrochemical derived technology in near future. Empathetically, electrode arrays are anticipated to be broadly used in base devices for organs on a chip which constitutes components of cell culture, microfluidic, and stimulates the physiology level of tissue organ with congruent profusion. This is the most efficient assessment of nanotoxicity in high throughput screening which circumvents the in vivo analysis of living animals which was presented by (Bhatia and Ingber, 2014) and (Shin et al., 2017). Fig. 3 gives the considerations involved in nanotoxicology studies and their employment in clinical management.

4. Strategies to outmanoeuvre nanotoxicity and challenges in the design of safer nanoparticles

There are perpetual strives to bestow an authentic foundation for the forecast of obnoxious hazards of nanomaterials, however, it is evident that present attempts entail further stipulations to attain the regulatory demands based on many instances on quantitative pitfalls of nanotoxicity assessment. The crucial challenges in facilitating the quantitative evaluation of risks and hazards of nanomaterials are the formidable process of producing data on the dose-response of nanoparticles for several endpoints of toxicity and the perplexity in coordinating these outcomes to actual levels of exposure in a range of settings including environment, workplaces and consumer exposure as highlighted by (Fadeel et al., 2007) and (Savolainen et al., 2010). The utmost solution to mitigate the nanoparticles is the contrivance of engineering controls with PPE i.e. personal protective equipment which exemplified coherent containment and further alleviated exposure to airborne nanoparticles. Experimental investigation of nanomaterials in waste disposal was extremely strenuous and remains an agile domain of research for engineers and scientists alike. Lately, nanomaterial facilities utilize a combination of PPE, standard operating procedures, engineering controls for disposal, operation, and preparation. A thorough and coherent quantitative examination of metabolism, absorption, excretion, and distribution of nanoscale materials can lead to amelioration in designing nanomaterials utilized in therapeutic and diagnostic applications. The probability and opportunities that come with the evolution of novel materials have been discerned at an early juncture, and economical means for exploration into new-fangled applications are being accorded by a range of programs all over the globe. It is lucid that there is a requirement of efficient and authentic strategies to examine nanotoxicological effects because the development of plausible severe impacts of nanoscale materials is a major concern. It is essential to explore electrochemical methods to evaluate nanotoxicity as electrochemistry can be easily implemented, economically viable, and can be utilized for both in vitro and in vivo methods. Noteworthy, with the evolution of nano and micro fabrication, a novel plan of action has evolved as appropriate tools for the analysis of single cells which could be implemented in the investigation of nanotoxicity. Consequently, numerous provocations remain to be sermonized the probability to utilized electroanalytical tools as a screening strategy which will help in the classification of the toxicity profile of nanoparticles.

In a landmark project NANoREG, uncertainties correlated to how one should address the environment, health, and safety aspects of nanoscale materials is presented in a systematic context. It focussed on the research required to replenish the gaps in the environment, health, and safety aspects, and on burgeoning a toolbox and framework for the assessment of risk and hazards of nanomaterials which was studied by (Fadeel et al., 2018). The aforementioned strategies along with high throughput screening and biology system techniques to generate a mechanistic comprehension of hazards of nanomaterials for the environment and human health are likely to permit a vital leap forward in contrary to traditional material by material strategy. They will proffer basis for more prevalent feature-driven toxicity evaluation of nanomaterials relying on the palette of techniques that provides guidance on toxicity features, protein expression, physicochemical properties, and modification of gene and on elucidating correlations amidst authentic data layers by implementing bioinformatics tools. These new-fangled strategies have not yet acquired regulatory affirmation but they may pave the approach for economically viable, reliable, and swift assessment of nanomaterials. Recently, research fraternity has made efforts on developing infrastructures and computational frameworks on nanoscale materials, adopting an interoperable design, and permitting integrated or effective strategies in the probable assessment. Scientists at the centre of Joint Research of the European Commission lately produced a robust review of the state of art on presently accessible computational strategies for assessment of nanoscale material's safety which was highlighted by (Worth et al., 2017). eNanoMapper, another EU funded international initiative worked on generating ontologies based on nano specific permitting standardization of terminologies in the domain of nanosafety and produced a considerable vocabulary to be implemented in the safety assessment of nanotechnology as presented by (Hastings et al., 2015). This ontology can be utilized for harmonization.

4.1. In vivo, in vitro and silico screening of nanotoxicity

To perceive the toxicity impact on cells, it is imperative to discern the screening assay of toxicity.

(a)
In vivo assay: To evaluate the toxicity of various substances, in vivo assessment is the key parameter. In this methodology, a small amount of toxic substance is regulated inside the animal framework like mice. The metabolism, distribution, cellular uptake, and removal of the pathway can be evaluated in this approach which was highlighted by (Wen et al., 2017). However, this methodology requires a considerable extent of cost and time but the outcome is more authentic in contrary to other conventional methods as presented by (Filip et al., 2015).
(b)
In vitro assay: It is a set of techniques designated for the screening of inherent toxic substances. In this method, a range of cell lines is exposed to various effective noxious substances that are left for incubation at different intervals. The cellular metabolism and proliferation of exposed cells are evaluated using distinct assays such as MTT, WST- 8, etc. These techniques are economically viable and highly efficient. Besides, they do not entail the utilization of animals. However, some limitations mimic cellular events that do not correlate with physiological results shown by (Stockert et al., 2012).
(c)
In silico assay: The necessity of reliable and rapid investigation of various materials has triggered scientists to contemplate other standard methods. It employs various theoretical strategies models to forecast the physiochemical characteristics of molecules. This congregation of computational methods is described as quantitative structure-property relationships. In this method, the toxicity of molecular compounds prognosticates the experimental data and further interpolation utilizing mathematical models. It is an extremely preferable and cost-effective method. Its major disadvantage is the type and amount of toxicity that defines the endpoint of toxicology after exposure as highlighted by (Gleeson et al., 2012) and (Aires et al., 2017)

5. Optimization of health reverberations

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Concerning the respiratory system, ousting of nanoparticles inhaled via lungs is the prime keynote of indagation in nanotoxicity. Lungs come in congruent proximity with the amalgamation of airborne nanoparticles and they comprise of exonerated structures that prevent pathogenesis and infections. Bronchitis, asthma, emphysema, and lung cancer are some of the diseases that resulted from inhaling nanoparticles.
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Nanoparticles could also infer into the gastrointestinal tract via nasal inhalation or oral exposure. Colon cancer, Crohn's disease, and epithelium injuries are concerned with the absorption of nanoparticles into the gastrointestinal tract.
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(Elder et al., 2006) and (Elder and Oberdörster, 2006) have elucidated that exposure to magnesium oxide nanoparticles entered into the bundle of olfactory underneath the forebrain through olfactory axons nerve of the nose such as in olfactory epithelium so that they can outreach the different parts of the brain also via systematic inhalation.
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Inhalation of carbon nanotubes leads to pulmonary inflammation ensuing intratracheal installation. It has been elucidated introduction of carbon nanotube into lungs actuate vigorous pulmonary response in this organ at an average dosage of the material whether pharyngeal aspiration, intratracheal installation, and inhalational exposure have been utilized. Inflammation is an efficient outcome derived as a defensive act in opposition to any infection. The impact of inflammation attributes to the nature of affected issues and external stimuli. The inflammatory framework constitutes an effector, mediator, inducers, and sensors and inflammation can arise in any tissue.
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The carcinogenic impacts of nanoparticles like asbestos have been proposed attributed to the local production of reactive nitrogen and oxygen species in correlation with producing inflammation which was investigated by (Takagi et al., 2008). These investigations may accord functional information for the recognition of plausible hazards i.e. carcinogenic impacts of carbon nanotubes.
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Nanoscale aerosols have been displayed to be correlated with the enhancement in cardiac mortality in humans (Radomski et al., 2005). investigated the single and multiwalled carbon nanotube actuated vascular thrombosis and platelet aggregation. The above findings mentioned that at least some specific types of nanomaterials can acquire systematic circulation via inhalation and they can have an allocated impact in the bloodstream on microcirculation.
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The ingress of micro-sized particles can be ceased by the epidermis of skin but this obstacle becomes inefficacious for materials in the nano dimension. Beneath the dermal layer, the skin is rich in blood vessels, nerve endings, dendritic cells, macrophages, and blood. Therefore, the nanoparticles can get easily absorbed under the various layers of skin which can promptly transport to the circulatory system as investigated by (Buzea et al., 2007). Fig. 4 presents an overview of nanotoxicity impact on different physiological systems of the human body.
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Fig. 4

6. The framework of handling nanomaterials

The toxic profile of nanoscale materials is an emerging account as its obnoxious impact is uncertain. Guidelines of protective and safe handling of nanomaterials are of utmost importance to eradicate the risk associated with it though these steps do not circumvent the hazardous matter. Therefore, the general recommendations for these guidelines are outlined as follows:

(a)
Identification and assessment of speculative risks in the production process or the utilization of material.
(b)
Apprentices and elaborating an efficient strategy to control and address the risks.
(c)
Controlling and obstructing vital exposure.
(d)
Validating the implemented procedure and executing mandatory measures towards it.
(e)
Investigation of exposure levels and assuring appropriate surveillance.
(f)
Commencing requisite analysis of health.
(g)
Protocols and pace to be undertaken on a preliminary basis in opposition to any exigency.
(h)
Appropriate guidance, pervading, and directing to workers or students of industries, organizations respectively.
(i)
There should be a critical debate among researchers and policymakers to perorate the commination posed by nanoscale materials.

7. Conclusion and future perspectives

With the augmentation in cognizance about the potential fatalistic repercussions of scientific innovative technologies, new frontlines are currently contemplated with more cynicism then before. Consequently, scientists and engineers directing to commence ingenious technologies must be coaxed off the benevolence of their contribution. As discussed above, a rational paradigm that could facilitate in perceiving the toxicological and biological impacts of nanoparticles which could contemplate the immune system and how it responds and recognizes the profusion of micro and nano organisms in the environment. This formidable review is a one-stop evaluation wanton to be the state of art cognizant of nanotoxicity. The utmost blasphemous inference is that there is no “nanotoxicology”. Ideally, one should assess interference or interaction of nanoscale materials with biological systems notwithstanding of any specific size. Synchronously, solitary can no longer adjourn safety rumination of nanomaterials and there is an imperative exigency to scrutinize the toxicity of nanomaterials. It could be delineated that electroanalytical tools can provide product information in the interpretation of toxicity of nanoparticles at the cellular and whole-organism levels. The need for expansion in prodigious technology in micro/nanofabrication of electrodes, electronics, and microfluidics implemented for bioelectrochemical strategies for assessment of nanotoxicity and their unification as a propitious tool for evolving definitive nanotoxicity assay in organs on a chip and high throughput screening configuration. Dynamic measures need to be fortified for creating sustainable nanotechnology. Eventually, a paradigm is only a framework, and the fundamental comprehension of biology will always be demanded.

Data availability

The processed data cannot be shared at this time.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

Authors would like to thank the Department of Chemistry, Netaji Subhas University of Technology, Delhi, India.