Toxicity of nanoparticles challenges and opportunitiesants, as well as cause NPs to become toxic by...

Applied MicroscopyRamanathan Applied Microscopy (2019) 49:2 https://doi.org/10.1007/s42649-019-0004-6

REVIEW Open Access

Toxicity of nanoparticles_ challenges and

opportunities

Amall Ramanathan

Abstract

Nanomaterials (NMs) find widespread use in different industries that range from agriculture, food, medicine,pharmaceuticals, and electronics to cosmetics. It is the exceptional properties of these materials at the nanoscale,which make them successful as growth promoters, drug carriers, catalysts, filters and fillers, but a price must be paid viathe potential toxity of these materials. The harmful effects of nanoparticles (NPs) to environment, human and animalhealth needs to be investigated and critically examined, to find appropriate solutions and lower the risks involved inthe manufacture and use of these exotic materials.The vast number and complex interaction of NM/NPs with different biological systems implies that there is nouniversal toxicity mechanism or assessment method. The various challenges need to be overcome and a numberof research studies have been conducted during the past decade on different NMs to explore the possiblemechanisms of uptake, concentrations/dosage and toxicity levels. This review article examines critically therecent reports in this field to summarize and present opportunities for safer design using case studies frompublished literature.

Keywords: Ecotoxic, Nanoparticles, Safer design, Mechanisms of uptake, Risk assessment, Testing protocols

IntroductionNanotechnology although a desirable and innovative sci-ence, presents a large number of risks to environmentand health. The very small size of NPs and the attractivesurface properties (due to the large surface to volume ra-tio) is an important factor for many applications. How-ever, this attractive feature may in addition, provide NPsurfaces that bind and transport toxic chemical pollut-ants, as well as cause NPs to become toxic by generatingreactive radicals. The NP size, shape, surface charge,functional groups and manufacturing methods influenceits behavior along with the environmental factors (Allegriet al. 2016; Erdem et al. 2015; Korshed et al. 2016;Beranová et al. 2014; Ye et al. 2018). The specific type oforganic matter or other natural particles present in sea/freshwater affects the pH and the state of aggregation ordispersion of the NPs, which plays an important role in itstoxicity. NPs tend to aggregate in hard water and seawaterand are greatly influenced by the surrounding environ-ment. Toxic effects of NPs on fish and aquatic organismseven at low concentrations have been shown in literature

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Correspondence: [email protected] of Physics, University of Jordan, Amman 11942, Jordan

(Lovern et al. 2007; Griffitt et al. 2008; Handy et al. 2011;Selck et al. 2016; Moore n.d.). Data also shows somemanufactured NMs may interact with other contami-nants, influencing their toxicity (Ye et al. 2018;Pulskamp et al. 2007).The enormous number of NPs with their different

shape, size, material, functionalities, processes of manu-facture, applications etc. makes it difficult to standardizeand adopt a universal measurement method for toxicity.The fate and behavior of manufactured NMs in the en-vironment and biological matrix must be well under-stood; change in original structure, size, reactivity andother factors that influence the transport and behaviorof NMs need to be systematically investigated as part ofthe toxicological studies. This is a huge challenge and atpresent a vast number of research studies have beenconducted on various NPs to explore the possible mech-anisms of uptake, concentrations/dosage and toxicitylevels. Owing to the complex interactions of NPs withdifferent biological systems there is no universal toxicitymechanism or assessment method. However, the exten-sive research in this area has resulted in some consensuson the following points:

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(a) Toxicity differs with NP type and preparation and ifthe methodology is carefully reported, one can atleast correctly interpret the whole body ofmeasurements. Classification to NP types withcommon testing procedures could be made.

(b) The utility of behavioral assays and the need todevelop more environmentally realistic bioassays.Organize existing data by relating likely exposurepathways (dermal, inhalation, ocular, ingestion) withexisting measurements of important characteristicsof NMs (particle number, mass, size distribution,charge) and to obtain data on toxicity mechanisms.

(c) The establishment of health risk assessmentmethodology of manufactured NMs is imperative.New types of exposure models that individuallytrack particles through the environment whilekeeping track of the particle shape, surface area,and other surface characteristics as the nanoparticlesare transformed or become reactive are required formodeling the behavior of NPs.

(d) Nanotoxicity is an emerging discipline and theimportance of further research on the mechanismsand factors that increase toxicity and riskmanagement cannot be minimized. The list ofNMs is growing fast and this is a research areawhere continuous update of information is ofvital importance.

In an attempt to put into perspective the environmen-tal and human risks involved, the present study is a crit-ical analysis of the toxicity of manufactured NPs basedon the results of recent investigations and reviews in thefield of nanotoxicity. The paper is arranged under theheadings: Introduction, Toxicity of NPs, NM types andtesting protocols, Case studies for safer design, andConclusions and recommendations.

Toxicity of nanoparticlesThe ever increasing rate of NP production with its po-tential effects on the ecosystem and health through itsintentional and unintentional release into the environ-ment is a serious concern that needs to be addressed.NPs in healthcare, paints, cosmetics and aerosols enterthe environment proportional to the use, whereas unin-tentional release from production facilities in the formof solid/ liquid wastes and atmospheric emissions is hardto measure and track. The NMs have the potential tocontaminate land and water and enter biological systemsthrough various pathways and cause nanostructuredtoxic responses. Inhalation exposure is possible with air-borne NPs of size ranging from a few nanometers to sev-eral micrometers in diameter. The NPs can deposit inthe respiratory system and lungs of individuals; higherdeposition efficiencies have been noted for asthmatic

and pulmonary disease patients as compared to healthyindividuals (Kreyling et al. 2006), which may be due tothe decreased clearance ability. The occupational expos-ure of miners and polishers to rare earth oxides cancause a severe form of pneumoconiosis (Li et al. 2014)and is discussed as a case study in section four.Typical examples of metal oxides NPs like TiO2 and

ZnO which are components of sunscreen lotions canpresent a potential risk upon bioaccumulation or deg-radation into smaller particles or transformation. Re-cently, researchers have come up with innovative saferdesign strategies for oxides of Zn and Cu (Xia et al.2011; Sotiriou et al. 2014; Naatz et al. 2017). More de-tails of their works are presented in section four. Towhat extent NPs can penetrate skin and how toxic arethey, are questions that need to be answered. The testingof NP toxicity is challenging with cases of contradictoryand confounding results due to the complex interactionsof the NM with the organism as shown in a schematicdiagram in Fig. 1. The different factors like NP coating,agglomeration, contaminants, release of ions and NMinterference can be the cause of inaccurate dosing andassay results.A useful tool and insight is how toxic are NMs at the

potential concentrations they might be used and howthe different factors play a role in its toxicity. The vari-ous NMs that pose a threat to humans and environmentare summarized in Table 1. The NP type, shape, size,coating and functional groups all affect the behavior andtoxicity of the NPs as seen from the results of recent re-search in this field. More details are available in thegiven respective references.A variety of methods of detection and identification of

NPs in different environments have been used and re-ported in literature. Atomic force microscopy, scanningtunneling microscopy, transmission electron microscopy,confocal laser scanning microscopy, fluorescent spec-troscopy, spectrophotometry, photothermal microscopy(PTM), X-ray and mass spectrometry are some of themethods used for detection and characterization (Nedo-sekin et al. 2015; Ostrowski et al. 2015; Hendricksonet al. 2011; Me’rian et al. 2012; Théoreta and Wilkinson2017). Although, dark-field microscopy faces challengeson account of low sensitivity and limited axial reso-lution, it has found wide use in the detection, identifica-tion, and tracking of various NPs with the assistance ofmultispectral imaging for spectral identification of NPs(Théoreta and Wilkinson 2017; Lee and Tung 2012;Mustafa et al. 2013). Confocal fluorescence microscopyremains a powerful biological and widely used techniqueamong the diverse imaging methods, but its drawback isthe need for fluorescent NPs. Non-fluorescent NPs needto be tagged with fluorescent labels in order to use thismethod. With the growing evidence of label induced

Fig. 1 A schematic diagram showing the ways in which contaminants in the NMs, NM agglomeration, interactions between the organism andNM coating, release of dissolved ions, or interference from the NM with the assay measurement (i.e., absorbance) can potentially cause inaccuratedosing or artefacts in nano-ecotoxicology assays. Reprinted with permission from the American Chemical Society (Petersen et al. 2014)


change in NPs, celluar structure and possible inducedtoxicity (Me’rian et al. 2012), using other detectionmethods is a wise precaution. PTM has a huge potentialfor absorption-based identification and quantification ofnon-fluorescent molecules/NPs. Recently, Nedosekinet al. (Nedosekin et al. 2015) have developed confocalPTM providing three-dimensional mapping and spectralidentification of multiple chromophores and fluoro-phores in live cells. PTM provides a high level ofsensitivity comparable to fluorescence methods withunprecedented real time detection of label free NPsin a biologically live and complex environment. Thisis a big plus, as the number of biomedical applica-tions of non-fluorescent NPs for drug delivery, mo-lecular imaging and disease diagnosis is on the rise.

NM types and testing protocolsThe extensive range of NMs in production and usetoday, calls for organized grouping into classes or cat-egories with common traits. A case by case risk assess-ment study of NMs is not practical due to the large timeand financial resources involved. A more intelligent op-tion is to use physiochemical (PC) characterization andgrouping to identify exposures and hazards and modeltesting procedures and safer design (Nel et al. 2013;Stone et al. 2014; Scott-Fordsmand et al. 2014; Artset al. 2015; Godwin et al. 2015; Cobaleda-Siles et al.

2017; Kraegeloh et al. 2018) strategies. This is a complexprocess of establishment of tools and methods tocharacterize the NM during its whole life cycle and torelate the different model components to exposure andhazard inputs and come up with predictable biological/environmental risks. The work of Stone et al. (Stoneet al. 2014) shows the proposed components of researchpriorities over different periods of time in Fig. 2. Thefigure depicts short, mid and long term research goals toform an intelligent testing strategy from a conclusivesize, shape, composition, crystallinity, surface and otherPC identification of NMs. It is then possible to maximizeboth functionality and safety by innovative design strat-egies that lower the toxicity of the NPs.As an attempt to compartmentalize and unify testing

methods the NPs can be broadly classified as metal andmetal oxide, non-metal and carbon based NPs. The big-gest class is the metal and metal oxide group and themost researched are Au, Ag, Cu, Zn, Si, Ti and their ox-ides. The effects of particle composition of Ag, Cu, Al,Ni, Co and TiO2 as NPs and as soluble salts on the tox-icity in aquatic organisms were reported by Griffitt et al.(Griffitt et al. 2008). As a model for feeding strategiesand trophic levels they used zebrafish, daphnids, andalgal species. Their results show that Ag and Cu NPscause toxicity in all organisms tested, with concentra-tions as low as 40 and 60 μg/L in Daphnia pulex adults,

Table 1 Summary of Nanomaterial potential risks

NM Shape/size/form/coatings Test organism Toxic effects/ behavioralresponses

Ref.

Silca NPs Zebra fish inflammation–coagulation andthrombotic effects

(Duan et al. 2018)

TiO2 Nano Daphnia magna no significant changes inmeasures of heart rate/hopingfrequency

(Lovern et al. 2007)

nanofibers mice significant toxic effects andmore bioactive than the TiO2NPs

(Allegri et al. 2016)

C60 suspension Daphnia magna significant change in heart rate (Lovern et al. 2007)

C60HxC70Hx suspension Daphnia magna hopping frequency andappendage movement toincrease

(Lovern et al. 2007)

Rare earth oxides Y2O3, La2O3, CeO2 etc. Mostly18–60 nm

Humans mice Lysosomal damage, Pulmonaryinflammation and fibrosis inmouse lungs.

(Li et al. 2014)

Gadolinium basedMRI agent

Gadodiamide Patients with renal failure Nephrogenic systemic fibrosis (Marckmann et al. 2006)

Ag NPs (laser generated) 5 types of human cells low human cell toxicity weakdecrease in cell survival forendothelial cells and the lungcells

(Korshed et al. 2016)

SiO2, TiO2, ZnO NP suspensions Gram-positive Bacillus subtilisGram-negative Escherichia coli

photosensitive and harmful tovarying degrees

(Adams et al. 2006)

TiO2 Various size and concentrationNP suspensions

Gram-positive Bacillus subtilisGram-negative Escherichia coli

induced lipid peroxidation andcellular respiration disruption

(Erdem et al. 2015)

Quantum dots CdSeCdTe

Mice toxicity on development ofmale sexual system

(Valipoor et al. 2015;Li et al. 2016)

Carboxyl and amine surfacecoating

Mice and human males lung injury and inflammation;pulmonary vascularthrombosis,

(Wu and Tang 2014;Geys et al. 2008)

Al2O3 NPs (1, 10, and40 mg L−1)

Suspensions with dissolvedorganic matter.

unicellular green alga(Scenedesmus obliquus)

Disrupt cell membranefunctions and trigger growthinhibition

(Ye et al. 2018)


whereas TiO2 did not cause toxicity in any of the tests.The toxicity and distribution pattern of silver NPs inzebrafish model was also studied by Asharani et al.(Asharani et al. 2008), who used starch and bovineserum albumin (BSA) as capping agents for Ag NPsynthesis.A classic example of shape effect on NM toxicity is

Gold (Au). Although Au NPS are generally not toxic theAu nanorods were found to be highly toxic by several re-search groups (Wang et al. 2008; Niidome et al. 2006;Takahashi et al. 2006; Hauck et al. 2008; Patra et al.2007). The toxicity of Au nanorods was attributed to thesurfactant, Hexadecylcetyltrimethylammonium bromide(CTAB) commonly used in the synthesis of the nanorods(Wang et al. 2008; Niidome et al. 2006). CTAB is awidely used surfactant that is used for growth assistanceof the seed mediated synthesis of Au nanorods from AuNPs and facilitates anisotropic growth along the longitu-dinal axis and it also stabilizes the nanorods in solution.This is due to the fact that CTAB-coated nanorods are

positively charged and the mutual repulsion prevents ag-gregation. The CTAB toxicity problem can be solved bycoating with friendly and biocompatible agents likepoly4-styrenesulfonic acid (PSS) (Wang et al. 2008)poly-ethylene glycol (PEG) (Niidome et al. 2006) andphosphatidylcholine (Takahashi et al. 2006). PEG isespecially known for reducing the binding of non-specific molecules to surfaces. All the studies showedlow/no toxicity of the treated nanorods. In fact it ispossible to tune the mammalian cellular uptake of Aunanorods from very high to very low by manipulatingthe surface charge and functional groups of the poly-electrolyte (PE) coating schemes, as shown by Haucket al. (Hauck et al. 2008). They used various layer-by-layer PE schemes, such as the common poly dia-llyldimethylammonium chloride (PDADMAC)-PSS sys-tem. In almost all cases the cell viability was found tobe greater than 90%, even at very high concentrations.Their results prove the suitability of coated goldnanorods for therapeutic applications, such as thermal

Fig. 2 Proposed research prioritization for generating an effective PC ID to form an Intelligent Testing Strategy (Stone et al. 2014)


cancer therapy, due to the tunable cell uptake andlow toxicity.Cytotoxicity also depends on the type of cells used for

testing as reported by Patra et al. (Patra et al. 2007). Intheir example, 33 nm citrate-capped gold nanosphereswere found to be cytotoxic to a human carcinoma lungcell line at certain concentrations, but not cytotoxic tobaby hamster kidney and human hepatocellular liver car-cinoma cells. In the proceeding examples we saw howtoxicity could be affected by a number of factors like,the method of synthesis, shape of NM and test organ-isms/cell lines etc. Toxicity is compellingly related tooxidative stress, gene expression, pro-inflammatory re-sponses and cellular signaling events. In vitro andin vivo studies are very important and advance the un-derstanding of the toxicity mechanisms to introduce asafer design and prevent unwarranted risks.

Case studies for safer designRare earth oxide nanoparticle hazard and opportunitiesfor safer designThe possibility of occupational exposure and adverse hu-man health effects from the mining of rare earth mate-rials (REO) for biological and commercial use is on theincrease and cases of a severe form of pneumoconiosisin miners and polishers is now common. In order toreap the benefits REO and decrease its risks by provid-ing a safer design, the cellular interaction mechanismswere studied by Li et al. (Li et al. 2014). They investi-gated if engineered REO nanoparticles undergo biotrans-formation in THP-1 cells, a myeloid cell line that is

often used as an in vitro model for studying the effectsof NPs on phagocytic cells.They found that REOs induce cellular and pulmonary

damage by a compartmentalized intracellular biotrans-formation process in lysosomes that results in urchinshaped structures. The ion shedding of REO in acidify-ing macrophage lysosomes leads to phosphate complex-ation and results in organelle damage due to stripping ofphosphates from the surrounding lipid bilayer. This setsin motion a series of events as shown in Fig. 3 andcauses Lung Fibrosis.An understanding of the surface interaction mechan-

ism of REO NPs has provided us with a safer designprinciple for producing rare earth nanoparticles for bio-logical use, since, the pretreatment of REO with phos-phate in a neutral pH environment stops the biologicaltransformation and pro-fibrogenic effects and preventslung fibrosis.

Doping as a safer design strategy for metal oxidesMetal oxide NPs have widespread use in a number ofconsumer products like food, cosmetics, clothing andfuel in addition to various biomedical applications. Thelarge amount of metal oxide NPs produced and their po-tential toxicity is a high health risk and requires safetyevaluation. Among the metal oxides the transition metaloxides ZnO, CuO and TiO2 have received the most at-tention due to their very appealling electronic and opto-electronic properties, which allows for applications inelectronics, gas sensing, solar cells, sunscreens etc.Moreover, their biocompability makes them suitable forbiomedical applications like artificial medical implants

Fig. 3 Schematics to explain the cellular mechanisms leading to the pro-fibrogenic effects of REOs. The internalization of REOs by macrophagesand lysosomal biotransformation, and triggering of events culminating in pulmonary fibrosis. The inserted panel at the bottom shows that themolecular mechanism of lysosomal damage is phospholipid dephosphorylation and nucleation of REPO4 on the NP surface


and biomimic membranes etc. Unfortunately, these ox-ides are known to be higly toxic and it is essential toadopt a safe design strategy for their manufacture.Xia et al. have come up with an innovative way of re-

ducing the toxicity of ZnO NPs by Fe doping. They haveshown that ZnO toxicity in mammalian cells is a resultof intracellular particle dissolution and Zn2+ ions shed-ding in the tissue culture medium, which induces mito-chondrial perturbation, lysosomal damage, generation ofreactive oxygen species (ROS), pro inflammatory re-sponses and cell death (Xia et al. 2008). Using a rapidthroughput screening assay they have also shown thatFe-doping alters the ZnO matrix and decreases particledissolution in tissue culture media, leading to a reduc-tion in the above toxicological responses (George et al.2010). In order to confirm that the doped and non-doped ZnO NPs exhibit different toxicity profiles, theycompared their abilities in an in vitro screening assaythat they previously developed to assess sub lethal andlethal toxicological responses in RAW 264.7 andBEAS-2B cells. More details of the screening methodand results in their publication (George et al. 2010).More recently, in order to demonstrate that the re-

duced toxicity of Fe doped ZnO in vitro is also reflectedin vivo, they performed toxicity studies of doped andnon-doped ZnO NPs using zerbra fish and rodent lungas models (Xia et al. 2011). ZnO NPs are known tointerfere with zebra fish hatching and have a pro-inflammatory effect on rodent lung. Humans are alsocharacterized by acute inflammation during occupational

exposure and the use of pulmonary inflammation in ro-dents as a basis for tracking in vivo ZnO toxicity istherefore very relevant.Their results on the three living models, show that Fe

doped ZnO reduced the inhibitory effects of ZnO NPson Zebra fish hatching and also reduced the pulmonaryinflammation and oxidative stress in mice and rats.Kindly refer to their publication for more details of thetesting procedure and elaborate discussion of results.The finding that Fe-doping leads to decreased in vitroand in vivo toxicity indicates that this is a safe designstrategy for ZnO NPs, provided that the doping does notaffect the electronic and commercial properties. At thelevel of doping required for safety, this is indeed so.Similar to ZnO, Fe doping on CuO also reduces its

toxicity as shown by Naatz et al. (Naatz et al. 2017).CuO is widely used in industry and its dissolution hasmajor toxic potential. So, in an attempt to reduce thedissolution by tighter binding of Cu to Fe in dopedCuO, and provide a safe design they doped CuO with 1–10% of Fe in a flame spray pyrolysis reactor. Figure 4shows a graphical abstract of their work. As shown inthe figure the Fe doping causes a reduction in thedissolution and toxicity and results in a safer designfor CuO NPS.They found a significant reduction in the apical Cu-O

bond length and a simultaneous increase in the planarbond length using XRD (xray diffraction), BET (Brunauer-Emmett-Teller), Raman spectroscopy, HRTEM (high reso-lution transmission electron microscopy), EFTEM (energy

Fig. 4 Graphical abstract (Naatz et al. 2017). Reproduced with permission from the American Chemical Society


filtered transmission electron microscopy) and EELS (elec-tron energy loss spectroscopy) for morphology and struc-tural properties. They also performed tocicity screeningand biological assessment using tissue culture cell linesand zebrafish embryos to detect the change in the hazard-ous effects of doped vs. non-doped particles. They demon-strated that with increased levels of doping, there was aprogressive decrease in cytotoxicity in BEAS-2B andTHP-1 cells, as well as an incremental decrease in the rateof hatching interference in zebrafish embryos. Pure CuONPs exposed to THP-1 and BEAS-2B cells showeddose-dependent cytotoxicity while CuO doped with ≥6%Fe showed protective effects even at high concentration.

Towards a safer multi-walled carbon nanotube designCarbon nanotubes (CNT) is a NM with a wide range ofapplications due to its unique electronic, mechanicaland thermal properties and now an indispensible mater-ial in many industries. Due to its light weight and nmsize it can be easily inhaled and the occupational expos-ure is high. Several studies on single walled (SWCNT)and multi walled CNTs (MWCNTS) show variouschronic inflammatory responses and indication of severepulmonary and other risks (Pulskamp et al. 2007; Porteret al. 2009; Fubini et al. 2010; Poland et al. 2008; Satoet al. 2005; Yamashita et al. 2010). The toxic response ofengineered NM is dependent on the physicochemicalcharacteristics like size, shape, aspect ratio, chemicalcomposition, stability, crystal structure, surface area, sur-face energy, surface charge and surface roughness(Fubini et al. 2010; Gatoo et al. 2014; Liu et al. 2013;Kostal et al. 2015). Table 2 lists some of the toxic resultsfor various types of CNTs, with the physiochemicalcharacterization and test cell/organism used by the re-search groups.Considering the potential health risks of CNTs in all

its different forms there is a growing demand for guide-lines for safer CNT design. Surface charge plays a majorrole in the interactions of NPs with the biological sys-tems (Lee et al. 2013; Bozich et al. 2014; Harper et al.

2011) and research groups have employed various waysto to reduce the NP toxic manifestations by screening ormodulating the surface characteristics. One such group,Gilbertson et al. (Gilbertson et al. 2016) have establisheda statistical model relating surface charge and embroyo-nic zebrafish mortality for a safer MWCNT design. Thezebrafish are a preferred in vivo vertebrate model organ-ism and have molecular and physiological conservationwith other vertebrates, particularly during embryonic de-velopment (Fako and Furgeson 2009; Rizzo et al. 2013;Usenko et al. 2007). It is a stable, rapid and sensitive bio-logical model with many genetic parallels with humansenabling understanding and translation to potential hu-man toxicity mechanisms. In their study the bioactivityof zebrafish was monitored upon exposure to systemat-ically modify and completely characterise MWCNTS.The surface charge, percent surface oxygen, dispersedaggregate size and morphology, and electrochemical ac-tivity were the four physicochemical properties ofMWCNTs that were considered by them. Their analysisindicted that the surface charge was the best predictorof zebrafish mortality at 24 h post fertilization (hpf ).This conclusion was obtained by their use of advancedmultivariate statistical methods, a model that identifiesthe physicochemical property that best estimates theprobability of observing an adverse response. This typeof statistical predictive approach has been identified asprimary research objective for optimization and safety ofNMs (Liu et al. 2013; Usenko et al. 2007). In the statis-tical model they considered seven samples with the fourPC properties and the surface charge quantified as pointof zero charge (PZC) values ranged from 3 to 9. Therelavance of this model is therefore for carbon nano-tubes with PZC properties within this range. Even withthe limitation of low sample size they were able to pre-dict and validate MWCNT surface charge as the bestpredictor of zebrafish mortality at 24 hpf and the identi-fication of this property-risk relationship establishes afoundation for the development of low risk design guide-lines for MWCNTs.

Table 2 List of some toxic effects of carbon nanotubes and associated physiochemical character and tests

Physiochemicalcharacter

CNT type Test cell/organism Toxic effects Ref.

Contaminants Commercial SWCNTs andMWCNTs with high contentof Fe, Co, Mo and Ni

NR8383; A549 dose and time dependentincrease of intracellular ROS anddecrease of mitochondrialmembrane potential

(Pulskamp et al. 2007)

Surface charge andmodifications

acid-treated, water-solubleSWCNTs

HMMs Are less aggregated in lysosomesand cytoplasm and cause nosignificant changes in cell viabilityor structure.

(Porter et al. 2009)

Shape pristine SWCNTs; oxidizedSWCNTs

HUVEC functionalized and pristineSWCNTs have limited cytotoxicity

(Fubini et al. 2010)

asbestos-like MWCNTs Normal mice length-dependent inflammationand formation of granulomas

(Poland et al. 2008)

tangled CNTs; needle-likeCNTs

human primarymacrophages

tangled CNTs are swallowed intocells; needle-like CNTs activatesecretion of IL-1R and IL-1β

(Palomaki et al. 2011)

Length MWCNTs 500 nm to 5 μm THP-1; rat average length of 825 nm inducehigher inflammation than thosewith an average length of 220 nm

(Sato et al. 2005)

MWCNTs: length 5 to15 μm, diameter 20-60 nm;SWCNTs: length 5 to 15 μm,diameter < 2 nm

A549; THP-1; normal mice long and thick MWCNTs inducethe strongest DNA damage similarSWCNTs caused little effect

(Yamashita et al. 2010)

long MWCNTs 1 to 20 μm p53+/ mice Long MWNTs can form fibrous orrod-shaped particles of around10–20 μm (μm) and inducemesothelioma

(Takagi et al. 2008)

Number of layers Pristine graphene RAW 264.7 depletion of the mitochondrialmembrane potential and increaseof intracellular ROS and apoptosis.

(Li et al. 2012)

SWCNTs; MWCNTsdiameters 10 to 20 nm

alveolar macrophage SWCNTs > MWCNTs (Jia et al. 2005)

Agglomeration agglomerated SWCNTs;better dispersed SWCNTbundlesCNT agglomerates; CNTbundles

SPC; DRGMSTO-211H

highly agglomerated SWCNTssignificantly decrease the overallDNA content

(Belyanskaya et al. 2009)

suspended CNT-bundles are lesscytotoxic than asbestos, rope-likeagglomerates

(Wick et al. 2007)


These case studies highlight the need for caution dur-ing the use and design of manufactured NPs to preventhuman and environmental adverse impacts, as well asthe importance of further research on the mechanismsand factors that increase toxicity to formulate a safe andrisk free NP/NMs design.

Conclusions and recommendationsIn conclusion, the widespread use of NPs in vari-ous applications over industries ranging from elec-tronics, medicine, pharmaceuticals, and cosmeticsto agriculture and food will result in intentional/unintentional human exposure to engineered NP/NMs via the dermal, inhalation, ingestion, andocular pathways. Control measures that can beadopted are

i. Reduce workplace exposures by using engineeringcontrols and personal protective equipment. Usealternative methods to assess exposure and theinfluence on bioavailability and toxicity.

ii. Find alternatives to the use of surfactants,templates, or other substances that are used tostabilize and control nanoparticle size and shapeduring synthesis which are toxic.

iii. Use green and sustainable synthesis methods ofmanufacture of NPs which depend on naturalresources like plant extracts, microorganisms andenergy saving methods in an economical and non-toxic manner (Ramanathan and Aqra n.d.; Ahmedet al. 2016; Dahoumane et al. 2016; Kitching et al.2015; Mahdavi et al. 2013).

iv. Use standard nanoparticle measurementmethods_respirable mass or number concentration


and extended in vivo and/or in vitro toxicity testingwith uptake, internal distribution and use of realisticrisk assessment methods.

v. Comprehensive NP/NM physiochemicalcharacterization and transformation studies inenvironmental and biological matrices and theconsequences for bioavailability and toxicity intest organisms.

vi. Develop excellent understanding of NP property-activity/risk relation to provide safe design.

It is highly recommended to develop a framework ofgreen nanoscience that can guide safe design, produc-tion, and application of NMs across a wide range of in-dustries by effective characterization of the NM duringthe entire product lifecycle using a defined set of stan-dardized metrics that can be consistently measured. Theoccupational, consumer and environmental exposureshould be monitored by devices capable of detecting thephysiochemical properties of the NP/NMs progress inthe exposure matrix even if they are transformed or be-come reactive and trigger biological responses. To reapthe potential benefits of products of nanotechnology,nano-safety research should be prioritized to develop anintelligent testing strategy and a set of NM risk manage-ment protocols (Nel et al. 2013; Stone et al. 2014;Scott-Fordsmand et al. 2014; Arts et al. 2015; Godwinet al. 2015; N.R.C 2012; Notter et al. 2014; Voutchkova-Kostal et al. 2012; Yang et al. 2014; Handy et al. 2012;N.N.I 2011).

AbbreviationsBET: Brunauer-Emmett-Teller; CNT: Carbon nanotube; CTAB:Hexadecylcetyltrimethylammonium bromide; EELS: Electron energy lossspectroscopy; EFTEM: Energy filtered transmission electron microscopy;hpf: Hours post fertilization; HRTEM: High resolution transmissionelectron microscopy; MWCNT: Multi-walled carbon nanotube;NMs: Nanomaterials; NPs: Nanoparticles; PC: Physiochemical;PDADMAC: Poly diallyldimethylammonium chloride; PEG: Poly-ethyleneglycol; PSS: Poly4-styrenesulfonic acid; PTM: Photothermal microscopy;PZC: Point of zero charge; SWCNT: Single-walled carbon nanotube

AcknowledgementsNOT applicable.

FundingNo funding was received for this work.

Availability of data and materialsNOT applicable

Authors’ contributionsAAR is the sole author and contributor to the Manuscript. The author readand approved the final manuscript.

Competing interestsThe author declares that she has no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Received: 10 January 2019 Accepted: 19 March 2019

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AbstractIntroductionToxicity of nanoparticlesNM types and testing protocolsCase studies for safer designRare earth oxide nanoparticle hazard and opportunities for safer designDoping as a safer design strategy for metal oxidesTowards a safer multi-walled carbon nanotube design

Conclusions and recommendationsAbbreviationsAcknowledgementsFundingAvailability of data and materialsAuthors’ contributionsCompeting interestsPublisher’s NoteReferences

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