Engineered nanoparticles: Hazards and Risk Assessment upon …abap.co.in/sites/default/files/CTBP-14-1-111-P-11.pdf · 2020-01-22 · it has been forecasted that the global nanotechnology

Current Trends in Biotechnology and PharmacyVol. 14 (1) 111-122, January 2020, ISSN 0973-8916 (Print), 2230-7303 (Online)DOI: 10.5530/ctbp.2020.1.11

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AbstractThe presence of engineered nanoparticles

(ENPs) in the environment can have significantdamaging effects for both environment and humanhealth. Emergent nanoscience andnanotechnology are projected to revolutioniseindustrial production, economy and consumercrossing point, as we know them today. However,widespread use of nanotechnologies may inviteand be a source of risks. People in many settings(academic, small and large industrial, and thepublic in industrialized nations) are eitherdeveloping or using products containing engineerednanoparticles. However, our understanding of theoccupational, health and safety aspects of ENMsis still in its formative stage. This review describesbriefly, ENPs and their applications, safety andrisk assessment upon exposure to engineerednanoparticles, the routes of human exposure, fateof engineered nanoparticles in the environmentand make recommendations on future researchin risk assessment of nanomaterials.

Keywords: Environmental risks, Human health,Nanomaterials, Risk characterizations,

IntroductionNanotechnology is a on the rise

interdisciplinary technology that is often seen aspart of a new industrial revolution. Added,nanotechnology is gradually attracting more globalattention owing to its wide range of applicationsin end-uses and end users. Rapid advancementsin nanotechnology in recent years have paved a

way for multibillion-dollar industry. For instance,it has been forecasted that the globalnanotechnology industry will grow to reach US$75.8 Billion by 2020 [1]. This scenario presenthuge opportunities for industry participants to tapthe fast growing market.

Nanotechnology is defined as the design,characterization and application of structures,devices and systems by controlling shape andsize at nanometer scale level (ranging from 1 to100nm) [2]. The current and projected applicationsof nanomaterials include catalysts, lubricants andfuel additives; paints, pigments and coatings;cosmetics and personal care products; medical,dental, drug delivery and bionanotechnology;functional coatings; hydrogen storage and fuelcells; nanoelectronics and sensor devices; opticsand optic devices; security and authenticationapplications: structural (composite) materials,conductive inks and printing; UV-absorbers andfree-radical scavengers; construction materials;detergents; food processing and packaging; papermanufacturing; agrochemicals, plant protectionproducts and veterinary medicines, plastics, andweapons and explosives [3-4].

A diversity of consumer products that includenanomaterials are already available in developedand developing countries worldwide. Case in pointof these include self-cleaning glass, anti-microbialwound dressing, paints and coatings, fuelcatalysts and cosmetics (The Woodrow WilsonNanotechnology Consumer Products Inventorywww.nanotechproject.org). Current market

Engineered nanoparticles: Hazards and Risk Assessmentupon Exposure-A Review

Krishna Suresh Babu Naidu1*,1. Department of Biomedical & Clinical Technology, Durban University of Technology,

Durban-4000, South Africa.*Corresponding author : [email protected]

Engineered nanoparticles: Hazards and Risk


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indicators suggest that many moreapplications of nanotechnologies will emerge inconsumer products in the coming years and theseare likely to impact on worker health and safetywithin a number of sectors [4]. The rapid use andintegration of nanotechnologies in production ofconsumer products has therefore raised a numberof technological, health and bio-safety,environmental, ethical, policy and regulatoryissues worldwide [5]. This is partially becauseproperties of manufactured nanomaterials mayvary widely from the ‘conventional’ micro or macro-forms of the same materials [6]. This fear hasarisen from a growing body of scientific evidencethat specifies that free nanoparticles can penetratecellular barriers, and that exposure to some formsof nanoparticle can lead to an increasedproduction of oxyradicals and cause potentialoxidative damage at the cell level (Fig 1) [5].

According to statistics published on the StatNano about 137500 articles on nanotechnology

have been indexed in the Web of Science (WoS)Database by the end of December 2016, which is9.5% of all articles indexed in this database in2016. China is in charge for 34% of these articleswhile USA has a share of 16%.

The overall objectives of this review paperare to 1). To reconnoiter the current state ofknowledge of the safety and risks upon exposureto ENPs 2) Assess what safety mechanisms/practices are presently in place, and 3) and makerecommendations on future research in riskassessment of nanomaterials.

Applications of engineered nanoparticles :Advancements in the fields of nanoscience

and nanotechnology have resulted in a myriad ofpossibilities for consumer product applications,many of which have already migrated fromlaboratory benches onto store shelves and e-commerce websites (Table 1) [6-7]. In 2009, itwas estimated that nanotechnology would haveimpacted more than $2.5 trillion worth of

Fig.1. Environmental monitoring and biological exposure to engineered nanoparticles

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manufactured goods by 2015 [8], although manyof these goods may contain only minute amountsof intentionally engineered nanomaterials.According to Stat Nano report(www.statnano.com), studies carried out on 6432products on the Nanotechnology ProductsDatabase (NPD) show that the United States andChina are the largest producers of carbonnanotubes in the world. However, Japan hasproduced the largest number of products in whichcarbon nanotubes have been used. TheInternational Risk Governance Council hasobserved that nanotechnology applications “willpenetrate and permeate through nearly all sectorsand spheres of life (e.g. communication, health,labour, mobility, housing, relaxation, energy andfood) and will be accompanied by changes in thesocial, economic, ethical and ecological spheres”[9].

Nanomedicine, the application ofnanotechnology to healthcare holds great promisefor revolutionizing medical treatments andtherapies in areas such as imaging, fasterdiagnosis, drug delivery and tissue regeneration,as well as the development of new medicalproducts (Fig. 2). Indeed, materials and devicesof nanometric dimensions are already approvedfor clinical use and numerous products are being

evaluated in clinical trials around the world [10].The major advantages of nanoparticles over largersized particles are their high surface-to-volumeratio and hence higher surface energy, uniqueoptical, electronic, and excellent magneticproperties [11] and so on. The high surface areaon nanoparticles are modified adequately toimprove its pharmacokinetic properties, increasevascular circulation lifetime, along with improvingbioavailability, especially for biomedicalapplications [12]. The improved properties are aboon in the field of drug delivery-: the increasedvascular circulation lifetime increases the efficacyof the drug; the enhancement of the drugbioavailability means a lot lesser dosage couldeffectively work instead of bulk drugs [13]. Asmentioned before, the most important property ofnanoparticles, which has attracted the attentionof researchers worldwide, is their ability to havebetter surface modifications, which not only helpsin targeted drug delivery but can serve the dualpurpose of drug monitoring and release. The useof nano materials provides unparalleled freedomto change fundamental properties such assolubility, diffusivity, blood circulation half-life, drugrelease characteristics, and immunogenicity [14].Over last two decades, a number of nanoparticle-based therapeutic and diagnostic agents havebeen developed for the treatment of cancer,diabetes, pain, asthma, allergy and infections [15].

Despite these potential benefits,nanotechnology applications in the agriculturalsector are still comparably marginal and have notyet made it to the market to any large extent incomparison with other industrial sectors[16]. Thewave of research discoveries seems to be mainlyclaimed by the academic sector or smallenterprises, while big industries reveal a largepatent ownership.

Safety & risk assessment upon exposure toengineered nanoparticlesNanoparticle exposure pathways : Criticalinformation such as nanomaterial size andconcentration are not generally known for mostproducts listed on the Consumer Product Inventory(CPI) and therefore; the actual health risks of these

Fig. 2. Biomedical applications of core shellnanoparticles (11)



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Fig. 3. Potential pathways of occupational, environmental and human exposure to ENPs (19)

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products remain largely unknown [17].Nevertheless, the CPI may be useful for inferringpotential exposure pathways from the expectednormal use of listed products. Hansen et al. [18]developed a framework for exposure assessmentin consumer products. In this framework, productsthat contain nanomaterials suspended in liquidand products that may emit airborne nanoparticlesduring use are expected to cause exposure (Fig.3).

Since metals and metal oxides are the mostcommon nanomaterial composition in the CPI,they are also the most likely materials to whichconsumers will be exposed during the normal useof product via dermal, ingestion, and inhalationroutes. Products containing nanomaterials ofunknown composition are most likely to lead toexposure via the dermal route.

In another study piloted by Beaudrie et al.[20] presented a critique of the original CPI in 2010,which focused primarily on the lack of data pertinentto the dosages of nanomaterials to whichconsumers might be exposed through CPI-listedproducts. This is a valid criticism given thatinformation used to populate the CPI is based

primarily on marketing claims made bymanufacturers. However, the most recentmodifications of the CPI offer a potential remedyfor data gaps through the contributions of third-party research teams. These modifications areespecially timely as there is a growing number ofpublished studies assessing consumer exposureto nanomaterials released during the use ofnanotechnology enhanced consumer products [1].Added, major challenge is that there are nostandardized methods for assessing consumerrisks from using nanotechnology-enabledconsumer products or a set of agreed uponmetrics for characterizing nanomaterials todetermine environmentally relevant concentrations[21]. The development of such standards is seenas a top policy for safe and sustainablenanotechnology development in the next decade.

Risk assessment of engineered nanoparticles: Concerns surrounding the health risk ofengineered nanomaterials, effective regulation andthe lack of specifically tailored insurance productsfor the nanotechnology sector are putting theindustry’s long-term economic viability at risk [22].In U.S., federal mistake of potentially toxic


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Fig. 4. Concerns for transport of nanomaterials from landfill sites to adrinking water well (35)


materials and products spans several federalagencies [20]. These include the EnvironmentalProtection Agency (EPA), the Food and DrugAdministration (FDA), the Occupational Safety andHealth Administration (OSHA), and the ConsumerProduct Safety Commission (CPSC). Eachagency is charged with enforcing regulations tocontrol risks from specific types or uses ofsubstances (i.e., chemicals, pharmaceuticals,and pesticides), or from potentially harmfulreleases in the workplace or into the environment.

The primary stage of Engineered NanoMaterials (ENM) product life cycle comprises fromthe transformation of raw materials intonanomaterials (e.g., manufacturing bulk silver intonanoscale silver particles) to the incorporation ofnanomaterials as a component of other products(e.g., nanosilver antimicrobial textile coatings).Three key statutes that come into effect at thisstage depend on the intended application of thenanomaterial. In USA, chemical substances andpesticides are regulated under the ToxicSubstances Control Act (TSCA) [23] and FederalInsecticide, Fungicide, and Rodenticide Act(FIFRA), respectively, and the EPA administers

both acts. Food additives and drugs are regulatedunder the Federal Food, Drug, and Cosmetic Act(FFDCA) [24] that is administered by the FDA.Together, TSCA, FIFRA, and FFDCA apply tochemical substances, pesticides, food additives,and drugs primarily through a “premarket” risk-assessment, registration, and managementapproach. With this approach, each substanceis evaluated and risk-management decisions aretypically made before a product is released foruse on the market.

The United States Environmental ProtectionAgency (EPA), defines “risk” with “respect to theabove definition of “hazard” as a measure of theprobability that damage to life, health, property,and/or the environment will occur as a result of agiven hazard. According to this definition, if theprobability of an exposure to a hazardous materialis high and the consequences for human healthor the environment are significant, then the risk isconsidered high. It is important to consider boththe frequency of the event and the degree of thehazard to estimate risk [25]. Usually twocategories of risk are distinguished in literature:known “risks” and “potential risks”. When the


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relationship between a cause and an effect isestablished, we talk of known “risks”. Theresponsibility for such risks can generally berecognized. When the causal relationship isestablished, prevention is possible. When therelationship between a cause and damage is notwell known, we talk of potential “risks”. In the caseof potential risks, it is unclear whether there is adanger, how significant the damage can be or whatis the probability of its occurrence [26]. Thissituation is considered by a state of suspicion(not awareness) and it is generally admitted thata precautionary approach can be applied in orderto prevent potential damage [26]. The risks ofENPs for the environment and human health fallinto the second category: potential risks. It is veryimportant to assess the risks of hazardous agentslike ENPs. The likelihood that a hazardoussubstance will cause harm (the risk) is thedeterminant of how cautious one should be andwhat preventative or precautionary measuresshould be taken.

Risk assessment of chemicals (CRA) hasbeen reflected as the most relevant approach tounderstand and quantify the related risks [18].CRA is a process, in which scientific andregulatory principles are applied in a systematicfashion in order to describe the hazards,associated with the environmental and/or humanexposure to chemical substances. It is definedas “a process, intended to calculate or estimatethe risk to a given target organism, system or(sub)population, including the identification ofattendant uncertainties, following exposure to aparticular agent, taking into account the inherentcharacteristics of the agent of concern, as wellas the characteristics of the specific target system[27]. The CRA is a four-step process, consistingof: (1) hazard identification, (2) dose-responseassessment, (3) exposure assessment and (4)risk characterization. Its main outcome is astatement of the probability that when humans orother environmental receptors (e.g., plants,animals) are exposed to a chemical agent, theywill be harmed and to what degree. The CRAmethodology is internationally recognized and

employed by major actors, such as the WorldHealth Organization (WHO) and the Organizationfor Economic Co-operation and Development(OECD), as well as by several European and U.S.agencies [28].

In order to address the objective 2 of thischapter, the current methods adopted for theassessment of risks of ENPs for the environmentand human health are summarized in relation toeach of the four elements of the CRA frameworkimportant scientific advancements, research gapsand limitations are identified and discussed.

Hazard identification : “Hazard identification” (HI)is defined as the “identification of the adverseeffects, which a substance has an inherentcapacity to cause” [29]. Hansen et al. [18] identified428 studies reporting on toxicity of ENPs. In thesestudies, adverse health effects of 965 tested ENPsof various chemical compositions were observed[30].

Dose-response assessment : “Dose-responseassessment” (DRA) is defined as “an estimationof the relationship between dose, or level ofexposure to a substance, and the incidence andseverity of an effect”. It is the process ofcharacterizing the relationship between the doseof an agent, administered to or received by anindividual, and the consequent adverse healtheffects. In toxicological studies a “dose” is thequantity of anything that may be received by oradministered to an organism. The “dose” isnormally measured in mass units (i.e., ìg, mg, g),as higher doses of the same compounds areexpected to cause more severe adverse effects.DRA studies with ENPs, however, suggest thatthe toxicity of some ENPs is not mass dependent,but influenced by other physico-chemicalcharacteristics (e.g., surface area, chemicalcomposition, and particle morphology) [31].Several studies found that the toxicity of low-soluble ENPs was better described by theirsurface area than by their total mass [30], numberof particles [32], functional groups [33]. Despitethese findings, however, it is still largely unknownwhich properties influence the toxicity of most


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ENPs and this gap in knowledge is partlyattributable to the fact that the tested ENPs areseldom well characterized [19].

Exposure assessment : “Exposure assessment”(EA) is defined as an estimation of theconcentrations/doses to which human populations(i.e., workers, consumers and citizens exposedindirectly via the environment) or environmentalcompartments (aquatic environment, terrestrialenvironment and air) are or may be exposed [19].EA is a very important element in risk assessmentof ENPs, since if no exposure to ENPs occur, itwould be impossible that they cause any harmand there would be no risk at all. EA can be dividedinto three sub-areas: (1) occupational exposureassessment (OEA), (2) environmental exposureassessment (EEA) (including indirect humanexposure from the environment) and (3) consumerexposure assessment (CEA).

Fate of engineered nanoparticles inenvironment : Engineered nanoparticles (ENPs)or Engineered nanomaterials (ENM) are exposedto environment during all stages of their life cycles:raw material production, transport and storage,industrial use (incl. processing and/or trade),consumer use, waste disposal (incl. wastetreatment, landfill and recovery) [29]. Moreover,fate of ENPs, released in the environment isdetermined by their mobility in different media (i.e.,soil, water, air), as well as by their potential tobiodegrade or undergo chemical transformation[2]. A recent study by Keller and Lazareva [34]estimated that 63–91% of over 300 kilo tonnes ofENMs produced globally ended up in landfills by2010; 8–28% entered the soils, 0.4–7% reachedthe surface water bodies, and 0.1–1.5% enteredinto the atmosphere. In the event of transport ofnanomaterials present in landfills or soils, it maydisperse into drinking water sources or majorsurface water bodies (Fig. 4). Given the largeproportion of nanomaterials ending up in soils, anunderstanding of the impact of thesenanomaterials on soil organisms or ecosystemsis required for informed risk assessments andpolicy discussions. Interestingly, most of thepotential hazards of these nanomaterials are

undocumented and there is lack of awarenessamong common people.

Fate of engineered nanoparticles in air : Thefate of ENPs in the air is determined by threemain factors: (1) the duration of time particlesremain airborne, (2) their interaction with otherparticles or molecules in the atmosphere and (3)the distance they are able to travel in the air [36]deliberate the mechanisms of diffusion,agglomeration, and deposition for nanoparticleaerosols, and the possible resuspension ofaerosol from deposited nanoparticles. In addition,the processes important to understand thedynamics of ENPs in the atmosphere are diffusion,agglomeration, wet and dry deposition andgravitational settling. With respect to the durationof time ENPs stay in the air, it is considered thatthey may follow the laws of gaseous diffusion.

It is generally considered that particles inthe nanoscale (d < 100 nm) have shorter residencetime in the air, compared to medium-sizedparticles (100 nm < d < 2,000 nm), because theyrapidly agglomerate into much larger particles andsettle on the ground [37]. ENPs with anti-agglomerate coatings make an exception and theirresidence time cannot be predicted. It is wellthought-out that deposited ENPs are usually notlikely to be re-suspended or re-aerosolized in theatmosphere. However, many nano-sized particlesare photoactive, but it is still unknown whetherthey are susceptible to photo degradation in theatmosphere.

Fate of engineered nanoparticles in water : Thefate of ENPs in water is directed by several factors:(1) aqueous solubility, (2) reactivity of the ENPswith the chemical environment and (3) theirinteraction with certain biological processes [38].Since ENPs have lower mass, ENPs generallysettle more slowly to the bottom than largerparticles of the same material. However, due totheir high surface-area-to-mass ratios, ENPsreadily sorb to soil and sediment particles andconsequently are more liable to removal from thewater column. However, some ENPs might besubjected to biotic and abiotic degradation [17],


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which can remove them from the water columnas well. In addition, abiotic degradation processesthat may occur include hydrolysis andphotocatalysis. Near to the surface ENPs areexposed to sunlight. It is likely that light-inducedphotoreactions can account for the removal ofcertain ENPs and for changing the chemicalproperties of others.

Fate of engineered nanoparticles in soil : Thefate of ENPs in soil vary depending on physicaland chemical properties of the material. SomeENPs can strongly sorb to the soil particles andbecome completely inert and immobile.Alternatively, if ENPs do not sorb to the soilmatrix, they might show even greater mobility thanlarger particles, because their small size mightallow them to travel easily through the pore spacesbetween the soil particles. The possibility to sorbto soil and the respective sorption strength ofENPs is influenced by their size, chemicalcomposition and surface characteristics [36].

Study by Zhang [39], indicated considerabledifferences in mobility of some insoluble ENPs inporous media. The properties of soil, such asporosity and grain size, further influence themobility of the particles. Just like the mineralcolloids, the mobility of ENPs, agglomerated incolloid-like structures might be strongly affectedby electrical charge differences in soils andsediments. Surface photoreactions mightinduce photochemical transformations on the soilsurface.

Conclusions & RecommendationsThough nanoparticles research is enduring

since more than 30 years, the development ofmethods and standard protocols required for theirsafety and efficacy testing for human use is stillin development [39]. ENPs are anticipated to affectliving organisms in different ways than their bulkalternatives and considering their significant range,it is expected that ENPs would also differ a lotfrom each other in terms of toxicity.

As there are very limited number of studiesare made in field of environmental fate of ENPs,their behavior in the environment is still largely

unmapped. When addressing the environmentalfate of ENPs, most of the current literature availableuses inaccurate general considerations andcomparison with data, obtained for larger particles.It is very imperative to study the environmentalfate of ENPs in order to understand their pathwaysof environmental and concern of human exposure.

Considering the availability of literatureabout nanoparticles for medical applications andtaking into account of different participants in thefield of nanomedicine including the communityworking in the field of nanotoxicology, we stronglyrecommend:A. Launching laboratories which allows a GMP

like synthesis including functionalization ofnanoparticles for medical application.

B. Regulatory bodies should implement strictexplicit checklist

C. In vivo and In vitro models used fornanoparticle-cell interactions should bevalidated.

D. To minimize damaging effects of ENPs it isessential to identify the exposure sourcesand pathways of ENPs in the workingsettings as well as to study the mechanismsbehind their dispersion and measure theirconcentrations

E. Comprehensive inventory of consumerexposure to ENPs and data generated needsto be elaborated and made easily accessibleto scientists and risk managers.

Employing above recommendations leading togrowth of nanomaterials for biomedicalapplications might be improved and hazard ofexposure to ENPs would be reduced substantially.This would reassure community to reduce the riskof exposure to ENPs and protect the environment.

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Engineered nanoparticles: Hazards and Risk Assessment upon …abap.co.in/sites/default/files/CTBP-14-1-111-P-11.pdf · 2020-01-22 · it has been forecasted that the global nanotechnology