International Journal of

Molecular Sciences Review

Toxicological Considerations, Toxicity Assessment, and Risk Management of Inhaled Nanoparticles Shahnaz Bakand 1,2 and Amanda Hayes 2, * 1 2

*

School of Health & Society, The University of Wollongong, Wollongong NSW 2522, Australia; [email protected] School of Chemistry, The University of New South Wales, Sydney NSW 2052, Australia Correspondence: [email protected]; Tel.: +61-2-4221-4794; Fax: +61-2-9385-6141

Academic Editors: Michael Routledge and Bing Yan Received: 16 March 2016; Accepted: 25 May 2016; Published: 14 June 2016

Abstract: Novel engineered nanoparticles (NPs), nanomaterial (NM) products and composites, are continually emerging worldwide. Many potential benefits are expected from their commercial applications; however, these benefits should always be balanced against risks. Potential toxic effects of NM exposure have been highlighted, but, as there is a lack of understanding about potential interactions of nanomaterials (NMs) with biological systems, these side effects are often ignored. NPs are able to translocate to the bloodstream, cross body membrane barriers effectively, and affect organs and tissues at cellular and molecular levels. NPs may pass the blood–brain barrier (BBB) and gain access to the brain. The interactions of NPs with biological milieu and resulted toxic effects are significantly associated with their small size distribution, large surface area to mass ratio (SA/MR), and surface characteristics. NMs are able to cross tissue and cell membranes, enter into cellular compartments, and cause cellular injury as well as toxicity. The extremely large SA/MR of NPs is also available to undergo reactions. An increased surface area of the identical chemical will increase surface reactivity, adsorption properties, and potential toxicity. This review explores biological pathways of NPs, their toxic potential, and underlying mechanisms responsible for such toxic effects. The necessity of toxicological risk assessment to human health should be emphasised as an integral part of NM design and manufacture. Keywords: inhalation; nanoparticles; nanomaterials; physicochemical properties; toxicity mechanism; risk assessment

1. Introduction Nanotechnology can be described as the science of precise manipulation and design of matter at the nanoscale level of approximately 1–100 nanometers (nm). Detailed terminology and definitions related to different types of nano-objects such as nanoparticle, nanofibre, and nanoplate have been described [1,2]. Nanotechnology has grown to a multibillion dollar industry worldwide [3]. Engineered nanomaterials (NMs) with their unique physicochemical characteristics are rapidly being implemented in the various fields of medicine, pharmaceutics, biotechnology, energy production, environmental sciences, crop protection, transportation, housing, and electronics [4–6]. Novel engineered NMs and composites are continually emerging with the potential for significant commercial applications. Engineered NMs can be manufactured from chemical elements such as metals, metal oxides, sulphides or selenides, carbon, polymers, and biological molecules such as lipids, carbohydrates, peptides, proteins, and nucleic acid oligomers [3]. The geometry of manufactured NMs may range from isometric NPs to one-dimensional (1D; nanofibres or nanotubes), and two-dimensional (2D; plate-like or disk-like NMs) forms (Table 1). Therefore, to represent the diversity of engineered NMs, Int. J. Mol. Sci. 2016, 17, 929; doi:10.3390/ijms17060929

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a matrix based on the combination of geometry and chemistry can be used for the classification of Int. Mol. 2016, 17, 2 2ofof1717 Int.J. J.based Mol.Sci. Sci.on 2016, 17,929 929 engineered NMs [3]. a matrix the combination of geometry and chemistry can be used for the classification of engineered NMs [3].on the combination of geometry and chemistry can be used for the classification of a matrix based Nano-Objects Geometrical Characteristics Example

a matrix based on the combination of geometry and chemistry can be used for the classification of Table 1. Nano-objects; related terms and geometrical characteristics. engineered NMs engineered NMs[3]. [3]. Table 1. Nano-objects; related terms and geometrical characteristics. Nanoparticle Table 1. Nano-objects; Nanofibre or Nanotube Nanoplate Table 1. Nano-objects;related relatedterms termsand andgeometrical geometricalcharacteristics. characteristics. Nano-Objects Nanoparticle One-dimensional Nanofibre(1D) or Nanotube Nanoplate (2D) Isometric Two-dimensional Nano-Objects Nanoparticle Nanofibre ororNanotube Nanoplate Nano-Objects in nanoscale Nanoparticle Nanofibre Nanotube Nanoplate 3 ext.Geometrical dimensions 2 ext. ext. dimensions in nanoscale 1 ext. dimension in(2D) nanoscale Isometric 3 One-dimensional (1D) 2 ext. Two-dimensional 1 ext. Geometrical Isometric One-dimensional Two-dimensional Geometrical Isometric One-dimensional(1D) (1D) Two-dimensional(2D) (2D) Characteristics dimensions in nanoscale dimensions in nanoscale dimension in nanoscale Bucky ball Graphene Characteristics 2 2ext. ininnanoscale 1 1ext. ininnanoscale Carbon (CNTs) Characteristics 3 3ext. ext.dimensions dimensionsininnanoscale nanoscale nanotubes ext.dimensions dimensions nanoscale ext.dimension dimension nanoscale Example Example

Bucky Bucky ball Buckyball ball

Carbon nanotubes Carbon (CNTs) Carbonnanotubes nanotubes(CNTs) (CNTs)

Graphene Graphene Graphene

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The Themost mostcommonly commonlyimplemented implementedNMs NMshave havebeen beenmade madeofoftransitional transitionalmetals metals(e.g., (e.g.,silver, silver,gold), gold),

The most commonly implemented NMs have been made of transitional metals (e.g., silver, gold), The most commonly implemented NMs have been made of transitional metals (e.g., silver, gold), carbon carbon(e.g., (e.g.,fullerenes, fullerenes,single singleand andmulti-walled multi-walledcarbon carbonnanotubes, nanotubes,graphene), graphene),and andmetal metaloxides oxides carbon (e.g., fullerenes, single andofof multi-walled carbon nanotubes, graphene), and metal oxides (e.g., (e.g., ZnO, TiO 2and ).2). Examples high commercial NMs include fullerenes, carbon (e.g., fullerenes, single multi-walled carbon nanotubes, graphene), and metal oxides (e.g., ZnO, TiO Examples high volume, volume, commercial NMs include nanosilver, nanosilver, fullerenes, ZnO,quantum TiO ). Examples of high volume, commercial NMs include nanosilver, fullerenes, quantum dots, carbon nanotubes, and metal oxide NPs [3]. NPs have already been applied in 2 quantum dots, metal oxide NPs [3]. include NPs have nanosilver, already been applied in (e.g., ZnO, TiO2). Examples ofcarbon high nanotubes, volume,and commercial NMs fullerenes, and products, food surfaces, disinfectants dots,sunscreens carbon nanotubes, and metal oxide NPs [3]. self-cleaning NPs have already been appliedand in clothing, sunscreens sunscreens andcosmetic cosmetic products, foodadditives, additives, self-cleaning surfaces, disinfectants and clothing, quantum dots,and carbon nanotubes, andadditives, metal products. oxide NPs [3]. have already beento applied in batteries, fuel AAvariety ofNPs have cosmetic foodand self-cleaning surfaces, disinfectants and clothing, batteries, batteries,products, fueladditives, additives, andother other products. variety ofNMs NMs havebeen beenengineered engineered toenhance enhance sunscreens andfuel cosmetic products, food additives, self-cleaning surfaces, disinfectants and clothing, medical devices, their functionality reliability. Nanostructured materials be applied toto medical devices, their functionality and reliability. Nanostructured materialsmay may be applied additives, and other products. A and variety of NMs have been engineered to enhance medical surfaces such as biomedical implants to enhance their biocompatibility, incorporated into surfaces such as biomedical implants to enhance their biocompatibility, incorporated into batteries, fuel additives, and other products. A variety of NMs have been engineered to enhance devices, their functionality and reliability. Nanostructured materials may be applied to surfaces such nanostructured solids oror composites toto improve conductivity, nanostructured solids composites improve strength, strength, conductivity, and durability, durability, and and as biomedical implants to and enhance their biocompatibility, incorporated into and nanostructured solids medical devices, their functionality reliability. Nanostructured materials may be applied to fabricated into complex, active structures for chemical ororbiological sensors ororother devices [3]. NMs fabricated into complex, active structures for chemical biological sensors other devices [3]. NMs or composites to improve strength, conductivity, and durability, and fabricated into complex, active surfaces such as have biomedical implants totissue enhance their biocompatibility, incorporated into inincell engineering, development ofofmedical encapsulation havebeen beenpromoted promoted celland and tissue engineering, development medicaldevices, devices, encapsulation structures for chemical or biological sensors or other devices [3]. NMs have been promoted in cell and and drug delivery, diagnostics, and genes [7]. An overview of applications of polymeric nano-carriers and drug diagnostics, and genes [7].strength, An overviewconductivity, of applications of polymeric nano-carriers nanostructured solids or delivery, composites to improve and durability, and tissueisengineering, development of medical devices, encapsulation and drug delivery, diagnostics, and provided for respiratory drug and gene delivery [8]. is provided for respiratory drug and gene delivery [8]. fabricated into complex, active structures for chemical or biological sensors or other devices drug [3]. NMs genes [7]. The An overview of applications of polymeric nano-carriers is provided for respiratory and Thedevelopment developmentofofNPs NPsfor forbiomedical biomedicalapplications applicationsand anddrug drugdelivery deliveryisisrapidly rapidlyexpanding. expanding. have been promoted in cell and tissue engineering, development of medical devices, encapsulation gene Future delivery [8]. isisprojected Futurenanomedicine nanomedicine projectedtotohave havean anenormous enormousimpact impacton onboth bothdiagnosis diagnosisand andtreatment, treatment, The development of NPs for biomedical applications and drug delivery is rapidly expanding. primarily in the field of cancer nanotechnology [9]. The application of nanotechnology to medicine isis and drug delivery, diagnostics, and [7].nanotechnology An overview applications of polymeric to nano-carriers primarily in the fieldgenes of cancer [9].of The application of nanotechnology medicine significant due the NPs the ofofessential ofofbiological nanomedicine is ability projected to to have an enormous impact on bothcomponents diagnosis and treatment, significant duetoto the ability NPs toresemble resemble thedimensions dimensions essential components biological is provided for Future respiratory drug and geneofof delivery [8]. molecules, totocross body more and organs and primarily in theto field ofable cancer nanotechnology [9].barriers The application of nanotechnology medicine molecules, tobe beable cross bodymembrane membrane barriers moreeffectively, effectively, andtotoaffect affectto organs and is The development ofatNPs for biomedical applications and drug delivery is rapidly expanding. tissues and levels. responses the tissues atthe the cellular and molecular levels.Biological Biological responses toNMs NMsatatcomponents theprotein proteinand and cellular significant due to cellular the ability ofmolecular NPs to resemble the dimensions oftoessential of cellular biological Future nanomedicine isdiffer projected to observed have anfor enormous impact on both diagnosis and treatment, levels from conventional materials. NPs and NM products may levels from those observed for conventional materials. NPs and NM products mayintroduce introduce molecules, todiffer be able tothose cross body membrane barriers more effectively, and to affect organs and tissues enhanced biological effects at cellular and molecular target levels, but the potential pitfalls oror is enhanced biological effects at cellular and molecular target levels, but the potential pitfalls primarily in theatfield of cancer [9]. The responses application of nanotechnology medicine the cellular and nanotechnology molecular levels. Biological to NMs at the protein andto cellular levels undesired effects of NMs in biological systems are also an important issue that should not be undesired effects in biologicalmaterials. systems are an important issue shouldenhanced not be from thoseof observed for conventional NPsalso andessential NM products maythat introduce significant due differ to the ability NPsoftoNMs resemble the dimensions of components of biological ignored ignored[10–13]. [10–13].Although AlthoughNPs NPssuch suchasassome somepolymeric polymericNPs NPsmay mayexhibit exhibitbiocompatible biocompatiblebehaviour behaviour biological cellularmembrane and molecularbarriers target levels, buteffectively, the potential pitfalls undesired effectsand of molecules, to be able toeffects crossat body more and tooraffect organs ininbiological systems, prior NPs undergo aacomprehensive biological systems, priortototheir theirtherapeutic therapeuticapplication, application, NPsshould should undergo comprehensive NMs physicochemical in biological systems are also an important issue that should not be ignored [10–13]. Although NPs characterization inin both and Examples ofof biosafety and characterization both dry dry andwet wet conditions. conditions. Examples biosafety and tissues at the cellularphysicochemical and molecular levels. Biological responses to NMs at the protein and cellular such biocompatibility as some polymeric NPs may exhibit biocompatible behaviour in biological systems,have prior been to their investigations of specific NMs used in regenerative medicine biocompatibility investigations of specific NMs used in regenerative medicine have been levels differ from those observed for conventional materials. NPs and NM products may introduce therapeutic application, NPs should undergo a comprehensive physicochemical reviewed [13]. include quantum dots, silica, NPs mostly reviewed [13].These These include quantum dots, silica,and andpolymer polymer NPsthat thatare arecharacterization mostlyused usedfor forin enhanced biological effects at cellular and molecular target levels, but the potential pitfalls or both fluorescence dry and wet conditions. Examples of biosafety and biocompatibility investigations of specific fluorescenceimaging; imaging;super-paramagnetic super-paramagneticiron ironoxide oxideNPs NPsused usedfor formagnetic magneticresonance resonanceimaging; imaging;and and NMsof used in regenerative have been reviewed These include quantum dots, silica, gold NPs that for imaging undesired effects NMs in biological systems are also[13]. an[13]. important issue that should notandbe gold NPs thatare areused usedmedicine forphotoacoustic photoacoustic imaging [13]. Available research has indicated that ultrafine particles (UFPs) often induce mild yet significant polymer NPs that are mostly used for fluorescence imaging; super-paramagnetic iron oxide NPs used Available research has indicated that ultrafine particles (UFPs) often induce mild yet significant ignored [10–13]. Although NPs such as some polymeric NPs may exhibit biocompatible behaviour pulmonary inflammatory responses asaswell effects [14]. exposure totoNPs pulmonary inflammatory responses wellas assystemic systemic effects [14].Pulmonary Pulmonary exposure NPs for magnetic resonance imaging; and gold NPs that are used for photoacoustic imaging [13]. in biological systems, prior to their therapeutic application, NPs should undergo a comprehensive induces response compared to particles ofof conventional material atat inducesaagreater greaterinflammatory inflammatory response compared tolarger larger particles conventional material Available research has indicated that ultrafine particles (UFPs) often induce mild yet significant physicochemical characterization in both dry and wet conditions. Examples of biosafety identical mass concentrations [15]. Following the exposure of human fibroblasts to ZnO and TiO 2and identical mass concentrations [15].asFollowing the exposure of human fibroblasts toexposure ZnO andto TiO 2 pulmonary inflammatory responses well as systemic effects [14]. Pulmonary NPs NPs, cell viability was significantly reduced in a dose-dependent manner using the MTS Tetrazolium NPs, cell viability was significantly reduced in a dose-dependent manner using the MTS Tetrazolium biocompatibility investigations of specific NMs used in regenerative medicine have been induces a greater inflammatory response compared to larger particles of conventional material at Salt ofofA549 totomicroand copper(II) oxide induced cell Saltassay assay[16]. [16].InInvitro vitroexposure exposure A549cells cellsthe microandnanosized nanosized copper(II) oxide induced cell mass concentrations [15]. Following exposure of human fibroblasts to ZnO and TiOfor reviewed [13]. identical These include quantum dots, silica, and polymer NPs that are mostly used 2 viability viabilityreduction reductionininaadose-dependent dose-dependentmanner; manner;however, however,NPs NPsreduced reducedthe thecellular cellularmetabolic metabolic NPs, cell viability was significantly reduced in a dose-dependent manner using the MTS Tetrazolium fluorescence imaging; super-paramagnetic activity more activity moreseverely severely[17]. [17]. iron oxide NPs used for magnetic resonance imaging; and Salt assaySerious [16]. Indamage vitro exposure of A549 cells to micro- and nanosized copper(II) oxide inducedtocell lung Serious damagetotothe thehuman human lungwas wasreported reportedininseven sevenfemale femaleworkers workerswho whowere wereexposed exposed to gold NPs that are used for photoacoustic imaging [13]. viability reduction in a dose-dependent manner; however, NPs reduced the cellular metabolic activity polyacrylate containing NPs over aa5–13 month exposure period. All seven workers presented with polyacrylate containing NPs over 5–13 month exposure period. All seven workers presented with Available research has indicated that ultrafine particles (UFPs) often induce mild yet significant moreshortness severely [17]. shortnessof ofbreath breathand andpleural pleuraleffusions effusions[18]. [18].The Thecompound compoundthat thatwas wasstated statedtotobe bepolyacrylic polyacrylicester ester pulmonary inflammatory responses welllung as systemic effects [14]. Pulmonary exposure to NPs Serious damage to theas human was reported in seven female workers who were exposed to polyacrylate containing NPs overcompared a 5–13 month period. Allof seven workers presented withat induces a greater inflammatory response toexposure larger particles conventional material of breath[15]. and pleural effusions The compound that was stated to be identical mass shortness concentrations Following the[18]. exposure of human fibroblasts to polyacrylic ZnO andester TiO2 NPs, cell viability was significantly reduced in a dose-dependent manner using the MTS Tetrazolium Salt assay [16]. In vitro exposure of A549 cells to micro- and nanosized copper(II) oxide induced cell

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consisted consisted of of NPs NPs of 30 nm, confirmed by electron microscopy analysis of both the paste compound used used and workplace workplace dust. Several Several cases cases of of human human exposure exposure to to NPs NPs that caused symptoms symptoms such as bronchiolitis, respiratory distress syndrome, and death have been reviewed [19]. While the potential toxic effects effects of ofNM NMexposure exposurehave havebeen been highlighted a concern, possible interactions of NMs highlighted as as a concern, the the possible interactions of NMs with with biological systems andprecise the precise mechanisms of their actions be understood. biological systems and the mechanisms of their toxic toxic actions have have yet toyet be to understood. As nanotech products, As research research and business business both both continue continue to to focus focus on nanotech products, more more research research is also needed potential adverse outcomes of NPs. NPs. Toxicological assessment should needed to assess the potential Toxicological risk assessment should be considered as an integral part of NM design and manufacture to ensure the health and safety considered as an integral part of manufacture to ensure health safety of workers, consumers, and the environment. Nanotoxicology is a new discipline of toxicology that aims to precisely precisely characterise characterise the the toxicity toxicity of NPs. Toxicological Toxicological risk risk assessment assessment of of NPs involves hazard identification, dose-response assessment, exposure assessment, and risk characterisation. Both identification, dose-response assessment, exposure assessment, Both in vivo and in vitro toxicity toxicity methods methods are are required for a comprehensive toxicity toxicity assessment assessment of of NPs. NPs. In In the the area of chronic chronic toxicity testing such such as as anti-cancer anti-cancer research, research, in in vivo vivo methods methods are are preferred. preferred. However, However, recent recent innovations in science and cell culture technology has allowed the development of alternative in vitro vitro assay systems systems that that are predictive, representative, representative, and and suitable suitable for toxicity toxicity screening, screening, e.g., e.g., for drug delivery delivery of of NPs. NPs. In In vitro vitro test test methods methods have have the the potential potential to to be be implemented implemented as as screening screening tools tools to to understand [16,20,21]. understand potential potential toxicity toxicity mechanisms mechanisms of of NPs NPs [16,20,21]. The The potential potential risks risks of of NPs NPs and and NM NM products products need need to to be be assessed assessed to to understand understand the the precise precise mechanisms responsible for such toxic effects and ultimately prevent human adverse effects. mechanisms responsible for such toxic effects and ultimately prevent human adverse effects. In In this this review, review, potential potential biological biological pathways pathways of of NPs NPs and and their their toxic toxic effects effects are are identified identified and and possible possible mechanisms recent advances andand limitations related to the mechanisms of of such sucheffects effectsare areinvestigated. investigated.Further, Further, recent advances limitations related to risk assessment and risk management of inhaled NPs are discussed. the risk assessment and risk management of inhaled NPs are discussed. NanoparticleExposure Exposureand andBiokinetic BiokineticPathways Pathways 2. Nanoparticle

With the exponential increase of production and commercialisation commercialisation of nanotechnology-based NPs may products, the pattern of human exposure to particulates has changed significantly [4,5]. NPs enter into into the thehuman humanbody bodyvia viainhalation, inhalation,dermal, dermal,oral, oral, and injection routes either unintentionally enter and injection routes either unintentionally or or deliberately (Figure 1).either In either the ability of NPs to cross biological barriers, such the deliberately (Figure 1). In case,case, the ability of NPs to cross biological barriers, such as theasskin, skin, gastrointestinal (GI)or tract, or blood–brain barrieris(BBB), is a prerequisite for their[9]. success [9]. gastrointestinal (GI) tract, blood–brain barrier (BBB), a prerequisite for their success Research Research findings on dermal absorption and skin penetration of NPs are inconsistent, and more findings on dermal absorption and skin penetration of NPs are inconsistent, and more data is needed data is needed to determine whether skin provides routeinto of entry of NPs into the body or While target to determine whether skin provides a route of entry ofa NPs the body or target tissues [22]. tissues [22]. While oral, and dermal may serve as important routes of deliberate entry injection, oral, andinjection, dermal routes may serveroutes as important routes of deliberate entry for nanoscale for nanoscale therapeutic and cosmetic products, inhalation is the most significant of entry for therapeutic and cosmetic products, inhalation is the most significant route of entryroute for occupational occupational NPs. The toxicological perspectives of therapeutics inhaled therapeutics andhave NPs been have exposures to exposures NPs. Thetotoxicological perspectives of inhaled and NPs been reviewed reviewed [21]. [21].

Figure 1. Biokinetics of nanoparticles (modified from [3]). Solid arrows: Confirmed routes; Dashed Figure 1. Biokinetics of nanoparticles (modified from [3]). Solid arrows: Confirmed routes; arrows: PotentialPotential routes; routes; CNS: Central nervous system; PNS: PNS: Peripheral nervous system; GI: Dashed arrows: CNS: Central nervous system; Peripheral nervous system; Gastrointestinal; IV: Intravenous. GI: Gastrointestinal; IV: Intravenous.

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Inhalation and deposition of particulates in the human respiratory tract is a size-dependent cascade in which the size distribution of particles plays a major role in determining particulate airborne behaviour [20,23]. Larger particles often are impacted in the nasopharyngeal region (5–30 µm), and smaller particles (1–5 µm) are deposited in the tracheobronchial region. However, very small particles including submicron particles (

Toxicological Considerations, Toxicity Assessment, and Risk Management of Inhaled Nanoparticles.

Novel engineered nanoparticles (NPs), nanomaterial (NM) products and composites, are continually emerging worldwide. Many potential benefits are expec...
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