A Review on Synthesis, Applications, Toxicity, Risk...

Velidandi et al. 35

A Review on Synthesis, Applications, Toxicity, Risk Assessment and Limitations of Plant Extracts Synthesized Silver Nanoparticles

NanoWorld Journal

Review Article Open Access

https://doi.org/10.17756/nwj.2020-079

Aditya Velidandi1, Swati Dahariya2, Ninian Prem Prashanth Pabbathi1, Divakar Kalivarathan1 and Rama Raju Baadhe1*

1Department of Biotechnology, National Institute of Technology, Warangal, India2Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India

*Correspondence to:Dr. Rama Raju BaadheAssistant ProfessorIntegrated Bio-Refinery Research Lab Department of BiotechnologyNational Institute of TechnologyWarangal, Telangana, India – 506004Tel: +91 8332969462E-mail: [email protected]

Received: August 07, 2020Accepted: August 25, 2020Published: August 27, 2020

Citation: Velidandi A, Dahariya S, Pabbathi NPP, Kalivarathan D, Baadhe RR. 2020. A Review on Synthesis, Applications, Toxicity, Risk Assessment and Limitations of Plant Extracts Synthesized Silver Nanoparticles. NanoWorld J 6(3): 35-60.

Copyright: © 2020 Velidandi et al.This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY) (http://creativecommons.org/licenses/by/4.0/) which permits commercial use, including reproduction, adaptation, and distribution of the article provided the original author and source are credited.

Published by United Scientific Group

AbstractIn recent years, fabrication of AgNPs via plant extracts has gained much

attention because of being environmentally friendly, non-hazardous and cost effective. The bio-fabrication of AgNPs using plant extracts as reducing, capping and stabilizing agents includes simpler, safer, less-toxic and energy efficient. AgNPs have been widely applied in numerous fields due to their bio-compatibility, multi-functionality, solubility, high stability, therapeutic and adhesive properties. This review focuses on the advantages of AgNPs synthesis using plant extracts and its applications in various fields for the betterment of mankind and environment with numerous examples and also highlights on explaining possible fundamental mechanisms involved in antimicrobial and anticancer activities of plant extract synthesized AgNPs.

KeywordsBiomedical, Applications, Nanoparticles, Toxicity, Risk assessment

IntroductionNanotechnology has revolutionized the way of human life in all the

aspects since its inception. Nanotechnology is considered as a multidisciplinary

mailto:[email protected]

NanoWorld Journal | Volume 6 Issue 3, 2020

A Review on Synthesis, Applications, Toxicity, Risk Assessment and Limitations of Plant Extracts Synthesized Silver Nanoparticles Velidandi et al.

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the materials into the preferred shape and size was achieved by employing tools which are controlled externally. The major drawback of this method is the inconsistency in the surface structure of metal NPs, which dictates their physicochemical properties [9]. Also, the massive energy utilization which is necessary to achieve the high temperature and high pressure conditions required throughout the synthesis process is another limitation in this method [9, 10]. Thermolysis, pyrolysis, radiation-induced and lithography are few examples for this method [9-11].

The bottom-up approach is known as the self-assembly method. In this method, AgNPs are fabricated primarily via the gathering of the atoms, molecules, or clusters [12]. Consequently, these primarily fabricated NPs are amassed into the final nanomaterial of desired size, using various biological and chemical processes. This method gives a significantly higher chance to fabricate AgNPs with and better homogeneous chemical composition and less surface imperfection at low cost. This method is generally desired for wet synthesis processes, like polyol [13], sonochemical [14], electrochemical [15] and chemical reduction [16]. These wet chemical processes have been recognized to be significantly low cost in fabrication of NPs at higher volumes [17]. These chemical processes have major drawbacks such as utilization of nonpolar organic solvents, toxic chemicals, synthetic capping agents and different stabilizing agents during the fabrication stage, which limits their biomedical applications. Due to the widespread use of perilous and volatile chemicals in these

branch of science which focuses majorly on the applications of nanoparticles (NPs). Unlike their bulk counterparts, Silver nanoparticles (AgNPs) show cases a broad range of significantly enhanced and novel physicochemical features. Material particles when present in the nanoscale range i.e., from 1–100 nm, they mostly display remarkable and sometimes fascinating features [1]. This is due to, the significant number of atoms existing at the material surface becomes, as the particles size reaches nanorange and the higher AgNPs surface area outweighs the contribution done by a small bulk of material [2]. Materials in nanoscale exhibit distinctive features, due to reduction in imperfections, presence of high number of atoms over the surface, high surface energy and also because of spatial confinement [3]. Compared to bulk materials, NPs have huge benefits, due to their properties such as, surface-enhanced raman scattering (SERS), surface enhanced rayleigh scattering, surface plasmon resonance (SPR) and surface plasmon light scattering [4]. Presence of these features in the AgNPs had led to the foundation for numerous biomedical, environmental, industrial, chemical sensing, electronics and optoelectronics applications [5, 6].

AgNPs synthesis approachesSynthesis of AgNPs is done either by a bottom-up or top-

down approach [7] (Figure 1). In top-down approach, AgNPs are synthesized through different chemical and physical processes to reduce the available bulk material to nanoscale material [8]. In this method, milling, cutting and shaping of

Figure 1: Schematic representation of various approaches involved in AgNPs synthesis.

NanoWorld Journal | Volume 6 Issue 3, 2020 37


methods, has given rise to severe alarms concerning about the potential adverse effects on the environment and safety of living beings by the AgNPs fabrication via chemical means [17, 18]. Various research groups were focused to develop a replacement of chemical synthesis by clean, benign, nontoxic, reliable, compatible and eco-friendly approach [19]. Hence, researchers have diverted their attention towards the “green” synthesis method for the AgNPs fabrication. Application of plant extracts for the fabrication of AgNPs has gained significant attention for its ecofriendly and biocompatibility.

Green synthesis of AgNPsPlant systems are the major photosynthetic autotrophs and

first-level producers in the food chain, which are responsible for the high biomass production in the environment. Through photosynthesis, plants have the potential to form biomass by transforming the energy from sunlight. This property has made plants and plant based products to be employed as sustainable and renewable means in the synthesis of AgNPs. Secondary metabolites produced in plants were extensively studied for their various biological properties and applications. In recent years, potential of the plant-based synthesis of AgNPs has being explored. When compared to the application of microbial systems in the fabrication of AgNPs, plant based applications is much advantageous [20]. Maintenance of microbial systems is costly and additionally they require downstream processing. As stated previously, application of plant based extracts in the synthesis of AgNPs has gained interest of researchers [21].

The capability of the plants to uptake, accumulate, utilize and recycle various minerals affects the synthesis of AgNPs using plant based extracts [22, 23]. Plant extract based fabrication can achieve highly stable AgNPs in bulk volumes at low cost and in less time [24]. By using this approach, fabrication of AgNPs can be performed on industrial scale by employing tissue culture and various downstream process techniques for optimization [25]. In comparison to conventional approaches, plant extract mediated fabrication methods have used aqueous system, requires room temperature and normal air pressure, which ultimately saves huge energy consumption [26]. Plant extract mediated fabrication fulfills all the criteria for eco-friendly method. Due to the above stated reasons, plant extracts based fabrication of AgNPs has considered as a feasible alternate method compared to that of conventional chemical, physical and including microbial systems [25, 27]. Following are the major features of plant extract mediated fabrication of AgNPs:

• Water based systems

• Easy accessibility

• Biocompatibility of plant extracts (biomedical applications)

• Simple procedure and no extra energy consumption (economical)

• Phyto-compounds acts as both stabilizing and reducing agent (economical)

• Minimum or no impurities (eco-friendly and safe for

clinical applications)

• Ease in scaling up

Plant Extract Mediated AgNPs SynthesisThe mechanism for synthesis of AgNPs from the plant

extracts; the phyto-compounds necessary for reduction of precursor are extracted and used for synthesis directly: this mechanism is known as extracellular synthesis (Figure 2). Various researchers have preferred this mechanism for the bio-fabrication of AgNPs, due to the ease in extraction and scaling up. Extracellular synthesis of AgNPs from plant extracts is widely applied, due to their capability in several biomedical applications. But, the most challenging task in this process is to fabricate AgNPs with mono-dispersion and having certain surface morphology, this is due to the consistently changing phyto-compounds composition and plant structures from various locations. Another drawback is the possibility of presence of contamination/ impurities within the plant biomasses is always high. This causes the bio-fabrication of AgNPs with preferred morphology, shape and size very difficult. This can be achieved by the application of explicit phyto-chemical composition mediated fabrication from a specific plant part. This is considered to be the key feature in the fabrication of AgNPs with high mono-dispersion and definite surface morphology. Hence, it is very difficult to identify the precise mechanism of biogenic AgNPs fabrication via plant extracts. Present research over fabrication of AgNPs through various plant extracts has given rise to a new dimension in eco-friendly, fast, renewable, nontoxic and biocompatible approaches in the synthesis of AgNPs. Various researchers have studied the fabrication of AgNPs by different plant extracts and their capability in various applications [28-35].

It has been reported that, mostly, the plant extract mediated fabrication of AgNPs results in the formation of highly reactive face-centered cubic (fcc) structure and more energetically supported spherical shape. It is well-understood that desired growth along the (111) plane and spherical shape supports the activity of AgNPs in diverse biomedical applications. This understanding has concluded that bio-fabrication through reduction of metal precursor is well controlled equilibrium mechanism, which regulates the AgNPs growth up to definite structure, size and shape and provided the much needed significance of this approach [36].

Components involved in AgNPs synthesisThe extracellular synthesis of AgNPs generally requires

three components: solvent system, stabilizing and reducing agents [33]. In application of plant extract for the fabrication of AgNPs, the phyto-compounds serve as both stabilizing and reducing agents. Preferably the solvent system used for the AgNPs synthesis is water and hence it is considered as a green process. At present, extensive research has been carried out on the bio-fabrication of AgNPs via plant extracts, yet the precise mechanism involved in the bio-fabrication of AgNPs is not well studied. Till date, few researchers have suggested the possible mechanisms involved in the fabrication of AgNPs



via plant extracts [12, 20]. Due to the presence of diverse phyto-constituents and complex nature in plant extracts, it is a puzzling work to identify the precise stabilizing and reducing agent accountable for the nanoparticle stability and fabrication. Until now, phyto-compounds like proteins, organic acids, and secondary metabolites such as terpenoids, flavonoids and phenolic acid are considered as feasible stabilizing and reducing agents for the AgNPs bio-fabrication. Yet, it is more possible that, for the reduction of metal precursor, various phyto-compounds of plant extracts act synergistically [37].

Effect of parameters on AgNPs synthesisThere is a tremendous necessity for the fabrication

of biocompatible and eco-friendly AgNPs. In spite of widespread applicability of bio-fabricated AgNPs in diverse fields, the poly-dispersion of the AgNPs synthesized during the fabrication process still remains as a hurdle. In this regard, various researchers have tried to define a steady process for the synthesis of AgNPs to achieve desired homogeneity, related to size, shape and morphology. Various researchers have experimented to get homogeneity, either through modifying parameters of bio-fabrication process or by varying and extracting the phyto-compounds [31, 33, 38, 39]. Reaction parameters like the ratio of plant extract to metal precursor, precursor and plant extract concentration, reaction exposure time, pH, reaction temperature, solvent system used and chemical composition of the plant extract were studied and evaluated to determine the homogeneity of the AgNPs (Figure 2). By altering one or more parameters, AgNPs with

definite homogeneity and high stability can be synthesized [31, 33, 34, 38-43].

The reaction parameters optimized in the synthesis of AgNPs from the Angelica keiskei aqueous powder extract were AgNO3 and plant extract concentration. As the concentration of AgNO3 increases, the absorbance and peak breadth increased. Intensity of the peaks explains the logarithmic trend in the synthesis of AgNPs as the concentration increases [33]. In another study, effect of parameters such as AgNO3 concentration, plant extract concentration and reaction incubation time were optimized for the biosynthesis of AgNPs from Berberis vulgaris aqueous root and leaf extracts. Survey shows that the AgNPs formation is directly proportional to the concentration of AgNO3 [31].

pH of the reaction mixture plays a vital part in the fabrication process by influencing the texture, size and shape of the AgNPs [44]. Effect of concentration of AgNO3, temperature, pH of the solvent system and incubation time for reaction were studied for the bio-fabrication of AgNPs from Arnebia hispidissima aqueous root extract. Results indicated that AgNPs synthesis is directly proportional to the AgNO3 concentration and reaction incubation time. As the AgNO3 concentration increases absorbance has shifted towards the higher wavelength (Red shift). Reaction temperature plays a major part in the synthesis of AgNPs, as it varies the synthesis rate affecting their size and shape. As the temperature increases, the absorbance has shifted towards lower wavelength (blue shift). pH of the solvent system affects the size and shape

Figure 2: Schematic representation of plant extract mediated synthesis of AgNPs.



of the AgNPs, since it will vary the charge (ionization state) of phyto-compounds, in turn affecting their stabilizing and capping properties [39].

The quality and morphology of the AgNPs fabricated using plant extracts are hugely influenced by the reaction incubation time [45]. Likewise, the efficacy and characteristics of the plant extracts mediated AgNPs were also altered with reaction incubation time, fabrication mechanism, exposure to light and also by storage conditions [46]. The variations in time like long reaction and storage time can cause aggregation or shrinkage of AgNPs affecting their shelf life and ultimately their potential [44].

Characterization of AgNPsCharacterization of AgNPs is of utmost significance

which helps in understanding and controlling NPs fabrication process. The physicochemical attributes of AgNPs are vital for their efficiency, efficacy, safety, bio-distribution, bio-accumulation and their behaviour [47]. Hence, AgNPs characterization is necessary to determine their functional and structural aspects. The AgNPs present a wide-range of challenges during their characterization studies which affect their in-depth and appropriate characterization. Therefore, it is essential to understand the problems faced during AgNPs characterization and choosing an appropriate characterization technique.

Particularly, AgNPs characterization is required to determine the properties such as size, shape, surface area, surface coatings, elemental composition, particle size distribution, crystallinity, pore size, porosity, surface charge, wettability, surface morphology, aggregation, spatial orientation, fractal dimensions, Brownian motion, intercalation and dispersion of NPs [48-50]. Different techniques are employed in order to evaluate different AgNPs parameters such as ultraviolet-visible (UV-Vis) spectrophotometer, zeta potential (ZP), dynamic light scattering (DLS), scanning electron microscope (SEM), transmission electron microscope (TEM), atomic force microscope (AFM), energy dispersive x-ray spectroscopy (EDX), x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), Brunauer–Emmett–Teller (BET) analysis, nanoparticle tracking analysis (NTA) and x-ray diffraction (XRD) [48, 50].

Initially, the occurrence of AgNPs during the fabrication process is confirmed using UV-Vis spectrophotometer by observing the AgNPs specific surface plasmon resonance (SPR). The particle size, shape and surface morphology are evaluated using SEM, TEM and AFM. AFM offers an advantage over conventional microscope instruments (SEM and TEM) is that AFM can measure three-dimensional (3D) structures such that it can calculate the volume and height of the AgNPs. DLS is employed to quantify the particle size distribution. Crystallinity, crystal structure and crystal lattice is determined by employing XRD. Composition of elements and purity of the AgNPs is determined using EDX and XPS. NTA is to determine Brownian motion [48, 50, 51].

Applications of AgNPsAgNPs have been employed in diverse fields (Figure 3).

Present review focuses on the applications of AgNPs which are categorized into biomedical and environmental applications. The major biomedical applications presented here are anti-bacterial, anti-fungal, anti-viral, anti-parasitic, anti-oxidative, anti-cancer and anti-diabetic activities. The AgNPs for environmental applications include removal of toxic pollutants like nitro-organic pollutants and textile dyes in wastewater.

BiomedicalThe use of AgNPs in biomedical field is growing because

of its significant potential for anti-microbial, anti-biofilm, anti-fungal, anti-parasitic, anti-oxidative, anti-cancer and anti-diabetic activities. AgNPs are integrated into topical ointments, ultrasound gels, surgical implants, wound dressings, bone cements and medical devices because of their antimicrobial nature [52-54]. Besides, they were also serving their purpose in food processing industry [55]. Recently there are research reports demonstrating the applications of AgNPs in the fields of targeted drug delivery [56], stem cell therapy [57], therapeutics [30] and cell imaging [55]. This is because of their cytotoxic [58], optical surface plasmon absorption and surface plasmon light scattering properties [38]. Applications of AgNPs for in vitro and in vivo anti-diabetic activities were also reported [60].

AntimicrobialThe significant increase for the need of new antimicrobial

agents was evident due to the continuing evolution of multidrug-resistant attributes in various microbial systems. Several metallic NPs, particularly AgNPs gained significant momentum in its application for antimicrobial activity due to their outstanding potential as antimicrobial agents [61]. The following paragraphs outline the fundamental and significant antimicrobial properties of the AgNPs prepared via green synthesis, presented in the literature.

The precise mechanism involved in the antimicrobial activity of the AgNPs is not clearly understood. Conversely, several feasible mechanisms were presented in the literature

Figure 3: Schematic representation of applications of AgNPs in diverse fields.



to understand the AgNPs antimicrobial activity. The ability of AgNPs to anchor over the cell wall surface of microbe which in turn penetrates up to the cell wall surface. This will eventually leads to structural damages within the cell wall and finally forming pits over the surface of the cell. This causes the aggregation of AgNPs under the microbial cell wall, which results in the death of microbe, is considered to be one such mechanism for antimicrobial activity [62]. Another mechanism expresses the AgNPs ability to spawn free radicals, which results in the death of microbe. Pores will be created in the cell wall due to the presence of free radicals, which eventually causes cell membrane damage leading the cell to its death [63]. The interaction between the Ag ions (liberated from AgNPs) and thiol groups present in several enzymes of microbe also causes cell death [64].

Presence of AgNPs hinders the DNA replication of microbe when interacted with the phosphorous and sulfur groups of DNA, which causes the microbial system to cease [65]. Microbial proteins are phosphorylated in the presence of AgNPs, interfering with the signal transduction of the microbe is also considered as an antimicrobial mechanism [66]. Figure 4 illustrates the credible mechanisms involved in the antimicrobial activity of the AgNPs. To understand the exact mechanisms involved in the microbial death via AgNPs further research is required.

To date, adequate amount of research was not performed over the antifungal properties of AgNPs when compared with research done over their antibacterial property. This may be related to the morphological and physiological features of the fungi. At lower concentrations AgNPs can get easily adsorbed over the bacterial cell wall, which will never happen with fungal cells. And also attachment of AgNPs over the bacteria cell wall ceases respiration activity across the cell wall, where as in eukaryotes such as fungi respiration happens via mitochondrial membrane [67]. Examples for plant extract synthesized AgNPs against bacterial and fungal systems are listed in table 1.

Likewise, only few reports are present over the AgNPs antiviral activity [86]. In the fields of health, medicine and agriculture, viruses are known to cause serious complications.

Focusing the research in this aspect will enhance the applicability of AgNPs as antiviral agents. Size-dependent interaction of AgNPs with human immune-deficiency, herpes simplex and human parainfluenza viruses was reported in few studies [87, 88]. Few examples for plant extract synthesized AgNPs against virus are listed in table 2.

Anti-parasiticAgNPs formed via green synthesis demonstrated

significant effect against various parasites causing diseases. AgNPs effect against parasites is proportional to their ability to penetrate membrane. Presence of AgNPs provokes a distress in proton motive force, which is essential in ATP production. This disruption causes a cellular function loss, finally leading to the cell death [94]. Interaction of NPs with the phosphorous-containing DNA and sulfur-containing proteins causes’ structural deformation and denaturation, which considered as AgNPs effect against parasites [61, 62]. Examples for plant-mediated AgNPs for anti-parasite were listed in table 3.

Anti-oxidativeMany notable diseases of severe repercussions like asthma,

senile dementia, cancer, atherosclerosis, degenerative eye disease, aging, inflammatory joint disease, Alzheimer’s disease, cardiovascular and diabetes are caused by the accumulation of free radicals [108, 109]. Hence, determining the AgNPs potential for scavenging free radicals is medically relevant. This will be beneficial for treating numerous free radical associated diseases and this also helps in understanding AgNPs properties significant for medicine. According to the reports published in recent years by different research groups demonstrated the remarkable capability of AgNPs via green synthesis by inhibiting the free radicals in in vitro studies [110-112]. Few examples for plant extract synthesized AgNPs for anti-oxidative activities were listed in table 4.

AnticancerEffect of AgNPs against wide range of cancer cell lines

was extensively reported. Death of cancer cells was caused by cytotoxic [120], anti-proliferative [41, 117], anti-metastatic [121] and apoptotic [122] mechanisms. AgNPs of smaller sizes can freely penetrate into the cells through easy diffusion or pass through receptors, ion channels and transporters across the membrane. The positive charge of Ag ions interact with the negative charged components of phospholipid bilayer is responsible for AgNPs uptake and internalization into the cancer cell. Once reached into inner environment of the cell, AgNPs and Ag+ ions interact with intercellular organelles and enzymes/proteins resulting in cytotoxic activity via ROS production. ROS induces the inhibition of cancer cell proliferation through promoting activation of p53 dependent signaling pathway to damage DNA. Furthermore, ROS production causes dysfunctioning of mitochondria, protein leakage by disturbing membrane permeability, breakdown of membrane and other adverse effect on the intracellular systems. Besides the direct effects on mitochondria, AgNPs alter the gene expression of caspase mediated apoptosis. ROS triggers the functioning of lysosome and phagosome, finally resulting in cell death (Figure 5). Few examples for plant

Figure 4: Schematic representation of mechanisms involved in antibacterial activity of AgNPs.



extract synthesized AgNPs for anticancer activities were listed in table 4.

Anti-diabetic Monosaccharides that are essential for absorption and

energy release are produced by the action of digestive enzymes like intestinal α-glucosidase and pancreatic α-amylase. These enzymes are responsible for the break-down of di- and oligo-saccharides into monosaccharides. The inhibition of these carbohydrate digestive enzymes results in decrease of blood glucose levels gradually. This effect is significantly useful in

treating non-insulin or type-2 diabetes [29, 123]. According to various in vivo and in vitro studies published in recent years AgNPs prepared through green synthesis showed tremendous potential for anti-diabetic activity, few examples were mentioned in table 5.

The significant inhibition of α -glucosidase activity hinders the function of α-glucosidase in the small intestine, which is economical in the reduction in carbohydrate consumption [138].

Other biomedicalThe primary requirement for the in vivo applications

Table 1: Antibacterial and antifungal activity of plant extract synthesized AgNPs.

Source Feature(s) Bacterial strain(s) Fungal strain(s) Method(s) Ref.

Grass waste(aqueous grass extract)

crystalline, spherical-oblate, 4-34 nm

A. baumannii andP. aeruginosa

F. solani andR. solani

Agar plate methods, MIC and MBC [68]

Indigofera tinctoria(aqueous leaf extract)

crystalline, spherical, 9-26 nm

B. pumilis, E. coli, Pseudomonas sp. and S. aureus

A. fumigatus and A. niger

Well diffusion method [30]

Tropaeolum majus L.(aqueous leaf extract)


E. coli, E. faecalis, P. aeruginosa, S. aureus and S. typhi

A. niger, C. albicans, Mucor sp., P. notatum and T. viridiae MIC [69]

Chlorophytum borivilianum L.(methanol callus extract)

crystalline, spherical, 35.1-168.0 nm

B. subtilis, E. coli, P. aeruginosa and MR-S. aureus C. albicans Disc diffusion

method [34]

Psidium guajava(aqueous leaf extract)

fcc structure, spherical, 20-35 nm, -20.17 mV

A. creatinolyticus, A. faecalis, B. aryabhattai, B. megaterium, B. subtilis and E. coli

A. niger, R. oryzae and S. cerevisiae


Phyllanthus amarus(aqueous leaf extract)

fcc structure, flower like, 30-42 nm, -45 mV

Bacillus sp., E. coli, Pseudomonas sp. and Staphylococcus sp.

A. flavus, A. niger and Penicillium sp.

Disc diffusion method [71]

Origanum vulgare L.(aqueous plant extract)

crystalline fcc structure, spherical, 2-25 nm

E. coli, M. luteus, P. aeruginosa, S. aureus, S. epidermidis, S. sonnei, S. typhimurium and MR-S. aureus

A. alternate, A. flavus, P. alba and P. variotii


Solanum trilobatum(aqueous bark extract)

crystalline, spherical,10-50 nm,-16 mV

Bacillus sp. andE. coli A. niger Well and disc

diffusion method [73]

Indigofera hirsute L.(aqueous leaf extract)

crystalline, spherical, 5-10 nm, -37 mV

B. subtilis, E. coli, P. aeruginosa and S. aureus

C. albicans, C. nonalbicansand C. tropicalis

Disc diffusion method and MIC [74]

Zingiber officinale(aqueous and ethanol plant extract)

spherical, 10.10-18.33 nm

B. subtilis, E. carotovora, S. aureus, K. pneumoniae and P. vulgaris C. albicans Disc diffusion

method [75]

Allium sativum L.(aqueous and ethanol plant extract)

spherical, 13.33-22.69 nm

B. subtilis, E. carotovora, S. aureus, K. pneumoniae and P. vulgaris C. albicans Disc diffusion

method [75]

Synedrella nodiflora(aqueous leaf extract)

crystalline, cubical, 20-88 nm

B. subtilis, E. coli, Pseudomonas sp. and Streptococcus sp.

Aspergillus sp. and Penicillium sp.


Mussaendra glabrate(aqueous leaf extract)

crystalline, fcc, spherical, 51.32 nm

B. subtilis, E. coli, P. aeruginosaand S. aureus

A. niger and P. chrysogenum


Bauhinia purpurea(aqueous leaf extract) fcc, spherical B. subtilis, E. coli, P. aeruginosa

and S. aureus A. nidulans and A. niger Well diffusion method [78]

Scoparia dulcis L.(aqueous leaf extract)

crystalline, spherical, 3-18 nm, -22.7 mV

B. subtilis, E. coli, P. aeruginosaand S. aureus A. niger and C. albicans Disc diffusion

method [79]

Petiveria alliacea(aqueous leaf extract)

crystalline, 16.70 - 33.74 nm

E. coli, K. pneumoniae and S. aureus A. niger and A. flavus Broth culture and

Agar plug method [80]

Clove eugenol(aqueous clove extract) twinned, 10-85 nm E. coli, P. aeruginosa

and S. aureus C. albicans Broth dilution and Well diffusion method [81]

Trigonella foenum-graecum(aqueous seed extract)

fcc structure, 108 ± 9.5 nm

E. coli, P. aeruginosa, P. vulgaris and S. aureus _ Disc diffusion

method [82]

Daucus carota(aqueous carrot extract)

crystalline, spherical, 20 nm

B. cereus, K. pneumoniae, P. aeruginosa and S. aureus _ Disc diffusion

method [83]

Dodonaea viscosa(methanol leaf extract)

fcc structure, spherical, 40-55 nm, -88.0 mV _ C albicans, C. glabrata

and C. tropicalis MIC and biofilm susceptibility assay [84]

Yucca shilerifera(aqueous leaf extract) 729 nm, 195.1 mV _ F. solani and M. phaseolina Dual culture

technique [85]



Table 3: Anti-parasitic activity of plant extract synthesized AgNPs.

Source Feature(s) Vector(s) Life stage(s) LC50 value(s) at respective life stage Outcome(s) Ref.

Cassia fistula(aqueous extract of fruit pulp)


A. albopictusand C. pipienspallens

larvae (I-IV instar) and pupae

8.3, 9.3, 12.0, 16.5 and 33.1 mg/L;1.1, 1.2, 4.6, 9.7 and 18.8 mg/L

shown excellent activity [95]

Aquilaria sinensis(essential oil)

crystalline, fcc, spherical, 15-55 nm A. albopictus


0.81, 0.83, 1.02, 1.12 and 0.90 mg/L

showed highest toxicity at low concentrations due to small size [96]

Pogostemon cablin(essential oil)

crystalline, fcc, spherical, 16-87 nm A. albopictus


0.85, 0.91, 1.04, 1.19 and 0.84 mg/L

showed highest toxicity at low concentrations due to small size of NPs

[96]

Chrysanthemum(ethanol leaf extract)

clustered and irregular shape, 40-100 nm

Ae. aegypti IV instar larvae 13.89 ppm effect of the particles was higher

than the extract by 7.57 times [97]

Holarrhena antidysentericaL.(aqueous bark extract)


Ae. aegypti andCx. quinquefasciatus

III instar larvae 5.53 and 9.3 ppm

NPs proved to be nontoxic against the non-target aquatic organism, M. thermocyclopoides Harada

[98]

Cleistanthus collinus(aqueous leaf extract)

crystalline, triangular and pentagonal, 66.27-75.09 nm

An. stephensi andAe. aegypti

IV instar larvae 11.05 and 11.38 mg/L dose-dependent activity [99]

Strychnos nux-vomica(aqueous leaf extract)

crystalline, irregular, spherical and round, 54.45-60.84 nm

An. stephensi andAe. aegypti

IV instar larvae 8.82 and 7.75 mg/L dose-dependent activity [99]

Artemisia herba-alba(aqueous leaf extract)

crystalline, spherical and round, 43-74 nm

(I) An. stephensi,Ae. aegypti andCx. quinquefasciatus

IV instar larvae

9.76, 10.7 and 11.43 μg/mL high larvicidal against all Indian

and South African strains [100](SA) Ae. aegypti and Cx. quinquefasciatus

IV instar larvae

33.58 and 38.06 μg/mL

Aglaia elaeagnoidea(aqueous leaf extract)

fcc structure, poly-dispersed, spherical, 2-6 nm

An. stephensi,Ae. aegypti andCx. quinquefasciatus

larvae 20.66, 22.80 and 24.91 μg/mL

particles were found safer to non-target larvivorous fish (G.affinis), backswimmer (A.bouvieri), and waterbug (D.indicus)

[101]

Carmona retusa(aqueous leaf extract)

fccstructure,spherical and cubic, 20-40 nm

An. stephensi,Ae. aegypti andCx. quinquefasciatus

early IV instar larvae

116.681, 198.766 and 83.553 ppm high larvicidal against all strains [102]

Table 2: Antiviral activity of plant extract synthesized AgNPs.

Source Feature(s) Strain Mode of application Outcome(s) Ref.

Andrographis paniculata(aqueous leaf extract)

spherical, 70-95 nm, -21.4 mV Chikungunya virus virus was propagated in

VERO cells75-100% inhibition at 31.25 μg/mL for cytopathic effect [89]

Phyllanthu sniruri(aqueous leaf extract)

spherical, 70-120 nm, -20 mV Chikungunya virus virus was propagated in

VERO cells did not show any significant inhibition [89]

Tinospora cordifolia(aqueous bark extract)

spherical, 50-70 nm, -17 mV Chikungunya virus virus was propagated in

VERO cells25-49% inhibition at 250 μg/mL for cytopathic effect [89]

Panax ginseng (aqueous root extract)


Influenza virus(strain A/PR/8)

MDCK cells were infected with virus

activity was detected by sulforhodamine B assay, 15.12% inhibition at 0.25 M [90]

Bruguiera cylindrica(aqueous leaf extract)


Dengue virus type-2New Guinea C strain

virus was propagated in C6/36 cells

NPs at 30 μg/mL inhibited the dengue viral envelope (E) protein production in vero cells and dengue viral E gene expression was down-regulated

[91]

Moringa oleifera(aqueous seed extract)

crystalline, fcc, spherical, 100 nm

Dengue virus type-2New Guinea C strain

virus was propagated in C6/36 cells

NPs at 20 μL/mL showed 3.2 log10 TCID50/mL, while control (no NPs) has 7 log10 TCID50/mL viral titer

[92]

Rhizophora lamarckii(aqueous leaf extract)

crystalline, spherical,12-28 nm

Human Immuno-deficiency Virus (HIV)

In vitro HIV-1 Reverse Transcriptase Assay

inhibition in a dose dependent manner, with an IC50 of 0.4 μg/mL [93]



Table 4: Anti-oxidative and anti-cancer activity of plant extract synthesized AgNPs.

Source Feature(s)Anti-oxidative activity Anti-cancer activity

Outcome(s) Ref.Assay IC50 (μg/

mL) Assay Cell line IC50 (μg/mL)

Manilkara zapota L.(aqueous leaf extract)

fcc, spherical, 10-80 nm _ _ MTT

HCT116 8 MTT assay, fluorescence, and SEM of cells stained with PI, AO/EB to assess cellular changes and apoptosis visualized by annexin V-FITC

[42]HeLa 6

A549 29

Combretum quadrangulare(95 % ethanol leaf extract)

spherical, 220-230 nm, -64.2 ± 0.3 mV _ _ MTT A549 545.2

morphological study, Hoechst staining, Annexin V/Phycoerythrin assay and cell cycle assay. Transwell assay to analyze anti-migratory effect

[113]

Pandanus odorifer(aqueous leaf extract) 5-9 nm _ _ MTT RBL 3.4

exhibits concentration dependent activity and anti-metastasis

Elephantopus scaber(aqueous leaf extract)

crystalline, spherical, 37.86 nm DPPH 6.629 MTT

A375 15.68 ± 0.15 Superior anticancer activity than plant extract

[111]L929 65.49 ± 0.40

Punica granatum(aqueous leaf extract)


DPPH 67MTT HepG2 70 Dose-dependent

cytotoxicity [29]ABTS 52

Allium sativum L.(aqueous garlic extract)

crystalline, fcc, spherical, 6.13-8.46 nm

DPPH 6.89 ± 0.66

MTT

MCF7 19.94 ± 1.13Apoptosis confirmation by Hoechst 33258 staining assay on A549 cells

[110]

ABTS 6.88 ± 1.08 HeLa 16.75 ± 0.27

Hydroxyl 10.24 ± 0.83 Hep2 27.63 ± 0.88

Superoxide 9.29 ± 0.67 A549 13.26 ± 1.01

H2O2 12.06 ± 0.15 NHDF > 100

Citrus x Clementina (aqueous peel extract)

crystalline, fcc, spherical, 5-25 nm

DPPH 63.4MTT C6 60 dose-dependent

activity [114]ABTS 49.6

Spermacoce hispida (aqueous leaf extract)

crystalline, fcc, rod and irregular, 19.23 m2 g-1

DPPH 42

MTT HeLa 48.98dose-dependent decrease in HeLa cell line viability

[115]ABTS 61

H2O2 33

Indigofera hirsute L.(aqueous leaf extract)

crystalline, fcc, spherical, 5-10 nm, -37 mV

DPPH 63.43

MTT

PC3 68.5percentage of cell viability decreases with increase in the concentration

[74]COLO205 85.2

H2O2 89.93B16F10 80.9

CHO 0

Carica papaya(aqueous latex extract)

crystalline, fcc, spherical, 12 ± 6 nm

Ae. aegypti andCx. quinquefasciatus

II and III instar larvae

1.46; 1.76 and 1.58; 2.47 ppm high larvicidal activity [103]

Sargassum polycystum(aqueous extract)

crystalline, cubical, 20-88 nm

An. stephensi,Ae. aegypti, Cx. quinquefasciatus and Cx. tritaeniorhynchus

IV instar larvae

3.07, 0.30, 0.57 and 4.8 μg/mL

Showed potential activity forAe. aegypti and Cx. quinquefasciatus

[104]

Cocoa beans(aqueous bean extract)

spherical, dispersed, 8.96-54.22 nm An. gambiae I instar

larvae 44.37 μg/mL showed good larvicidal activity [105]

Musa paradisiaca(aqueous stem extract)

crystalline, fcc, spherical, 30-60 nm An. stephensi


3.642, 5.497, 8.561, 13.477 and 17.898 ppm

dose dependent effect was found [106]

Hugonia mystax(aqueous leaf extract)


An. stephensi, andCx. quinquefasciatus

late III instar larvae

14.45 and 17.46 μg/mL

NPs have affected the survival of all the tested larvae [107]



is the biocompatibility of AgNPs with the cells. AgNPs synthesized using Toxicodendron vernicifluum aqueous bark extract were observed to be biocompatible to mouse embryo fibroblast cell line (NIH3T3 cells) at various concentrations [139]. Althaea officinalis leaf extract synthesized AgNPs were tested for genotoxicity evaluation in vivo on Zebra-fish (Danio rerio). Exposure of zebra-fish to AgNPs resulted in fish death after 24 h, signifying high toxicity. Eco-toxicity was also evaluated using Allium cepa. Treating with AgNPs resulted in mitotic indexes increase and also showed higher aberration indexes [140]. AgNPs synthesized using Clinacanthus nutans leaves extract were evaluated for its non-toxicity towards normal mouse embryonic fibroblast (3T3-L1) cell lines [141]. Fabrication of biocompatible AgNPs with no side effects can be advantageous in making cancer treatment very successful.

AgNPs synthesized using Gum acacia and loaded with hesperidin (HP) were used as nano-drug in arthritic rats to check for its anti-arthritic potential. HP loaded AgNPs were synthesized successfully and evaluated for arthritic phenomenon intruding TLR-2 and TLR-4 mechanism. Results indicated that nano-formulation enhanced the efficacy

of pure compound and can be a promising future therapeutic agent for arthritis [142]. Anticoagulant activities of AgNPs synthesized from Petiveria alliacea L. aqueous leaf extract was evaluated, which resulted in inhibition of coagulation of human blood [80]. Anti-urolithiatic potential of aqueous leaf extract of Tragia involucrate mediated synthesis of AgNPs was evaluated in Ethylene glycol-induced hyperoxaluria wistar rat model. AgNPs showed potent inhibitory activity on formation of CaOx stones [143].

Wound-healing property of AgNPs from Catharanthus roseus methanol leaf extract was studied. The wound-healing activity of synthesized AgNPs was determined through an excision wound model using male albino mice. Mice treated with AgNPs have shown significant potential for wound healing when compared with control groups. Wounds treated with AgNPs have shown no sign of microbial contamination, pus formation or bleeding during the duration of treatment, whereas inflammation was observed in wounds of control groups. At the end of experiment duration, 98% of wound closure was observed in AgNPs treated groups, whereas only 85% closure was noticed in control groups [54]. Delonix elata aqueous leaf extract synthesized AgNPs were studied as wound healing agent in the wound care after anorectal surgery. It is evident from the results that the wounds treated with AgNPs displayed a significant wound epithelialization in comparison with control groups. This is attributed to the capability of AgNPs in affecting the cytokine cascade, which in turn could improve appearance of wound through immune-modulation [144].

EnvironmentalDue to the properties of AgNPs such as: high selectivity,

stability and activity along with the large surface area per volume ratio; AgNPs are extensively employed as catalysts for numerous environmental applications such as in the degradation or reduction of numerous pollutants or organic dyes which are toxic for environment and ecosystem [36].

Cassia angustifolia(aqueous flower extract)

crystalline, fcc, spherical, 10-80 nm, -9.1 mV

DPPH 47.24 ± 0.5

MTT MCF7 73.82 ± 0.50 Dose-dependent cytotoxic activity [116]H2O2 78.10 ± 1.2

FRAP 63.21 ± 0.75

Derri trifoliate(aqueous seed extract)

crystalline, spherical, 16 ± 7 nm, -21 mV DPPH 8.25 MTT A549 86.23 ± 0.22

exhibited moderate anti-proliferative activity

[117]

Arnebia hispidissma L.(aqueous root extract)

crystalline, irregular, 10-75 nm, -23.6 mV

DPPH 9.86MTT HeLa 4.44 dose-dependent

activity [39]H2O2 53.78

Bauhinia purpurea(aqueous leaf extract) fcc, spherical DPPH 42.37 MTT A549 27.97 dose-dependent

activity [78]

Thymus kotschyanus(aqueous plant extract)

fcc, spherical, 40-50 nm DPPH _ MTT HeLa _ Lack of cytotoxicity [118]

Phoenix dactylifera(aqueous root hair extract)

crystalline, spherical, 15-40 nm _ MTT MCF7 29.6

apoptosis confirmation by acridine orange/ethidium bromide staining and cell cylce analysis

[119]

Figure 5: Schematic representation of the mechanisms involved in anticancer activity of AgNPs.



Reduction of nitro-organic pollutantsApplication of nitro-organic compounds in the production

fungicides, pesticides, plasticizers, pharmaceuticals, explosives and dyes has resulted in the accumulation of these pollutants in water and soil, raising an alarm for serious environmental

problem [145]. USEPA (United States Environment Protection Agency) has classified these anthropogenic compounds as “priority pollutants” due to their hazardous nature when released into the environment. These pollutants are retained for longer duration by the soil and water due

Table 5: Anti-diabetic activity of plant extract synthesized AgNPs.

Source Feature(s) Mode of experiment

IC50 (μg/mL) Outcome(s) Ref.

Punica granatum(aqueous leaf extract)


in vitro – enzymes inhibition

α - glucosidase and α - amylase

65.2 and 53.8 Dose-dependent inhibition [112]

Bauhinia variegate(aqueous flower extract)


in vitro – enzyme inhibition α – amylase 21 Non-competitive inhibition mode, Line-weaver

and Burk kinetics [124]

Argyreia nervosa(aqueous leaf extract)


in vitro - enzymes inhibition


51.7 and 55.5

NPs showed significant inhibition for α - glucosidase and α - amylase [125]

Musa paradisiaca(aqueous stem extract)


in vivo - male albino rats

Sprague-Dawley strain _ blood glucose levels were decreased and insulin

and glycogen levels were increased simultaneously [106]

Gymnema sylvestre(aqueous leaf extract)

crystalline, spherical, 21.5 nm

in vivo - male albino rats Wistar strain _ shown profound effect by regulating blood

glucose levels, insulin levels and lipid profile [126]

Saraca asoca(aqueous leaf extract)


in vitro – enzyme inhibition α – amylase 0.35 mM [127]

Pouteria sapota(aqueous leaf extract) _

in vitro - enzyme inhibition α – amylase 240 inhibition % is more in the case of NPs

compared with the leaf extract[60]

in vivo - female albino rats Wistar strain _ significant reduction in blood sugar levels were

noted in rats

Holoptelea integrifolia(aqueous leaf extract)


in vitro - enzyme inhibition α – amylase _ 100 μL concentration 86.66±5.03% inhibition [128]

Trigonella foenum-graecum (aqueous seed extract)

spherical, irregular, 73.18 nm

in vivo - male albino rats Wistar strain _ potential therapeutic agent in the management

of type 2 diabetes [129]

Psoralea corylifolia(aqueous seed extract)

crystalline, irregular, 15-25 nm

in vitro - enzyme inhibition

Phosphatase 1B (PTP 1B) _ 10 μM showed 37.16% inhibition [130]

Cinnamomum cassia(aqueous plant extract) _ in vivo - male

albino ratsSprague-Dawley strain _ regenerative potential in diabetes-induced

kidney damage [131]

Avicennia officinalis(aqueous leaf extract)

crystalline, 181.4 nm



150 and 280 good inhibitory effect [123]

Xylocarpus granatum(aqueous bark extract)

crystalline, 98.77 nm



130 and 190 good inhibitory effect [123]

Lawsonia inermis(aqueous leaf extract)


in vivo - male albino rats Wistar strain _

may be due to their less particle size, greater surface area glucose levels were controlled at dose of 200 mg/kg

[132]

Momordica charantia(aqueous fruit extract)

crystalline, spherical, 22.5 nm

in vivo - male albino rats Wistar strain _ shown potent hypoglycemic property [133]

Eysenhardtia polystachya(aqueous: methanol bark extract(1:1))

spherical, 10-12 nm,-32.25 mV

in vivo –fish model

adult zebrafish _

hyperlipidemia, insulin secretion-enhanced hyperglycemia and promotes pancreatic β-cell survival in glucose-induced diabetic zebra fish

[134]

Heritiera fomes(aqueous leaf extract) fcc, 50 nm in vitro - enzyme

inhibition α – amylase 280.39 displayed better anti-diabetic potential [135]

Sonneratia apetala(aqueous leaf extract) fcc, 20-30 nm in vitro - enzyme

inhibition α – amylase 273.48 displayed better anti-diabetic potential [135]

Lonicera japonica(aqueous leaf extract)

crystalline, fcc, spherical, hexagonal, 53 nm, -35.6 mV


α - glucosidase and α – amylase

37.86 and 54.56

NPs were identified to be reversible noncompetitive inhibitors and Ki values of 25.9 mg (α - amylase) and 24.6 mg (α - glucosidase)

[136]

Solanum nigrum(aqueous leaf extract)


in vivo - male albino rats Wistar strain _ improved the dyslipidemic condition and reduced the

blood glucose level over the treatment period [137]



to their high stability and solubility index. Nitro-organic pollutants are reported for causing serious health hazards upon ingestion by the living beings [146, 147]. Various research groups have extensively worked on the degradation of these nitro-organic pollutants using sodium borohydride (NaBH4) and plant synthesized AgNPs as catalyst, few examples were mentioned in table 6.

The AgNPs synthesized from plant extracts are effectively utilized for their catalytic activity in the degradation of the nitro-organic pollutants present in the wastewater or effluents from industries. This catalytic activity is achieved due to the possibility of efficient transfer of electrons from borohydride ions (BH4-) to the nitro-organic pollutants. This is achieved due to high driving force of NPs-facilitated electron transfer because of their high Fermi level shift in the presence of highly electron injecting BH4- ions. These reactions are carried out in an aqueous medium and at room temperature [36].

Reduction of organic dyesEffluent from the industries causes severe environmental

pollution concerns due to the extensive usage of numerous organic dyes in the food, paper, pharmaceutical, paints, cosmetics and textile industries [159, 161, 163]. These organic dyes were degraded by employing numerous remediation operations [164, 165]. It has been proven very intricate to reduce or degrade these dyes from the effluents of industries due to their structure complexity and high stability. Because of the above stated reason, many research groups have shown extensive interest in the organic dyes degradation using plant mediated AgNPs, few examples were mentioned in table 6.

It is well-known that the photo-catalytic activity is dependent over the size of AgNPs. Due to their redox potential metals in bulk form are chemically stable [166]. An effective catalyst will have redox potential in between the redox potential of acceptor and donor system [167]. Based on the above-stated fact, many researchers have suggested that biogenic metal NPs can act as redox catalyst by mediating electron transfer between organic dyes (acceptors) and plant extract (donors). This mechanism is known as an electron relay effect [168].

Toxicity of AgNPsAccording to the literature, various biological models

have been used to evaluate the toxicity of the plant extract mediated AgNPs such as bacteria, fungi, protozoa, virus, mammalian cells, plants, crustaceans, fish and mammals which offer different levels of complexities (Table 7). Yet still, the exact mechanisms involved in the toxicity of AgNPs were not completely understood for any biological models. This statement signifies the development of new strategies which enables to study the mechanisms involved in the toxicity towards various organisms and also to compare the toxic effects of AgNPs fabricated via conventional, traditional and green mechanisms.

AgNPs which are employed in different applications will enter into the environment followed by formation of

complex with other metal-based materials, binding to organic matter and sometimes dissociate into ions. This in turn causes disruption in normal biological and ecological processes at cellular level, this result in the potential toxicological effects of AgNPs [183]. Leaching of AgNPs from commercial products and deliberate release of AgNPs into contaminated and wastewater are the main sources of AgNPs entry into the environment [183]. According to the various reports published in recent years, parameters such as ionic strength, composition of natural organic matter, pH, aggregation, stability, light and temperature conditions greatly influence the AgNPs toxicity as well as their fate in the natural environment [184, 185]. Presence of AgNPs in the natural environment will affect the lower trophic levels first, i.e., microbes. AgNPs have been already proved to be toxic to both anaerobic and aerobic bacteria isolated from wastewater treatment plants [186].

As the use of AgNPs in the consumer products has been increasing alarmingly, it is wise to evaluate their potential toxic effects on microorganisms, plants, humans and environment related with their increased usage (Figure 6). The potential routes for human exposure could be skin, gastrointestinal and respiratory systems, which acts as interface between the external environment and internal organs of human body [187]. Additional possible entry routes can be the genital tracts because of the application of AgNPs in various hygiene related products, also by systemic administration (use of AgNPs in MRI imaging, Photo-imaging and therapeutic purposes), incorporating in catheters, medical implants and lastly through wound dressings [55, 188-190].

AgNPs are normally reported as potent antimicrobial agents, which show less or no toxicity towards normal mammalian cells. However, several in vitro studies reported the toxicity of AgNPs towards different cell lines such as human lung epithelial cells, murine stem cells, rat hepatocytes and neuronal cells [191, 192]. The AgNPs toxicity was also assessed using various in vivo models. The toxicity investigations conducted on rat ear model demonstrated that exposure to AgNPs has caused severe mitochondrial dysfunction leading to permanent or temporary loss of hearing which is dependent on exposure-dose response. Even AgNPs at minimal dose were absorbed by retinal cells leading to oxidative stress which

Figure 6: Impact of AgNPs toxicity on microorganisms, plants, humans and environment.



Table 6: Catalytic activity of plant extract synthesized AgNPs.

Source Feature(s) Nitro organic pollutant(s) Outcome(s) Organic dye(s) Outcome(s) Ref.

Elephantopus scaber(aqueous leaf extract)

crystalline, fcc, spherical, 37.86 nm

4-nitrophenol,4-nitroaniline and2-nitroaniline

successfully reduce organic nitro compounds

eosin Ysuccessfully degraded by NPs

[111]

Albizia chevalier(aqueous bark extract)

crystalline, spherical, 30 nm 4-nitrophenol 83% reduction in

11 min congo red 93% reduction in 6 min [148]

Thymbra spicata(aqueous leaf extract)

crystalline, spherical, 7 nm 4-nitrophenol reduction happened

in 1 minrhodamine B and methylene blue

reduction of dyes in 1 min [149]

Cicer arietinum(aqueous leaf extract)

spherical, 88.8 ± 4 nm, –13.6± 0.6 mV 4-nitrophenol 90% reduction in

10 minmethylene blue and congo red

reduction in 15 min [150]

Hyphaene thebaica(aqueous fruit extract) spherical, 20 nm 4-nitrophenol formation of silver

complex with 4-AP congo red 80% reduction in 10 min [151]

Cuminum cyminum(aqueous seed extract)

crystalline, spherical, 16 ± 2 nm 4-nitrophenol reduction under 16

minmethylene blue, methyl red and rhodamine B

reduction under 2 min [152]

Mussaendra glabrate (aqueous leaf extract)

crystalline, fcc, spherical, 51.32 nm 4-nitrophenol reduction under 9

minrhodamine B and methyl orange

reduction under 9 and 7 min

[77]

Aglaia elaeagnoidea (aqueous flower extract)

crystalline, fcc, spherical, 17 nm 4-nitrophenol reduction under 15

minmethylene blue and congo red

reduction under 5 and 10 sec [153]

cassia auriculata(aqueous flower extract)

crystalline, fcc, triangle, spherical, 10-35 nm

4-nitrophenol reduction under 12 min methyl orange reduction

under 16 min [154]

Acorus calamus(aqueous rhizome extract)

spherical, 31.83 nm, -32.3 mV

4-nitrophenol,3-nitrophenol and2,4,6-trinitrophenol

reduction under 8, 9 and 16 min

acridine orange, congo red, coomassie brilliant blue, cresol red, eosin Y, eriochrome black T, methylene blue, methyl orange, methyl red, phenol red and rhodamine B

reduction under 60, 10, 5, 6, 8, 16, 12, 3, 15, 18 and 3 min

[155]

Stemona tuberosa L.(aqueous plant extract)

crystalline, spherical, 25 nm 4-nitrophenol 90% reduction in

1 minmethylene blue, methyl orange and methyl red

90, 60 and 0% reduction in 1 min

[156]

Sterculia acuminate(aqueous fruit extract)

crystalline, spherical, ~10 nm, -39.2 mV 4-nitrophenol reduction in 22 min

methylene blue, methyl orange, direct blue 24 and phenol red

reduction in 3, 3, 3 and 6 min [157]

Plumeria alba(aqueous flower extract)

fcc, spherical, 36.19 nm 4-nitrophenol reduction in 8 min methylene blue and

ethidium bromidereduction in 2 and 3 h [158]

Piper longum(aqueous catkin extract)

crystalline, spherical, 15-40 nm, -24.3 mV o-nitrophenol reduction in 3 min methylene blue and

methyl orangereduction in 5 and 4 min [159]

Indigofera tinctoria(aqueous leaf extract)

crystalline, spherical, 9-26 nm o- and p- nitroaniline NPs catalyzed

reaction is very fast _ _ [30]

Prosopis juliflora(aqueous bark extract) _ 4-nitrophenol 90% reduction in

80 min _ _ [28]

Coffea sp.(aqueous bean extract) _ 4-nitrophenol reduction under 2

min _ _ [160]

Bauhinia purpurea(aqueous leaf extract) fcc, spherical _ _ methylene blue and

rhodamine Breduction in 4 min [78]

Leucas aspera(aqueous leaf extract)

crystalline, fcc, spherical, 20-40 nm _ _ optilan red and lanasyn

blue

20.8 and 14.75% degradation in 45 min at 125 μg/mL

[161]

Bridelia retusa(aqueous leaf extract) _ _ _ rhodamine B reduction in

9 min [162]



eventually caused severe functional and structural disruption [193].

To analyze, assess and understand the adverse effects as well as mechanisms related to AgNPs-based products, in-depth systematic methodologies are to be developed considering cellular, organ and animal models. In regard to the in vivo bio-distribution and biocompatibility investigations, there is evidence that AgNPs can cause severe alterations to vital organs (physiological, functional and structural). For instance, AgNPs inhaled might result in deposits inside the regions of alveoli, causing injuries to lung and might also result in severe alterations in the kidney, liver as well as nervous system. Deposition of AgNPs in intratracheal region can upset vascular reactivity and can lead to intense ischemia injury or cardiac reperfusion [194, 195].

AgNPs exposure to humans can occur from work places (manufacturing, processing, disposal and recycling facilities) and surrounding environment [196]. AgNPs exposure are categorized into two main types: engineered or fabricated AgNPs (conventional, traditional and green synthesis approaches) and combustion derived AgNPs (welding fumes, exhaust particles and particulate matters). Engineered or fabricated AgNPs are mono-dispersed and definite in physicochemical features. Their toxicity is defined based on the toxicological laboratory investigations [196]. In contrast, combustion derived AgNPs are poly-dispersed, highly or poorly soluble, complex in chemical nature and their toxicity is not defined (due to the modifications which occur due to the environmental interactions) and dependent on the physicochemical features of the NPs [196, 197]. Few

Table 7: Biological models used to determine the plant extract mediated AgNPs toxicity.

Source Feature(s) Study model Organism(s) Ref.

Ficus carica(aqueous fruit extract) spherical, 54-89 nm Animal Swiss albino female rat [169]

Acorus calamus(aqueous rhizome extract) spheres, 31.83 nm, -32.3mV Animal male Wistar rats [170]

Passiflora caerulea(aqueous leaf extract) crystalline, 15.95 nm, spherical Fish (embryos/larvae) Zebra-fish [171]

Ocimum tenuiflorum(aqueous leaf extract) spherical, 40-60 nm Animal male albino mice [172]

Rumex acetosa(aqueous flower extract) spherical , 20-30 nm, -13.43 mV

Cell line human umbilicalvein endothelial cells [173]

Fish (embryo) Zebra-fish

Cissus quadrangularis(aqueous stem extract) _

Fish (larvae) Poecilia reticulata[174]Micro-crustacean

(adults) Ceriodaphnia cornuta

Alcea rosea(aqueous leaf extract)

fcc, crystalline, spherical and quasi-spherical

Phytoplankton Chlorella vulgaris

[175]Zooplankton Daphnia magna

Fish Danio rerio

Desmodium gangeticum(aqueous root extract) spherical, 1.24 nm

Cell line Pig kidney epithelial cells[176]

Animal male albino Wistar rats

Solanum nigrum(aqueous leaf extract)

fcc, crystalline, spherical, 10-50 nm, -23.5 mV

Fish (larvae) Poecilia reticulata

[177]Micro-crustacean Ceriodaphnia cornuta

Protozoan Paramecium sp.

Eichhornia crassipes(aqueous leaf extract) 58.25 nm, -18.5 mV Plant Allium cepa [178]

Ferulago macrocarpa(aqueous flower extract) crystalline, spherical, 14-25 nm

Bacteria E. coli and S. aureus

[179]Fungi Candida albicans

Cells Peripheral blood mononuclear cells

Leonotis nepetifolia(aqueous leaf extract)

fcc, crystalline, spherical, irregular, 37.5 nm, -12.3 mV

Insect Spodoptera litura

[180]Cotton bollworm Helicoverpa armigera

Mosquito (larvae) C. quinquefasciatus and A. aegypti

Lampranthus coccine(Methanol aerial parts extract) spherical, 10.12-27.89 nm Virus HSV-1, HAV-10 and Coxsackie B4 [181]

Sphaeranthus indicus(aqueous leaf extract) crystalline, spherical, 25 nm

Crustacean Artemia nauplii[182]

Plants A. cepa and Gloriosa superba



epidemiological investigations have reported that exposure to increased levels of combustion derived AgNPs can result in severe health effects in humans, which includes increase in mortality and morbidity rates associated with cardiovascular as well as pulmonary diseases among vulnerable populaces [197, 198].

In general NPs cause more toxicity in comparison to micro-particles and their bulk counterparts, mainly because of their capacity to infiltrate into living cells, move within the body and affect the physiological, structural integrity along with the functioning of primary organs [199]. The adverse health effects depend on NPs dose, concentration and composition [199]. One primary concern is the identification and separation of toxicity caused by NPs from other particles and components associated toxicology effects is nearly impossible. This can further result in exposure quantification errors upon the use of central monitoring data sheet instead of individual exposure data sheet [197]. The durability, dose and dimension commonly referred as “3-D’s” are the major significant properties which will determine the toxicity of AgNPs upon their association with live cells [200]. Furthermore, AgNPs toxicity can also be influenced by small size, shape, stability, aggregation, surface chemistry, mass and number of particles [197]. Severity of the toxicity of the AgNPs is also influenced by the mode of administration and exposure duration [201]. AgNPs in in vitro conditions undergo further modifications based on the ionic strength, pH, kinetic facility of electron transfers, ion species concentration, thermodynamic feasibility and finally reduction-oxidation potentials [197].

Though, nanomedicine and nanotechnology are advantageous to the field of medicine, the mechanisms involved in the AgNPs toxicity is not yet understood. Diverse cell lines, different exposure durations and numerous colorimetric assays were used in various investigations thus making it challenging to correlate the information obtained [197, 200]. The AgNPs dose and concentration range employed in in vitro investigations are often higher in comparison to in vivo investigations [197]. In vitro studies have certain limits: for instance, they cannot replicate various molecular as well as cellular associations occurring inside the living organism. Moreover, they cannot assess the functional, structural, physiological and developmental events occurring inside the individual [196]. For these reasons, a combination of both in vitro and in vivo experiments could enhance our capacity to understand and investigate the mechanisms involved in AgNPs toxicity [196, 197].

Field of nano-toxicology has gained significant momentum which applies traditional, conventional and standardized methods in the assessment of NPs toxicity. Although, standardization in assessment methods like type of test model (cell line, microbial species and animal species) and exposure conditions (dosage intervals, AgNPs concentration range, duration of exposure, cell density and animal weight) are required to correlate investigations performed by various research groups [202]. However, there is no proper understanding as to what constitutes minimum toxicity [197].

This might be due to the absence of reference NPs system which can be employed as a standard during evaluation. Even though, AgNPs based cytotoxicity and genotoxicity has been conveyed by numerous research groups, it is essential to understand that in vitro test results can vary from in vivo test results; hence they may not be relevant clinically. The concentration of AgNPs required for biomedical applications is yet to be standardized, hence the levels at which public might be exposed is highly uncertain [197, 199, 201].

The AgNPs toxic effects are inversely proportional to their dimensions. The smaller AgNPs have higher surface to volume ration, which means enhanced reactivity [203], damage to nucleic acids [204] and free radical production [197]. The toxicology investigations have demonstrated that small AgNPs (<100 nm) causes more severe respiratory health impacts and inflammation in comparison to bigger AgNPs (> 100 nm) [197, 200, 203]. Generally, small AgNPs demonstrate a higher degree of toxicity in comparison to large AgNPs of the same chemical composition, crystalline and lattice structure due to their removal from the environment is not easy as well as less efficient. They can also penetrate the cellular membrane with ease [197].

Aggregation of AgNPs has also considered as an element in determining their toxicity. Higher concentrations of AgNPs can promote NPs accumulation thus reducing their toxicity when compared with smaller concentration [197, 203]. Most of the aggregates estimated are greater than 100 nm in size and showed less toxicity due to their smaller reactive surface area and also the translocation of the AgNPs is fairly restricted. Furthermore, inorganic AgNPs are highly vulnerable to accumulation or aggregation in biological systems compared to organic AgNPs [202]. AgNPs tendency for aggregation in seawater, hard water and fresh water are mainly influenced by the particular type of organic matter or other natural colloidal particles present [50, 205]. The dispersion rate and state will affect the toxicity of AgNPs. However, there is every need to investigate the influence of several abiotic parameters (such as salinity, pH, organic matter, pressure and humidity) on the toxicity of AgNPs during eco-toxicology studies [205].

Lethality and cell mortality are two main factors which are evaluated in in vitro and in vitro investigations to determine the AgNPs toxicity. AgNPs have the tendency to exhibit toxicity through various routes and mechanisms which depend on their size as well as concentration. AgNPs can cause hemolysis, hem-agglutination and abnormal sedimentation in erythrocytes [206]. Various investigations have demonstrated that AgNPs can increase the levels of cellular hydrogen peroxide, nitric oxide, induce oxidative stress along with the up-regulation of the genes related to inflammation. Reactive oxygen species (ROS) production in human cell lines are dependent on the shape and size of AgNPs [207]. AgNPs can also obstruct in functional regulation of PLK1 protein, cytokinesis, centrosome duplication and chromosome segregation. AgNPs exposure for short term duration enhanced the ROS production, ERK signaling activation, cell



proliferation and cell survival. However, long-term exposure resulted in disrupting cell transformation, chromosomal instability, replicated segregation of genomes and hindered cell cycle in human fibroblast cells [208]. AgNPs also showed necrosis and induction through mitochondrial mechanism in human monoblastoid cells and lymphocytes [209]. They also exhibited severe toxic effects on oyster embryonic development causing increased expression of metallothionien gene in embryos, lysosomal destabilization in adult oysters, aggregation in gill tissues of fish inducing chromosomal aberrations and aneuploidy. p53 protein expression and p53-linked pro-apoptotic genes (p21, Bax and Noxa) are up-regulated and oxidative stress in the liver of zebra fish also part of the AgNPs toxicity [210-212].

AgNPs enter into the surrounding environment via air, soil and water during several human actions. Mostly, the employment of AgNPs for wastewater treatment, removal of toxic pollutants and textile dyes deliberately inserts or dumps manufactured or engineered AgNPs into the land or water habitats [50]. Once released into the environment, AgNPs dissociate into Ag ions when the thermodynamic factors of the habitat favors the AgNPs dissolution, these Ag ions cause more severe toxicity than AgNPs in the biological systems [50].

The toxicity of AgNPs is comparatively decreased by employing the green synthesis approach via plant extracts. The main factor for the reduced toxicity of the AgNPs depends upon its reducing, stabilizing and coating molecules, which are usually compatible with biological systems and environment. However, the main reason for coating of the AgNPs is to provide stability and thus preventing agglomeration or accumulation, but the biocompatibility feature of the coating makes the plant extract fabricated AgNPs employable for various biomedical applications [213]. Degree of biocompatibility of the AgNPs was evaluated using various in vitro and in vivo assays such as immunocytochemistry and cell viability assays by employing several types of normal cell lines such as human vascular endothelial cells, human lung cell line (MRC5) and Chinese hamster ovary cells [214]. Few investigations performed by various research groups provided the evidence needed to support the biocompatibility nature of the plant extract mediated fabrication of AgNPs [215, 216]. AgNPs synthesized using plant extracts of Rosa damascene showed compatibility with erythrocytes [215]. In another study, erythrocytes and human fibroblasts showed biocompatibility when exposed to Salacia chinensis aqueous bark extract synthesized AgNPs [216]. However, further in-depth investigations are much required to fully evaluate the biocompatibility of plant extract fabricated AgNPs using various in vitro, in vivo and animal models.

Risk Assessment of AgNPsThe advent of nanomedicine and nanotechnology has

made striking impact and their rise was considered as the major technological as well as engineering innovation after the industrial revolution. However, it is also considered as a

double-edged sword, which has not only valuable and useful applications but also has adversarial and hazardous impacts on microorganisms, plants, humans and environment as discussed in the previous section (Figure 6). Based on this reason, numerous governments, non-government organizations along with certified authorities (such as Environmental Health Services, World Health Organization, European Union, etc.) have recognized the significance for assessment of risk concerning the production, use and application of AgNPs based products around the world [201, 217].

Steps involved in risk assessmentRisk assessment is an intricate practice which evaluates

the risk/ hazard, exposure and dose-response information to describe as well as characterize the risk. In-turn, this information or data can be used to support, develop, set exposure and toxicity limits leading to risk estimation along with risk management services [217]. Following are the fundamental steps involved in the overall risk assessment (Figure 7)

i. Risk identification / formulation

ii. Risk assessment / evaluation

iii. Risk characterization

iv. Risk management

v. Risk communication

Identification or formulation of risk is a first step which evaluates the nature of the risk and provides information which is needed to identify the risk. This step decides the efficiency and

productivity of risk assessment by identifying the information which adds more value which is much needed during the decision-making process at the initial stages of the assessment. Hazard assessment evaluates the level and severity of the adverse effects on biological as well as environmental systems (usually during toxicology and eco-toxicology investigations). Exposure assessment determines the dose, concentration and duration of the exposure to living organisms along with the environment. Dose-response assessment (by toxicology and eco-toxicology investigation using in vitro, in vivo and animal models) provides necessary data on the predicted or model-

Figure 7: Schematic representation for Framework of risk assessment of AgNPs.



based dose exposure and biological responses that are deemed significant to living organisms and environment [218-220].

Risk characterization studies the outcomes related to hazard, exposure and dose-response assessments in order to deliver the information much needed to provide support during the risk management decision making as well as risk communication. Risk management develops the procedures and protocols required for managing as well as controlling the risk [218, 221]. Actively efficient risk communication is paramount in translating research and investigation outcomes to risk management practices [219]. In the absence of total risk characterization or presence of big uncertainties, additional precautions are required to control the exposure in order to safeguard the biological and eco-system [219]. Risk assessment is mandatory to make certain that human health and environment safety are not outweighed by commercial benefits.

Risk assessment methodologiesAt present, there are no authorized, certified and approved

guidelines required for development of risk assessment methods and testing procedures. The production and application of AgNPs on commercial scale is relatively different compared to their bulk counterparts. Also, there is very less amount of information accessible on the impact of AgNPs as well as AgNPs based products on microorganisms, plants, humans and environment. Risk assessment methodologies of the AgNPs based product manufacturing and applications should address the following considerations more specifically. Execution of these considerations will positively progress the risk assessment methodologies and also help in developing of dependable, robust and validated tools for screening as well as analysis [217-219, 221, 222].

• Safety of workers during the manufacturing process.

• Consumer safety from AgNPs based products.

• Safety of living organisms as well as environment due to the release of AgNPs from production and processing facilities.

• Risks involved in the disposal and recycling of AgNPs based products.

• Rigorous characterization and behavioural studies throughout the AgNPs life cycle.

• Dose-response investigations pertinent to public health exposure limits.

• Application of appropriate in vivo, in vitro and animal models which reveal the human exposure route along with their responses.

• Dose and time dependent investigations.

• Use of appropriate and reliable controls to enhance the data interpretation of toxicity studies.

• AgNPs exposure should be measured in terms of number of particles, total surface area, mass or in combination with other pollutants.

• AgNPs tendency to bioaccumulation or aggregation in

living organisms and in the environment.

• Route of human exposure to AgNPs (such as inhalation, implantation, injection, dermal contact and ingestion).

To this extant, there is no dependable and consistent data available on the impact of simultaneous exposure to several types of AgNPs, or on association between NPs as well as other pollutants or contaminants. Hence, risk assessment should be made on case-by-case basis [136]. Manufacturing process of products containing AgNPs should be investigated individually as well as thoroughly to assess the safety of human health along with the environment surrounding the production and processing facilities. In the absence of appropriate material safety data sheet, extra precaution should be exercised in regard to the AgNPs which are expected to be very reactive and persistent in living organisms along with the surrounding environment [218]. To detect the effects related to AgNPs exposure, a viable and robust testing method should be developed to decide whether the AgNPs will cause severe health issues or not. Several safety precautions and protocols are required to assess the safety of novel and emerging technologies rather than already existing safety measures. If these precautions are not in place, then public might not welcome or even castoff the AgNPs based products produced through nanotechnology.

Challenges involved in risk assessmentThe AgNPs properties may alter depending on the

synthesis parameters. The effects of AgNPs on living organisms (in vivo toxicity studies using animal models) under laboratory test conditions may differ from which observed in actual environmental conditions. Investigative studies conducted in laboratory on chosen animal models provide detail information on the possible adverse effects of AgNPs; however, laboratory conditions are simple in comparison to complicated environmental conditions [223].

Generally, the eco-toxicity investigative studies have been conducted on model organisms (such as bacteria, fungi, algae, small crustaceans, worms, shrimp, rats and fish) when exposed to AgNPs in a uniform experimental medium setup (such as sediment, solid media and water) for limited duration (1-day to 8-weeks) [169, 174, 177, 182]. Hence, it is possible to determine the toxic effects and mechanisms involved in the toxicity of AgNPs in regard to specific organism or species. Rarely, more intricate studies were executed to determine the toxic effects on entire microcosms. Such experiments are performed for a longer period of time (up to 1 year) and are implemented on numerous organisms (such as zooplankton, fish, algae and plants). Such experiments replicate the conditions of small habitats (such as ponds, rivers and fields) to an extent [223].

The risk assessment of AgNPs impact on environment is highly challenging because of the interaction of AgNPs with the surrounding components in several ways. Due to this reason, both indirect and direct effects have to be investigated. It is difficult to distinguish the indirect and direct effect of AgNPs on the environment. Indirect effects are usually associated with the transformation of AgNPs within the environment



or organisms. Toxic effects caused due to the modified AgNPs which are not present previously, in its original arrangement are categorized under indirect effects. AgNPs can dissolve in water, attach to other pollutants or contaminants or can undergo degradation to form different particle causing complications during quantification or measurement of the relevant AgNPs concentration to which individual species are exposed in a given habitat. These modified or transformed AgNPs may cause less or more adverse effects than the original AgNPs [217, 218, 221].

Based on the above reasons, it can be said that quantification of indirect effects through eco-toxicity investigations is not easy. Overall, investigation of the AgNPs fate, behavior and life cycle is much needed before quantifying the total impact of indirect as well as direct toxicity [218]. Moreover, intricate investigations (such as exposure, dose and effect assessments) need longer duration and further cause additional set of challenges during the interpretation of experiment results along with its analysis [201, 218]. These investigations are very costly, challenging to replicate and still has issues in extrapolating the experiment results to real life conditions [201, 217]. The methodologies to quantify and investigate the behaviour as well as fate of the AgNPs in the real-life environmental conditions are still under development.

Limitations of risk assessmentThe following are the limitations to overcome in order

to develop satisfactory risk assessments of AgNPs to provide safety to living organisms and environment:

• The leaching rate and leaching mechanism of AgNPs from processes and products.

• To develop protocols to assess the release of AgNPs from manufacturing processes and AgNPs based products.

• To determine the accurate exposure levels for both humans and environment.

• To calculate the toxicity of AgNPs based on the data available from their bulk counterparts.

• AgNPs effect at cellular, molecular and organ level and their responses to multiple dosages.

• Movement and behavior of AgNPs inside the living organisms.

• Exposure dose, exposure time as well as health related effects of workers associated with manufacturing, processing, disposal and recycling of AgNPs.

• Behavior of AgNPs in the ecosystem; their association, distribution and accumulation.

• Toxic effects of AgNPs on other species in ecosystem.

• New, reliable and robust techniques to measure the exposure levels in living organisms and environment through regular use of AgNPs based products.

• Insufficient in vitro, in vivo and animal model studies.

• Standard operating protocols and guidelines for toxicity

and eco-toxicity testing.

• Availability of information on the past and current exposure of AgNPs to public health and environment.

• To extrapolate the information available on the toxicity of Ag micro- and macro-particles to AgNPs and AgNPs of various morphologies.

Limitations and Future Research Prospectives

Even though green synthesized NPs have wide applicability in various fields, there are certain concerns which need to be addressed such as:

• Due to the diverse and complexity present in the phyto-composition of plant extracts, determining their role in the redox reactions to control the size, shape and crystal structure of the AgNPs under the experimental conditions is still puzzling.

• Various phyto-chemicals are either down- or up-regulated during the plant growth because of internal or environmental exposures, which in turn affects reproducibility, scaling up, homogeneity and poly-dispersion of the AgNPs.

• Experimental parameters such as extract volume, precursor concentration, temperature, pH, incubation time, stirring, solvent type and phyto-composition should be optimized, these can affect the AgNPs characteristics.

• Factors such as aggregation/agglomeration, surface area, purity, surface chemistry, cell-specific targeting, bio-distribution and controlled release should be studied extensively.

• Synthesis of AgNPs using plant extracts could reduce the toxicity of the AgNPs to some extent. However, evaluation of the toxicity biosafety and biocompatibility of these AgNPs is mandatory for its in vivo applications. It also provides information about the interaction and behavior of AgNPs within the cells and tissues.

• Better data is required on the present usage and discharge rates of dissolved AgNPs from consumer products as well as from manufacturing facilities. Preferably, this data should be integrated with online monitoring models.

• Reusability is an important feature for pollutant removal and waste water treatment applications. It is significant to determine the reusability of the AgNPs, without losing its adsorption efficiency.

• Extensive research should be carried out to synthesize AgNPs not only for specific pollutant removal but also for multi-pollutants and co-existing heavy metal systems.

• Behavior and adsorption mechanism of the AgNPs should be studied in the real waste water and adsorption systems.

• Long term stability of the AgNPs should be evaluated. It is essential that the AgNPs should remain stable, without any substantial differences in their structure, size, shape, activity



and morphology.

• There is an immediate necessity to develop analytical and quantifiable approaches which could identify, measure and characterize the AgNPs under normal environment. This data can be employed to detect both hazardous and adverse conditions.

• So far, cost estimation for bio-fabrication of AgNPs and also operational cost for waste water treatment were not reported in comparison to chemical and physical methods.

ConclusionAlthough there are numerous benefits of plant extract

synthesized AgNPs, there are many limitations and concerns which should be addressed as mentioned in above section. One major concern is the diverse and complex compositions of the phyto-compounds occur in the plant extracts, which depends upon numerous factors like: seasonal variations, nutrition, origin, mineral intake, etc. Although bio-fabrication of AgNPs is environmental friendly and simple, yet some challenging features such as strength of precursor, phyto-composition, plant extracts volume, solvent system, pH, temperature and reaction incubation time should be well studied because these can affect the size, morphology, crystal structure, magnetic behaviour and overall charge of NPs. So far, plant extract synthesized AgNPs are commonly studied only with reference to their overall composition, charge, shape and size. But, other features like surface chemistry, purity, aggregation, surface area are rarely reported in the literature. For the complete characterization and understanding, these features should also be studied well before employing bio-synthesized AgNPs in various applications. To establish the complete cytotoxicity and eco-toxicity profiles of bio-synthesized AgNPs, more efficient research is needed, if AgNPs are to be employed in biomedical and environmental applications. Another significant aspect which needs to be studied is the stability of the AgNPs, it is imperative that NPs should remain stable without any significant change in structure, size, shape, charge and morphology. Overall, fabrication of AgNPs using plant extracts is not only an eco-friendly choice but also a promising technology for low economic countries.

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