Nanoparticles, nanotechnology and pulmonary nanotoxicology

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Soares Pires, P. Caetano Mota, N. Melo, D. Costa, J.M. Jesus, R. Cunha, S. Guimarães, C. Souto-Moura, A. Morais" "autores" => array:9 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Soares Pires" ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Caetano Mota" ] 2 => array:2 [ "nombre" => "N." "apellidos" => "Melo" ] 3 => array:2 [ "nombre" => "D." "apellidos" => "Costa" ] 4 => array:2 [ "nombre" => "J.M." "apellidos" => "Jesus" ] 5 => array:2 [ "nombre" => "R." "apellidos" => "Cunha" ] 6 => array:2 [ "nombre" => "S." "apellidos" => "Guimarães" ] 7 => array:2 [ "nombre" => "C." "apellidos" => "Souto-Moura" ] 8 => array:2 [ "nombre" => "A." "apellidos" => "Morais" ] ] ] ] ] "idiomaDefecto" => "pt" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173511512000541" "doi" => "10.1016/j.rppnen.2012.06.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173511512000541?idApp=UINPBA00004E" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0873215912000918?idApp=UINPBA00004E" "url" => "/08732159/0000001900000001/v2_201509041433/S0873215912000918/v2_201509041433/pt/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Special article" "titulo" => "Nanoparticles, nanotechnology and pulmonary nanotoxicology" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "28" "paginaFinal" => "37" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A.J. Ferreira, J. Cemlyn-Jones, C. Robalo Cordeiro" "autores" => array:3 [ 0 => array:4 [ "nombre" => "A.J." "apellidos" => "Ferreira" "email" => array:1 [ 0 => "ajofe@sapo.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Cemlyn-Jones" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Robalo Cordeiro" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Centre of Pneumology, Coimbra University Medical School, Coimbra, Portugal" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Nanopartículas, nanotecnologia e nanotoxicologia pulmonar" ] ] "textoCompleto" => "IntroductionThe second half of the XX Century saw the emergence of a truly revolutionary era of nanotechnology.The development of new materials, systems and structures through research at atomic, molecular, or macromolecular levels has enabled new applications.The nanoscale is typically a scale of matter under 100nm. According to several authors, unique and unusual physical, chemical, and biological properties can be seen at this dimensional level.Nanotechnology involves imaging, measuring, modeling, and manipulating matter at this scale. Some of the most promising uses of these technologies have emerged in some fundamental sectors, such as energy, communications, water purification, pollution reduction and environmental progress, improved materials and new products, medical and biomedical applications.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>Besides industrial and household uses, nanoparticles (NPs) can be used in Medicine (creating the new field of nanomedicine) for cancer treatment, infectious diseases, immunization purposes and diagnostic procedures with new imaging sensors and agents.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a>As nanotechnology penetrates the marketplace and attracts attention, the public is starting to develop opinions about it. Those opinions will shape the market for consumer goods using these new technologies.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Nanotechnology is a sector of high-tech industry that has already created a multibillion $US market, and is widely expected to grow to 1 trillion (1018) US dollars by 2015.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Nanotechnology research and development can integrate the nanoscale structures into larger material components, systems, and architectures.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>The majority of the NPs currently in use today have been made from transition metals, silicon, different forms of carbon (carbon nanotubes; fullerenes), and metal oxides (such as zinc dioxide and titanium dioxide).In sensu lato, inorganic nanoparticles do not contain carbon molecules; carbon nanotubes and carbon fullerenes are usually addressed as organic nanoparticles. But it must be stated that, strictly from a chemical point of view, these forms containing pure carbon molecules without bonds to hydrogen, constitute allotropes of carbon and are part of what is now known as the Inorganic Chemistry of Carbon.New applications are constantly emerging. The Nanotechnology Consumer Products Inventory, kept by the Woodrow Wilson Institute, listed over 1317 products or product lines as of April 2012.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Nanomaterials vary widely in terms of their composition, properties, and uses. Common products include cosmetics and personal care products, wound dressing pads, pregnancy tests, toothpaste, food supplements and food storage, appliances, clothing, coatings, electronics and computers and sporting goods.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>With the increasing technological complexity of nanotechnology, several generations of NPs can be reported:First generation ∼2001: Passive nanostructures (nanostructured coatings, nanoparticles, nanostructured metals, polymers, ceramics, catalysts, composites, displays).Second generation ∼2007: Active nanostructures (transistors, amplifiers, targeted drugs and chemicals, actuators, adaptive structures, sensors, diagnostic assays, fuel cells, solar cells, high performance nanocomposites, ceramics, metals).Third generation ∼2010: 3-D nanosystems and systems of nanosystems (various assembly techniques, networking at the nanoscale and new architectures, biomimetic materials, novel therapeutics/targeted drug delivery).Fourth generation ∼2015: Molecular nanosystems (molecular devices “by design”, atomic design, emerging functions).<a class="elsevierStyleCrossRef" href="#bib0045">9</a>The expression “nanoparticle” is commonly used to describe engineered structures with diameters of <100nm, that are created by chemical and/or physical processes, with very characteristic properties usually not present at a macro-scale level.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Reducing the size of a particle increases the ratio of surface area to mass. Because the reactive portion of the particle is on the surface, increasing the relative surface area will increase reactivity of a given amount of material. Also, at the nanoscale, both classical physics and quantum physics can direct the behaviour of a particle. The influence of quantum effects can change important material properties, such as optical, magnetic, and electrical properties.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>NPs may be suspended in a gas (as a nanoaerosol), suspended in a liquid (as a colloid or nano-hydrosol), or embedded in a matrix (as a nanocomposite).<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Some authors state that the main difference between NPs and ultrafine particles (UFP) refers to the fact that the term UFP is commonly used to describe nanometer-size particles that have not been intentionally produced, but are the incidental products of industrial processes or different types of combustion, and even volcanic activities.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>UFP (or incidental nanoparticles) show more complex chemical composition, irregular shapes, and polydispersed size distribution as compared to engineered particles.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>These particles could exert their effects per se or through a multitude of substances that could be adsorbed on their surfaces. For instance, some engineered NPs exist as nanocrystals composed of a number of compounds such as silicon and metals (quantum dots).<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Carbon fullerenes represent NPs with identical dimensions in all directions (i.e., spherical). They are carbon allotropes rolled up to form closed-cage, hollow spheres. Some of their characteristics such as their small size, large surface area and high reactivity make them interesting in technological and medical fields. They were initially discovered by Kroto, Smalley and Curl (who later won the 1996 Nobel Prize in Chemistry) as a new form of carbon, buckminsterfullerene or C60.<a class="elsevierStyleCrossRefs" href="#bib0025">5,14,15</a>Single-walled carbon nanotubes (SWCNTs) typically form convoluted, fibre-like NPs with a diameter below 100nm. Many particle morphologies can be created at the nanoscale, including “flower” and “belt”-like structures.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>Multi-walled carbon nanotubes (MWCNT) are larger and consist of many single-walled tubes stacked one inside the other.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Carbon nanotubes (CNTs) are distinct from carbon fibres, because the latter consist of strands of layered graphite sheets and are not single carbon molecules. CNTs are reported to be physically very strong and stiff. For example a SWCNT can be up to 10 times as strong as steel and 1.2 times as stiff as diamond.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a>Close-packed nanotube structures could have a yield strength exceeding 45±7GPa, which is over 20 times the yield strength of typical high-strength steels.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>As would be expected from the above statements, it is now understood that potential occupational and environmental exposure to manufactured NPs is on the increase.Nanomedicine and the lungThe field of nanomedicine is the science and technology of diagnosing, treating and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body. Its objectives encompass monitoring, control, construction, repair, defense and improvement of human biological systems, using engineered devices and nanostructures for medical benefit.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Nanomedicine involves the best knowledge about the science and technology of intricate systems of nanometre-scale size, with several components, one of which is an active principle, with the whole system leading to a special function connected to the diagnosis, treatment and/or prevention of disease.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Nanomedicine also includes the identification of new molecular targets, the creation of new synthetic low molecular weight drugs, nanofluidics for targeted synthesis, nanodetection for target identification, the discovery of natural macromolecules, including antibodies, proteins and genes with biological activity and the creation of drug delivery systems (liposomes and nanoparticles–nanopharmaceuticals), promoting disease-specific targeting, in order to thoroughly control the release of the drugs over the desired period of time, or even to supply suitable routes of administration that can reach locations in the body that are traditionally difficult to access, such as the brain.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Nanotechnology has an enormous potential in the field of human imaging and early recognition of disease, with the tailoring of specific nanoagents for molecular imaging in the context of Magnetic Resonance Imaging, ultrasound, optical imaging, and X-ray imaging.<a class="elsevierStyleCrossRefs" href="#bib0090">18–23</a>Other medical areas include gene and oncologic therapy using multicomponent, nanosized delivery vectors. Nanotube drug delivery is promising for cancer therapy with high treatment efficacy and minimum side effects. There is an increasing use of NPs as carrier systems for chemotherapeutic drugs because of the ability to specifically target cancer cells, improve efficacy and reduce systemic toxicity.<a class="elsevierStyleCrossRef" href="#bib0120">24</a>Noble metal NPs can efficiently target several kinds of tumours, as they present highly tunable optical properties that can be adjusted to desirable wavelengths according to their shape and composition with possible uses in tumour targeting, gene silencing and drug delivery; they can also efficiently convert light or radiofrequencies into heat, promoting thermal ablation.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>CNTs can be effective in delivering drugs such as paclitaxel to retard tumour growth in experimental models of cancer.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a>Solid lipid nanoparticles (SLN) are ideal carriers for weakly soluble drugs, and are alternatives to current colloidal carriers. Inhaled SLN–paclitaxel could represent a potential system for regional delivery to the lungs, with special efficacy on the lymphatic system, fundamental in the progression of lung adenocarcinomas.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Therefore, targeted nanoparticle delivery to the respiratory system is one of the future trends in nanomedicine, as it can improve drug therapies systemically and locally using advanced drug delivery systems based in more or less complex nanostructures. In the specific area of lung cancer treatment, NPs can revolutionize future chemotherapy options. Other areas of development are the improvement of monoclonal antibodies for lung targeting (attaching antibodies to drug molecules or drug delivery systems), lung imaging, gene delivery, cystic fibrosis treatment (gene therapy and nano-selective and sustained delivery of proteasome inhibitor drugs) and tuberculosis diagnosis and treatment (as macrophage involvement make NPs a perfect drug carrier).<a class="elsevierStyleCrossRefs" href="#bib0140">28–31</a>Environmental challenges of exposure to nanoparticlesSoon after the great development and commercial introduction of these materials, some authors raised significant questions about the potential impact on human health and the environment.In the 1990s, toxicology and epidemiology research on ultrafine aerosols began developing in combination. However, the emerging field of nanotechnology stimulated the actions toward developing a more complete understanding of what unexpected and unanticipated impact nanoscale materials might have on health.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>In recent decades there has been human exposure to nanoscale particles in the form of diesel soot and bulk UFPs from diverse industrial procedures, essentially in the form of combustion-derived UFPs, but also from natural sources such as forest fires and volcanoes.Exposure to these particles has been associated with pulmonary inflammation, immune changes, and adverse systemic effects including blood hypercoagulability, contributing to undesirable cardiovascular effects.<a class="elsevierStyleCrossRefs" href="#bib0160">32–35</a>Consistent with cross-sectional findings and animal studies, there seems to be an association between exposure to air pollution and the progression of atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Some studies report the association of particulate matter <2.5 um (PM2.5) and carotid intima-media thickness.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Oxidative stress, inflammation, induction of a pro-coagulatory state and dysfunction of the autonomic nervous system can enhance respiratory and cardiovascular diseases. Changes in lung function, heart rate, blood pressure and inflammatory state, and also respiratory symptoms, thrombosis, myocardial infarction, arrhythmia, strokes, and death are more often seen in polluted environments, causing shorter life expectancy.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>A lot of the concern related to the exposure to nanomaterials comes from our knowledge from the reports of inhalation of ultrafine particles found in occupational settings and also ultrafine aerosols resulting from combustion. There seems to be an important link between several chronic diseases and the inhalation of UFPs, such as Clara cell carcinomas (polycyclic aromatic hydrocarbons), mesothelioma (asbestos), and berylliosis (beryllium). Some syndromes associated with exposure to aerosols include coal worker pneumoconiosis, emphysema (combustion products), and metal fume fever (zinc, tin, and other transition metals).<a class="elsevierStyleCrossRef" href="#bib0025">5</a>However, the technical requirements for the detection and characterization of nanoparticles in the environment push the limits of modern sampling techniques and instrumentation.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>At present, there are no legal thresholds for nanoparticle number concentrations in ambient air, so local observation networks do not generally monitor them. The development of ambient particle regulations has been limited for technical and practical reasons, such as the lack of standard methods and instrumentation, and the uncertainty about repeatability and reproducibility of measurements.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>Assessment of the risk associated with nanoparticles requires knowledge about the ability of a material to reach a sensitive site of action, and the type and magnitude of the resultant response at the sensitive site.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>NanotoxicologyThe lung is the primary and probably the most important target of nanomaterials, but NPs can enter the circulation and migrate to various organs and tissues, where they can build up and injure organ systems that are sensitive to oxidative stress. The types of toxicological response will probably vary between molecular and nano-sized forms.The size of the NPs suggests that the physiological responses could be of an immune or inflammatory nature. These adverse effects may not follow a classic dose-response curve, and can display high unpredictability within the population, potentially dependent on individual sensitivity.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Nanoparticle toxicity is extremely complex and multifactorial and depends on a multiplicity of physicochemical properties such as size and shape, as well as surface properties (charge, area, and reactivity). Ultrafine or nanosize range (<100nm) particles seem to be more toxic on a mass-based exposure metric compared to larger particles of identical chemical composition. Also, particle surface area dose is a better predictor of the toxic and pathological responses to inhaled particles than particle mass dose.<a class="elsevierStyleCrossRefs" href="#bib0045">9,40</a>Differences in physico-chemical properties between NPs and larger particles determine their behaviour as aerosol, their biodistribution following translocation from the portal of entry, their cellular interactions and effects. Secondary organs are usually affected differently from the primary target of these particles.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>In 1990, the Journal of Aerosol Science published two of the first cornerstone papers on a higher than expected effect on lung inflammation patterns in rats exposed to NPs, effects that could not be predicted by just taking the chemical composition and the inhaled amounts of the particles into account.<a class="elsevierStyleCrossRefs" href="#bib0205">41–43</a>One of the first important assumptions, that is still of great importance, is that NPs have the potential to show previously unrecognized biological behaviour.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>A major report concerning the uncertainties of nanotechnologies was published in 2004 by the Royal Society and the Royal Academy of Engineering.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> This was one of the first reports to highlight the potential risks to health and the environment that may arise from exposure to nanomaterials, especially NPs (which included nanomaterials such as nanotubes). Since then, more than fifty national and international reviews carried out by government departments, industry associations, insurance organizations and researchers have considered nanoparticle risk issues.A workshop co-sponsored by the National Science Foundation and the US Environmental Protection Agency has identified a number of potential risks regarding manufactured NPs, such as exposure assessment of manufactured NPs; toxicology of manufactured NPs; the ability (or not) to extrapolate manufactured nanoparticle toxicity using existing particle and fibre toxicological databases; environmental and biological fate, transport, persistence, and transformation of manufactured NPs, recyclability and overall sustainability of manufactured nanomaterials.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>The ability of absorbed particles to generate local toxic effects at the site of initial deposition as well as very significant systemic toxic responses shows how dangerous they can be in real-life settings. The potential for adverse health effects may arise from direct exposure to intentionally produced nanomaterials and/or byproducts associated with their applications.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Toxicological assessment of manmade nanomaterials requires information about the route (inhalation, oral, dermal) of exposure, as well as their complete physicochemical characterization of them in order to provide thorough information. The most common scenarios for human exposure to NPs are occupational, environmental and consumer ones.Inhalation hazards of nanoparticlesOne of the most widespread routes of human exposure to airborne NPs is inhalation in the workplace and the environment.As seen before, at present there are large numbers of nanomaterials; as their technological and toxicological properties vary considerably, so will their risk profiles.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> We are now able to consider that the extensive and heterogeneous group of NPs of diverse scale constitutes an inhalation hazard of unknown potential.The deposition of NPs in the respiratory tract is determined essentially by the particle aerodynamic or thermodynamic diameter (depending on particle size).<a class="elsevierStyleCrossRef" href="#bib0055">11</a>According to the classical model developed by the International Commission on Radiological Protection (ICRP), the probability of nanoparticles reaching the alveoli peaked at a size of approximately 20nm, with lower probabilities of deposition in the alveoli for both smaller and larger nanoparticles. Nanoparticle deposition, in particular for smaller particles, is governed by Brownian movements.<a class="elsevierStyleCrossRef" href="#bib0060">12</a>There are still issues that have not yet been fully resolved about how exposure to NPs can be thoroughly measured and quantified; they are usually described as mass concentration (units mgm−3); number concentration (units per m−3) and surface area concentration units (m2m−3).As stated before, the possible health effects arising from exposure to NPs may be better correlated with surface area, rather than with mass concentration.<a class="elsevierStyleCrossRefs" href="#bib0030">6,16</a>NPs have some essential properties that could be directly related to their pathogenicity:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-As particles less than 100nm, they may have more toxicity than larger sized particles.</li><li class="elsevierStyleListItem" id="lsti0010">-Generally they are considered as fibre shaped, and so might behave like some other pathogenic fibres (asbestos, man-made fibres).</li><li class="elsevierStyleListItem" id="lsti0015">-As most of the NPs have an essentially graphitic constitution, they are expected to be biopersistent in biological settings, such as the respiratory system.<a class="elsevierStyleCrossRef" href="#bib0080">16</a></li></ul>Commercial NPs could also contain some impurities, a common result of the synthesis process, such as metals (Co, Fe, Ni, and Mo), organic compounds, and support material.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Smaller particles are likely to be more aggressive to the lung than larger particles; particles with more inert surfaces may be aggressive, exerting their effects on cells by reason of having a large surface area. Particles with more reactive surfaces can affect cells without necessarily having large surface areas.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>Shape, biopersistence, presence of transition metals and the power to generate reactive oxygen species also explain the potential for lung damage. In fact, some of the main experimental studies in rodents and cell cultures have shown that the toxicity of UFPs or NPs is greater than that of the same mass of larger particles with a similar chemical composition, posing specifically a higher respiratory and systemic health threat.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>At equivalent mass doses, insoluble ultrafine particles cause more damage than larger particles of a similar composition in terms of pulmonary inflammation, tissue damage, and lung tumours.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>From the alveoli, NPs have the potential to enter the bloodstream from the lungs and even translocate to other organs.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> For instance, biokinetic studies show that inhaled NPs can translocate via olfactory neurons from the nose to the Central Nervous System.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>The biokinetics of NPs in the body varies, depending on the portal of entry. The same NPs entering the lung (via inhalation or intratracheal instillation) or intravenously, interact with different biological media and will receive different secondary coatings, affecting nanoparticle biodistribution to target organs.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>At present, carrying out risk assessment of NPs can only be done sensibly on a case-by-case basis.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Most of the studies about the effects of respiratory exposure to NPs involve pulmonary models and are performed through instillation, aspiration and inhalation of carbon nanotubes (the most studied NPs) in rodent species.<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes some of the main in vivo investigations regarding the respiratory effects of carbon nanotubes.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Many of the most pressing health and safety concerns regarding NPs and nanotechnologies come from the lack of knowledge about levels of occupational and other types of exposure during their production and use.<a class="elsevierStyleCrossRef" href="#bib0305">61</a>Among the particles with potential respiratory risks, CNTs are one of the specialized structures of engineered NPs that are widespread. Discovered more than 20 years ago, they have increasing potential uses in biomedical, aeronautic, and industrial fields due to their unique conductive and electrochemical properties.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>As seen before, CNTs are classified according to their structure: single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT).Nanotubes can have features of both NP and conventional fibres. The literature currently available suggests that CNT may have toxic effects beyond those predictable for their mass exposure. For instance, they have more adverse effects than the same mass of NP carbon and quartz, a commonly used comparator amongst harmful inhalable particles.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>CNTs can induce oxidative stress and inflammation, and several studies imply that they could cause granuloma formation and fibrogenesis.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>In occupational contexts, CNTs should be considered in the same way as other biopersistent fibres in the workplace, with implications for at least similar approaches to control and assessment.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>It would appear that the main mechanism of engineered nanomaterial toxicity is related to oxidative stress, caused by the activation of responsive transcription factors. Chronic inflammation and oxidative stress observed during and after exposure can induce adverse health effects such as fibrosis, genotoxicity and cancer caused by fibres or secondary mutation.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>One of the first studies on the subject of CNTs exposure was performed by Lam et al.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> In this study mice were instilled intratracheally with 0, 0.1, or 0.5mg of carbon nanotubes, a carbon black negative control, or a quartz positive control, and lung pathology studied 7 or 90 days after exposure. All nanotube products induced dose-dependent epithelioid granulomas and, in some cases, interstitial inflammation, which was more pronounced in the 90-day group. Some animals had peribronchial inflammation and necrosis, extending to the alveolar septa. On a same weight basis, when CNTs reach the lungs, they are much more toxic than carbon black and can be more toxic than quartz.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Inhalation studies are able to provide more information and reproducibility of occupational and environmental risks. However, instillation studies are less complex and cheaper, so they could represent a form of screening for the potential harm and toxicity of NPs.<a class="elsevierStyleCrossRef" href="#bib0310">62</a>In the experiments where intratracheal instillation of NPs was performed, more pronounced and severe effects were observed, when compared with inhalation studies.<a class="elsevierStyleCrossRefs" href="#bib0310">62,63</a>CNTs have toxicologically significant structural and chemical similarities to asbestos, and experiments have shown that they cause pulmonary inflammation, granuloma formation and fibrosis after entering the respiratory system of rodents, as observed after exposure to asbestos. Some studies confirm for MWCNTs a well established asbestos-like pathogenicity that is associated with long fibres.<a class="elsevierStyleCrossRefs" href="#bib0295">59,64</a>In addition, the impact of some impurities, such as metals, present in some MWCNTs cannot be underestimated in the forms in which the lung could be affected.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>According to Pacurari et al., the fibrous characteristics of MWCNT, their durability and their ability to generate reactive oxygen species at low levels in cellular systems may contribute to the initiation and progression of asbestos-like pathological responses.<a class="elsevierStyleCrossRef" href="#bib0330">66</a>Shvedova et al. demonstrated that SWCNT inhalation resulted in mutations of K-ras gene locus in the lung of C57BL/6 mice. This is one of the mutated genes that can be implicated in pulmonary tumourigenesis.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Aerosolized inhalation in animal studies supports a common sequence of biological events following single CNT exposure: important acute phase inflammation similar to a foreign body response, followed by formation of multifocal granulomas, and early onset fibrosis.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>MWCNTs and other carbon NPs in fine (<2.5μm) particulate matter (PM) aggregates have been related to the combustion of methane, propane, and natural-gas flames of some stoves; indeed, indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs.A very recent study from Teeguarden et al. used high sensitivity based proteomics – HPLC–FTICR–MS (high performance liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometry) to assess some of the major differences in exposure to three materials – SWCNT, asbestos, and ultrafine carbon black (UFCB).<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Rodent exposure to SWCNT led to a significantly greater inflammatory response, when compared with crocidolite asbestos and UFCB, with an increase in polymorphonuclear neutrophils (PMNs) and total cell count of bronchoalveolar lavage fluid (BALF). Also, moderate multifocal inflammation was present in all lungs from SWCNT exposed mice, with granuloma formation near bronchioles and adjacent alveoli consisting of round clusters of large macrophages and multinucleated giant cells. Statistically significant differences in some cytokines (TARC, IL-12 and MDC) were also seen, proving the high inflammogenic potential of SWCNT. In addition, the proteomic analysis conducted by the authors supports the conclusion that lung tissue and lung infiltrate responses were generally greater on a mass dose basis for SWCNT.The potential for particles to cause fibrotic reactions within the lung depends on the particle size, composition, surface activity, and retained dose. Particles containing certain transition metals have a greater capacity to generate reactive oxygen species, in addition to those already generated by inflammatory neutrophils and activated alveolar macrophages.<a class="elsevierStyleCrossRef" href="#bib0290">58</a>Recently, Wang at al. demonstrated that chronic exposure to SWCNT can produce malignant transformation of human lung epithelial cells. Also, SWCNT-transformed cells injected in immunodeficient mice led to tumour growth at the injection site in mice receiving SWCNT-transformed BEAS-2B cells, whereas mice receiving control BEAS-2B cells did not develop tumours, showing also the potential role of p53 in this process.<a class="elsevierStyleCrossRef" href="#bib0300">60</a>Like other areas of knowledge regarding nanotechnologies, studies of the carcinogenic potential of carbon nanotubes are still in the early stages, but there are some data suggesting that these structures are not risk free, and can be widely dependent on several other physico-chemical and biological characteristics, and also specific composition and type and size of impurities.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Also, fullerenes (NPs with identical dimensions in all directions) following exposure via the pulmonary route are capable of eliciting localized responses that are pro- or anti-inflammatory in nature, with the type of response initiated likely to be reliant on the fullerene in question, exposure method and the dose used. However, inhalation studies regarding the effects of fullerenes are still limited.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>Fullerene toxicity probably involves an oxidant response, suggesting the potential of fullerenes to cause oxidative stress and related consequences (such as inflammation or genotoxicity). Generally, the greater the water solubility exhibited by a fullerene sample, the lower the toxicity associated with exposure.<a class="elsevierStyleCrossRef" href="#bib0030">6</a>In addition, recent studies in murine models prove that titanium dioxide (TiO2) or gold (Au) NPs can interfere with the modulation of the asthmatic response regarding diisocyanate induced asthma, as they can aggravate pulmonary inflammation and airway hyperreactivity.<a class="elsevierStyleCrossRef" href="#bib0335">67</a>There is still a shortage of publications addressing the in vivo, real world effects of nanoparticle exposure. However, some of these are very worrying; for instance, Chinese workers exposed to polyacrylate consisting of NPs in a print plant have shown shortness of breath, and the same clinical findings of pleural effusion and pericardial effusion. The study of these workers revealed nonspecific pulmonary inflammation, pulmonary fibrosis and foreign-body granulomas of the pleura; BALF elicited increased lymphocytes and neutrophil leukocytes. Two young patients subsequently died from respiratory failure.<a class="elsevierStyleCrossRef" href="#bib0340">68</a>Conclusions and future trendsRespiratory exposure to NPs can cause important adverse respiratory effects, such as multifocal granulomas, peribronchial inflammation, progressive interstitial fibrosis, chronic inflammatory responses, collagen deposition, oxidative stress, pleural lesions and gene mutations, at least in experimental animal studies.At this point in time, it is fundamental to know more about the toxicological effects of NPs, to address the increased concern of potentially harmful public and occupational exposures.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>A very wide range of endpoints have to be considered when testing potential risks derived from NPs. Hazards should be tested according to their potential routes within the human body.According to Oberdörster in a recent paper regarding the safety assessment for nanotechnology, although many of the current engineered nanomaterials with a potential for human exposure are not likely to induce significant adverse effects, some could cause an asbestos-type disaster if it is not controlled.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>There is, therefore, an urgent need for the development of criteria for extrapolating toxicological data in biological systems in order to predict the risk of adverse outcomes in humans.<a class="elsevierStyleCrossRef" href="#bib0325">65</a>Not only traditional tests, but also newer models reflecting the permanent evolution of nanotoxicology as an emerging field, should be used to shed light on the mechanisms of NP toxicity. The combination of in vitro and in vivo tests should contribute to hazard assessment in the future. A multidisciplinary team approach is fundamental to addressing respiratory human risks related with Nanotechnology.At present, there are several extremely relevant attempts currently under way in order to formulate a science-based risk management research framework. One of them is the US. National Nanotechnology Initiative/Environmental, Health, and Safety Research Strategy; the main research needs to include, among other points, the development of measurement tools for the determination of physico-chemical properties of engineered nanomaterials (ENMs), their detection and monitoring in realistic exposure media and conditions during the life cycle, the evaluation of transformations of ENMs in relevant media, the further assessment of biological responses, the better understanding of the processes and factors that determine exposures to nanomaterials, the identification of population groups exposed to ENMs and their health surveillance, and the development of appropriate, reliable, and reproducible assays and models to predict human responses to ENMs.With appropriate strategies that integrate risk assessment into decision-making frameworks for risk management, and incorporate and standardize risk communication within the risk management framework, better esults should be expected in the future.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Now is the time to promote, on a global scale, an in-depth discussion and evaluation of the human and environmental risks of these new materials; as stated by Maynard et al.,<a class="elsevierStyleCrossRef" href="#bib0215">43</a> these resources are “merely the vanguard of a new era of complex materials, where novel and dynamic functionality is engineered into multifaceted substances. If we are to meet the challenge of ensuring the safe use of this new generation of substances, it is time to move beyond “nano” toxicology and toward a new toxicology of sophisticated materials.”Ethic disclosuresProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this investigation.Confidentiality of dataThe authors declare that no patient data appears in this article.Right to privacy and informed consentThe authors declare that no patient data appears in this article.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres547865" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec565733" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres547864" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec565734" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Nanomedicine and the lung" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Environmental challenges of exposure to nanoparticles" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Nanotoxicology" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Inhalation hazards of nanoparticles" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions and future trends" ] 10 => array:3 [ "identificador" => "sec0035" "titulo" => "Ethic disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "Right to privacy and informed consent" ] ] ] 11 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-04-09" "fechaAceptado" => "2012-09-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec565733" "palabras" => array:6 [ 0 => "Nanoparticles" 1 => "Nanotoxicology" 2 => "Nanotubes" 3 => "Fullerenes" 4 => "Lung" 5 => "Toxicology" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec565734" "palabras" => array:6 [ 0 => "Nanopartículas" 1 => "Nanotoxicologia" 2 => "Nanotubos" 3 => "Fulerenos" 4 => "Pulmão" 5 => "Toxicologia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The recently emergent field of Nanotechnology involves the production and use of structures at the nanoscale. Research at atomic, molecular or macromolecular levels, has led to new materials, systems and structures on a scale consisting of particles less than 100nm and showing unique and unusual physical, chemical and biological properties, which has enabled new applications in diverse fields, creating a multimillion-dollar high-tech industry. Nanotechnologies have a wide variety of uses from nanomedicine, consumer goods, electronics, communications and computing to environmental applications, efficient energy sources, agriculture, water purification, textiles, and aerospace industry, among many others.The different characteristics of nanoparticles such as size, shape, surface charge, chemical properties, solubility and degree of agglomeration will determine their effects on biological systems and human health, and the likelihood of respiratory hazards. There are a number of new studies about the potential occupational and environmental effects of nanoparticles and general precautionary measures are now fully justified.Adverse respiratory effects include multifocal granulomas, peribronchial inflammation, progressive interstitial fibrosis, chronic inflammatory responses, collagen deposition and oxidative stress.The authors present an overview of the most important studies about respiratory nanotoxicology and the effects of nanoparticles and engineered nanomaterials on the respiratory system." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "O campo recentemente emergente da nanotecnologia envolve a produção e o uso de estruturas em nanoescala. A pesquisa a níveis atómicos, moleculares e macro moleculares conduziu a novos materiais, sistemas e estruturas numa escala constituída por partículas menores que 100nm, apresentando propriedades físicas, químicas e biológicas únicas e incomuns, o que tem permitido novas aplicações em diversos campos, criando uma indústria de alta tecnologia multimilionária. As nanotecnologias têm uma vasta variedade de usos, desde a nano medicina, bens de consumo, eletrónica, comunicações e informática, até às aplicações ambientais, fontes de eficiência energética, agricultura, purificação de água, têxteis e indústria aeroespacial, entre muitos outros.As diferentes características das nanopartículas, tais como tamanho, forma, carga de superfície, propriedades químicas, solubilidade e grau de aglomeração, determinarão os efeitos sobre os sistemas biológicos e na saúde humana e a probabilidade de riscos respiratórios. Existem alguns novos estudos sobre os potenciais efeitos ocupacionais e ambientais das nanopartículas, sendo totalmente justificadas as medidas gerais de precaução.Os efeitos respiratórios adversos incluem granulomas multifocais, inflamação peribrônquica, fibrose intersticial progressiva, respostas inflamatórias crónicas, deposição de colagénio e stress oxidativo.Os autores apresentam um resumo dos mais importantes estudos sobre nanotoxicologia respiratória e dos efeitos das nanopartículas e dos nanomateriais artificiais sobre o sistema respiratório." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Animal species, agent and method of administration \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Results \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal instillation of CNT containing soot on guinea pigs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No induction of any abnormalities of pulmonary function or measurable inflammation. No lung pathology was performed in this study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Huczko et al. (2001)<a class="elsevierStyleCrossRef" href="#bib0235">47</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal instillation of different SWCNT samples (three SWCNT products made by different methods and containing different types and amounts of residual metals) on mice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">All nanotube products induced dose-dependent persistent epithelioid granulomas. The lungs of some animals also revealed peribronchial inflammation and necrosis extending into the alveolar septa. The lungs of mice treated with carbon black were normal, whereas those treated with high-dose quartz revealed mild to moderate inflammation. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lam e al. (2004)<a class="elsevierStyleCrossRef" href="#bib0240">48</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal instillation of SWCNT on Sprague-Dawley rats \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas, which were evidence of a foreign tissue body reaction and were non uniform in distribution and not progressive beyond 1 month post exposure. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Warheit et al. (2004)<a class="elsevierStyleCrossRef" href="#bib0245">49</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intrapharyngeal aspiration of purified SWCNT on mice (C57CL/6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Acute inflammation, early onset of formation of granulomas, and progressive fibrosis. SWCNT-induced granulomas, mainly associated with hypertrophied epithelial cells surrounding the dust aggregates, and diffusive interstitial fibrosis and alveolar wall thickening. Lung lesions were dose-dependent and progressive. Bronchial alveolar lavage fluid (BALF) increases in total protein concentration, cell counts, concentration of transforming growth factor beta (TGF-β), lactate dehydrogenase (LDH), and γ - glutamyltranspeptidase activities, and glutathione depletion (biomarkers of inflammation, oxidative stress, and cytotoxicity). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shvedova et al. (2005)<a class="elsevierStyleCrossRef" href="#bib0250">50</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal instillation of MWCNT on Sprague-Dawley Rats \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Inflammation, collagen rich granulomas, and fibrosis. Hydroxyproline and soluble collagen, increased in the lung tissues in a dose-dependent fashion. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Muller et al. (2005)<a class="elsevierStyleCrossRef" href="#bib0255">51</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intrapharyngeal instillation of SWCNT on mice (C57CL/6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Activation of heme-oxygenase-1 (HO-1), a marker of oxidative insult, in lung, aorta, and heart tissue. Aortic mtDNA damage at 7, 28, and 60 days after exposure. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Li et al. (2007)<a class="elsevierStyleCrossRef" href="#bib0260">52</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal Instillation+inhalation of MWCNT on Kunming mice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Difference in lung pathological lesions induced by instilled and inhaled MWCNTs probably due to different size and distribution of aggregations of MWCNTs in lung. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Li et al. (2007)<a class="elsevierStyleCrossRef" href="#bib0035">7</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Whole-body inhalation of MWCNT on mice (C57CL/6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The experiment did not result in significant lung inflammation or tissue damage, but caused systemic immune function alterations. BALF demonstrated particle-laden macrophages. Nonmonotonic systemic immunosuppression. Decreased NK cell function. No changes in gene expression were observed in lung. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mitchell et al. (2007)<a class="elsevierStyleCrossRef" href="#bib0265">53</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Intratracheal instillation of SWCNT on mice \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alveolar macrophage activation, several chronic inflammatory responses, and severe pulmonary granuloma formation. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chou et al. (2008)<a class="elsevierStyleCrossRef" href="#bib0270">54</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Whole-body inhalation of SWCNT on mice (C57CL/6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Development of multifocal granulomatous pneumonia and interstitial fibrosis. SWCNT inhalation caused more inflammatory response, oxidative stress, collagen deposition, fibrosis and mutations of K-ras gene when compared with aspiration. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shvedova et al. (2008)<a class="elsevierStyleCrossRef" href="#bib0275">55</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Wistar rats. MWCNT–Acute inhalation study. Positive control: alpha quartz. Negative control: air \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pulmonary inflammogenicity following exposure to MWCNT was concentration-dependent with evidence of regression over time. Alpha-quartz (positive controls) resulted in progressive changes over time. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ellinger-Ziegelbauer et al. (2009)<a class="elsevierStyleCrossRef" href="#bib0280">56</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Wistar rats. 90-day inhalation toxicity study with MWCNT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pronounced multifocal granulomatous inflammation, diffuse histiocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis were observed in lung and lung-associated lymph nodes, incidence and severity related. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ma-Hock et al. (2009)<a class="elsevierStyleCrossRef" href="#bib0285">57</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Wistar rats. MWCNT – Acute inhalation with 3 months postexposure period; Repeated inhalation exposure with 6 months postexposure period \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sustained pulmonary inflammation related to pulmonary overload of NPs resulting probably from stasis of clearance. Macrophages with enlarged and/or foamy appearance; increased influx of inflammatory cells and septal thickening, slight to moderate inflammation, focally with granulomatous appearance; interstitial fibrosis. Thickening of the visceral pleura. Inflammation did not decrease in severity with increasing post-exposure duration. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pauluhn (2010)<a class="elsevierStyleCrossRef" href="#bib0290">58</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">C57BL/6 mice. Repeated pharyngeal aspiration of SWCNTs, crocidolite, and ultrafine carbon black \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The incidence and severity of inflammatory and fibrotic responses were greatest in mice treated with SWCNTs. The proteomic analysis suggested that lung tissue and lung infiltrate responses to SWCNT and crocidolite asbestos were similar, but as for several histopathological endpoints, the response was generally greater on a mass dose basis for SWCNT, when compared with asbestos or ultrafine carbon black. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Teeguarden et al. 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Nanoparticles, nanotechnology and pulmonary nanotoxicology

Nanopartículas, nanotecnologia e nanotoxicologia pulmonar

A.J. Ferreira

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ajofe@sapo.pt

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, J. Cemlyn-Jones, C. Robalo Cordeiro

Centre of Pneumology, Coimbra University Medical School, Coimbra, Portugal

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The second half of the XX Century saw the emergence of a truly revolutionary era of nanotechnology&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The development of new materials&#44; systems and structures through research at atomic&#44; molecular&#44; or macromolecular levels has enabled new applications&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The nanoscale is typically a scale of matter under 100<span class="elsevierStyleHsp" style=""></span>nm&#46; According to several authors&#44; unique and unusual physical&#44; chemical&#44; and biological properties can be seen at this dimensional level&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nanotechnology involves imaging&#44; measuring&#44; modeling&#44; and manipulating matter at this scale&#46; Some of the most promising uses of these technologies have emerged in some fundamental sectors&#44; such as energy&#44; communications&#44; water purification&#44; pollution reduction and environmental progress&#44; improved materials and new products&#44; medical and biomedical applications&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Besides industrial and household uses&#44; nanoparticles &#40;NPs&#41; can be used in Medicine &#40;creating the new field of nanomedicine&#41; for cancer treatment&#44; infectious diseases&#44; immunization purposes and diagnostic procedures with new imaging sensors and agents&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">As nanotechnology penetrates the marketplace and attracts attention&#44; the public is starting to develop opinions about it&#46; Those opinions will shape the market for consumer goods using these new technologies&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Nanotechnology is a sector of high-tech industry that has already created a multibillion &#36;US market&#44; and is widely expected to grow to 1 trillion &#40;10<span class="elsevierStyleSup">18</span>&#41; US dollars by 2015&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Nanotechnology research and development can integrate the nanoscale structures into larger material components&#44; systems&#44; and architectures&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The majority of the NPs currently in use today have been made from transition metals&#44; silicon&#44; different forms of carbon &#40;carbon nanotubes&#59; fullerenes&#41;&#44; and metal oxides &#40;such as zinc dioxide and titanium dioxide&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">In <span class="elsevierStyleItalic">sensu lato</span>&#44; inorganic nanoparticles do not contain carbon molecules&#59; carbon nanotubes and carbon fullerenes are usually addressed as organic nanoparticles&#46; But it must be stated that&#44; strictly from a chemical point of view&#44; these forms containing pure carbon molecules without bonds to hydrogen&#44; constitute allotropes of carbon and are part of what is now known as the Inorganic Chemistry of Carbon&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">New applications are constantly emerging&#46; The Nanotechnology Consumer Products Inventory&#44; kept by the Woodrow Wilson Institute&#44; listed over 1317 products or product lines as of April 2012&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Nanomaterials vary widely in terms of their composition&#44; properties&#44; and uses&#46; Common products include cosmetics and personal care products&#44; wound dressing pads&#44; pregnancy tests&#44; toothpaste&#44; food supplements and food storage&#44; appliances&#44; clothing&#44; coatings&#44; electronics and computers and sporting goods&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">With the increasing technological complexity of nanotechnology&#44; several generations of NPs can be reported&#58;</p><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">First generation</span> &#8764;2001&#58; Passive nanostructures &#40;nanostructured coatings&#44; nanoparticles&#44; nanostructured metals&#44; polymers&#44; ceramics&#44; catalysts&#44; composites&#44; displays&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Second generation</span> &#8764;2007&#58; Active nanostructures &#40;transistors&#44; amplifiers&#44; targeted drugs and chemicals&#44; actuators&#44; adaptive structures&#44; sensors&#44; diagnostic assays&#44; fuel cells&#44; solar cells&#44; high performance nanocomposites&#44; ceramics&#44; metals&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Third generation</span> &#8764;2010&#58; 3-D nanosystems and systems of nanosystems &#40;various assembly techniques&#44; networking at the nanoscale and new architectures&#44; biomimetic materials&#44; novel therapeutics&#47;targeted drug delivery&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Fourth generation</span> &#8764;2015&#58; Molecular nanosystems &#40;molecular devices &#8220;<span class="elsevierStyleItalic">by design</span>&#8221;&#44; atomic design&#44; emerging functions&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The expression &#8220;nanoparticle&#8221; is commonly used to describe engineered structures with diameters of &#60;100<span class="elsevierStyleHsp" style=""></span>nm&#44; that are created by chemical and&#47;or physical processes&#44; with very characteristic properties usually not present at a macro-scale level&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Reducing the size of a particle increases the ratio of surface area to mass&#46; Because the reactive portion of the particle is on the surface&#44; increasing the relative surface area will increase reactivity of a given amount of material&#46; Also&#44; at the nanoscale&#44; both classical physics and quantum physics can direct the behaviour of a particle&#46; The influence of quantum effects can change important material properties&#44; such as optical&#44; magnetic&#44; and electrical properties&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">NPs may be suspended in a gas &#40;as a nanoaerosol&#41;&#44; suspended in a liquid &#40;as a colloid or nano-hydrosol&#41;&#44; or embedded in a matrix &#40;as a nanocomposite&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Some authors state that the main difference between NPs and ultrafine particles &#40;UFP&#41; refers to the fact that the term UFP is commonly used to describe nanometer-size particles that have not been intentionally produced&#44; but are the incidental products of industrial processes or different types of combustion&#44; and even volcanic activities&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">UFP &#40;or incidental nanoparticles&#41; show more complex chemical composition&#44; irregular shapes&#44; and polydispersed size distribution as compared to engineered particles&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">These particles could exert their effects <span class="elsevierStyleItalic">per se</span> or through a multitude of substances that could be adsorbed on their surfaces&#46; For instance&#44; some engineered NPs exist as nanocrystals composed of a number of compounds such as silicon and metals &#40;quantum dots&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Carbon fullerenes</span> represent NPs with identical dimensions in all directions &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; spherical&#41;&#46; They are carbon allotropes rolled up to form closed-cage&#44; hollow spheres&#46; Some of their characteristics such as their small size&#44; large surface area and high reactivity make them interesting in technological and medical fields&#46; They were initially discovered by Kroto&#44; Smalley and Curl &#40;who later won the 1996 Nobel Prize in Chemistry&#41; as a new form of carbon&#44; buckminsterfullerene or C<span class="elsevierStyleInf">60</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;14&#44;15</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Single-walled carbon nanotubes &#40;SWCNTs&#41;</span> typically form convoluted&#44; fibre-like NPs with a diameter below 100<span class="elsevierStyleHsp" style=""></span>nm&#46; Many particle morphologies can be created at the nanoscale&#44; including &#8220;flower&#8221; and &#8220;belt&#8221;-like structures&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Multi-walled carbon nanotubes &#40;MWCNT&#41;</span> are larger and consist of many single-walled tubes stacked one inside the other&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Carbon nanotubes &#40;CNTs&#41; are distinct from carbon fibres&#44; because the latter consist of strands of layered graphite sheets and are not single carbon molecules&#46; CNTs are reported to be physically very strong and stiff&#46; For example a SWCNT can be up to 10 times as strong as steel and 1&#46;2 times as stiff as diamond&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Close-packed nanotube structures could have a yield strength exceeding 45<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7<span class="elsevierStyleHsp" style=""></span>GPa&#44; which is over 20 times the yield strength of typical high-strength steels&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">As would be expected from the above statements&#44; it is now understood that potential occupational and environmental exposure to manufactured NPs is on the increase&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Nanomedicine and the lung</span><p id="par0150" class="elsevierStylePara elsevierViewall">The field of nanomedicine is the science and technology of diagnosing&#44; treating and preventing disease and traumatic injury&#44; of relieving pain&#44; and of preserving and improving human health&#44; using molecular tools and molecular knowledge of the human body&#46; Its objectives encompass monitoring&#44; control&#44; construction&#44; repair&#44; defense and improvement of human biological systems&#44; using engineered devices and nanostructures for medical benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Nanomedicine involves the best knowledge about the science and technology of intricate systems of nanometre-scale size&#44; with several components&#44; one of which is an active principle&#44; with the whole system leading to a special function connected to the diagnosis&#44; treatment and&#47;or prevention of disease&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Nanomedicine also includes the identification of new molecular targets&#44; the creation of new synthetic low molecular weight drugs&#44; nanofluidics for targeted synthesis&#44; nanodetection for target identification&#44; the discovery of natural macromolecules&#44; including antibodies&#44; proteins and genes with biological activity and the creation of drug delivery systems &#40;liposomes and nanoparticles&#8211;nanopharmaceuticals&#41;&#44; promoting disease-specific targeting&#44; in order to thoroughly control the release of the drugs over the desired period of time&#44; or even to supply suitable routes of administration that can reach locations in the body that are traditionally difficult to access&#44; such as the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Nanotechnology has an enormous potential in the field of human imaging and early recognition of disease&#44; with the tailoring of specific nanoagents for molecular imaging in the context of Magnetic Resonance Imaging&#44; ultrasound&#44; optical imaging&#44; and X-ray imaging&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;23</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Other medical areas include gene and oncologic therapy using multicomponent&#44; nanosized delivery vectors&#46; Nanotube drug delivery is promising for cancer therapy with high treatment efficacy and minimum side effects&#46; There is an increasing use of NPs as carrier systems for chemotherapeutic drugs because of the ability to specifically target cancer cells&#44; improve efficacy and reduce systemic toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Noble metal NPs can efficiently target several kinds of tumours&#44; as they present highly tunable optical properties that can be adjusted to desirable wavelengths according to their shape and composition with possible uses in tumour targeting&#44; gene silencing and drug delivery&#59; they can also efficiently convert light or radiofrequencies into heat&#44; promoting thermal ablation&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">CNTs can be effective in delivering drugs such as paclitaxel to retard tumour growth in experimental models of cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Solid lipid nanoparticles &#40;SLN&#41; are ideal carriers for weakly soluble drugs&#44; and are alternatives to current colloidal carriers&#46; Inhaled SLN&#8211;paclitaxel could represent a potential system for regional delivery to the lungs&#44; with special efficacy on the lymphatic system&#44; fundamental in the progression of lung adenocarcinomas&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Therefore&#44; targeted nanoparticle delivery to the respiratory system is one of the future trends in nanomedicine&#44; as it can improve drug therapies systemically and locally using advanced drug delivery systems based in more or less complex nanostructures&#46; In the specific area of lung cancer treatment&#44; NPs can revolutionize future chemotherapy options&#46; Other areas of development are the improvement of monoclonal antibodies for lung targeting &#40;attaching antibodies to drug molecules or drug delivery systems&#41;&#44; lung imaging&#44; gene delivery&#44; cystic fibrosis treatment &#40;gene therapy and nano-selective and sustained delivery of proteasome inhibitor drugs&#41; and tuberculosis diagnosis and treatment &#40;as macrophage involvement make NPs a perfect drug carrier&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;31</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Environmental challenges of exposure to nanoparticles</span><p id="par0195" class="elsevierStylePara elsevierViewall">Soon after the great development and commercial introduction of these materials&#44; some authors raised significant questions about the potential impact on human health and the environment&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">In the 1990s&#44; toxicology and epidemiology research on ultrafine aerosols began developing in combination&#46; However&#44; the emerging field of nanotechnology stimulated the actions toward developing a more complete understanding of what unexpected and unanticipated impact nanoscale materials might have on health&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">In recent decades there has been human exposure to nanoscale particles in the form of diesel soot and bulk UFPs from diverse industrial procedures&#44; essentially in the form of combustion-derived UFPs&#44; but also from natural sources such as forest fires and volcanoes&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Exposure to these particles has been associated with pulmonary inflammation&#44; immune changes&#44; and adverse systemic effects including blood hypercoagulability&#44; contributing to undesirable cardiovascular effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#8211;35</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Consistent with cross-sectional findings and animal studies&#44; there seems to be an association between exposure to air pollution and the progression of atherosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Some studies report the association of particulate matter &#60;2&#46;5 um &#40;PM<span class="elsevierStyleInf">2&#46;5</span>&#41; and carotid intima-media thickness&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Oxidative stress&#44; inflammation&#44; induction of a pro-coagulatory state and dysfunction of the autonomic nervous system can enhance respiratory and cardiovascular diseases&#46; Changes in lung function&#44; heart rate&#44; blood pressure and inflammatory state&#44; and also respiratory symptoms&#44; thrombosis&#44; myocardial infarction&#44; arrhythmia&#44; strokes&#44; and death are more often seen in polluted environments&#44; causing shorter life expectancy&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">A lot of the concern related to the exposure to nanomaterials comes from our knowledge from the reports of inhalation of ultrafine particles found in occupational settings and also ultrafine aerosols resulting from combustion&#46; There seems to be an important link between several chronic diseases and the inhalation of UFPs&#44; such as Clara cell carcinomas &#40;polycyclic aromatic hydrocarbons&#41;&#44; mesothelioma &#40;asbestos&#41;&#44; and berylliosis &#40;beryllium&#41;&#46; Some syndromes associated with exposure to aerosols include coal worker pneumoconiosis&#44; emphysema &#40;combustion products&#41;&#44; and metal fume fever &#40;zinc&#44; tin&#44; and other transition metals&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">However&#44; the technical requirements for the detection and characterization of nanoparticles in the environment push the limits of modern sampling techniques and instrumentation&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">At present&#44; there are no legal thresholds for nanoparticle number concentrations in ambient air&#44; so local observation networks do not generally monitor them&#46; The development of ambient particle regulations has been limited for technical and practical reasons&#44; such as the lack of standard methods and instrumentation&#44; and the uncertainty about repeatability and reproducibility of measurements&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Assessment of the risk associated with nanoparticles requires knowledge about the ability of a material to reach a sensitive site of action&#44; and the type and magnitude of the resultant response at the sensitive site&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Nanotoxicology</span><p id="par0245" class="elsevierStylePara elsevierViewall">The lung is the primary and probably the most important target of nanomaterials&#44; but NPs can enter the circulation and migrate to various organs and tissues&#44; where they can build up and injure organ systems that are sensitive to oxidative stress&#46; The types of toxicological response will probably vary between molecular and nano-sized forms&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">The size of the NPs suggests that the physiological responses could be of an immune or inflammatory nature&#46; These adverse effects may not follow a classic dose-response curve&#44; and can display high unpredictability within the population&#44; potentially dependent on individual sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Nanoparticle toxicity is extremely complex and multifactorial and depends on a multiplicity of physicochemical properties such as size and shape&#44; as well as surface properties &#40;charge&#44; area&#44; and reactivity&#41;&#46; Ultrafine or nanosize range &#40;&#60;100<span class="elsevierStyleHsp" style=""></span>nm&#41; particles seem to be more toxic on a mass-based exposure metric compared to larger particles of identical chemical composition&#46; Also&#44; particle surface area dose is a better predictor of the toxic and pathological responses to inhaled particles than particle mass dose&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;40</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">Differences in physico-chemical properties between NPs and larger particles determine their behaviour as aerosol&#44; their biodistribution following translocation from the portal of entry&#44; their cellular interactions and effects&#46; Secondary organs are usually affected differently from the primary target of these particles&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">In 1990&#44; the Journal of Aerosol Science published two of the first cornerstone papers on a higher than expected effect on lung inflammation patterns in rats exposed to NPs&#44; effects that could not be predicted by just taking the chemical composition and the inhaled amounts of the particles into account&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#8211;43</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">One of the first important assumptions&#44; that is still of great importance&#44; is that NPs have the potential to show previously unrecognized biological behaviour&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">A major report concerning the uncertainties of nanotechnologies was published in 2004 by the Royal Society and the Royal Academy of Engineering&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> This was one of the first reports to highlight the potential risks to health and the environment that may arise from exposure to nanomaterials&#44; especially NPs &#40;which included nanomaterials such as nanotubes&#41;&#46; Since then&#44; more than fifty national and international reviews carried out by government departments&#44; industry associations&#44; insurance organizations and researchers have considered nanoparticle risk issues&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">A workshop co-sponsored by the National Science Foundation and the US Environmental Protection Agency has identified a number of potential risks regarding manufactured NPs&#44; such as exposure assessment of manufactured NPs&#59; toxicology of manufactured NPs&#59; the ability &#40;or not&#41; to extrapolate manufactured nanoparticle toxicity using existing particle and fibre toxicological databases&#59; environmental and biological fate&#44; transport&#44; persistence&#44; and transformation of manufactured NPs&#44; recyclability and overall sustainability of manufactured nanomaterials&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">The ability of absorbed particles to generate local toxic effects at the site of initial deposition as well as very significant systemic toxic responses shows how dangerous they can be in real-life settings&#46; The potential for adverse health effects may arise from direct exposure to intentionally produced nanomaterials and&#47;or byproducts associated with their applications&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Toxicological assessment of manmade nanomaterials requires information about the route &#40;inhalation&#44; oral&#44; dermal&#41; of exposure&#44; as well as their complete physicochemical characterization of them in order to provide thorough information&#46; The most common scenarios for human exposure to NPs are occupational&#44; environmental and consumer ones&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Inhalation hazards of nanoparticles</span><p id="par0295" class="elsevierStylePara elsevierViewall">One of the most widespread routes of human exposure to airborne NPs is inhalation in the workplace and the environment&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">As seen before&#44; at present there are large numbers of nanomaterials&#59; as their technological and toxicological properties vary considerably&#44; so will their risk profiles&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> We are now able to consider that the extensive and heterogeneous group of NPs of diverse scale constitutes an inhalation hazard of unknown potential&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">The deposition of NPs in the respiratory tract is determined essentially by the particle aerodynamic or thermodynamic diameter &#40;depending on particle size&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0310" class="elsevierStylePara elsevierViewall">According to the classical model developed by the International Commission on Radiological Protection &#40;ICRP&#41;&#44; the probability of nanoparticles reaching the alveoli peaked at a size of approximately 20<span class="elsevierStyleHsp" style=""></span>nm&#44; with lower probabilities of deposition in the alveoli for both smaller and larger nanoparticles&#46; Nanoparticle deposition&#44; in particular for smaller particles&#44; is governed by Brownian movements&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">There are still issues that have not yet been fully resolved about how exposure to NPs can be thoroughly measured and quantified&#59; they are usually described as mass concentration &#40;units mg<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">&#8722;3</span>&#41;&#59; number concentration &#40;units per m<span class="elsevierStyleSup">&#8722;3</span>&#41; and surface area concentration units &#40;m<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">&#8722;3</span>&#41;&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">As stated before&#44; the possible health effects arising from exposure to NPs may be better correlated with surface area&#44; rather than with mass concentration&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;16</span></a></p><p id="par0325" class="elsevierStylePara elsevierViewall">NPs have some essential properties that could be directly related to their pathogenicity&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0330" class="elsevierStylePara elsevierViewall">As particles less than 100<span class="elsevierStyleHsp" style=""></span>nm&#44; they may have more toxicity than larger sized particles&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0335" class="elsevierStylePara elsevierViewall">Generally they are considered as fibre shaped&#44; and so might behave like some other pathogenic fibres &#40;asbestos&#44; man-made fibres&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0340" class="elsevierStylePara elsevierViewall">As most of the NPs have an essentially graphitic constitution&#44; they are expected to be biopersistent in biological settings&#44; such as the respiratory system&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p></li></ul></p><p id="par0345" class="elsevierStylePara elsevierViewall">Commercial NPs could also contain some impurities&#44; a common result of the synthesis process&#44; such as metals &#40;Co&#44; Fe&#44; Ni&#44; and Mo&#41;&#44; organic compounds&#44; and support material&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall">Smaller particles are likely to be more aggressive to the lung than larger particles&#59; particles with more inert surfaces may be aggressive&#44; exerting their effects on cells by reason of having a large surface area&#46; Particles with more reactive surfaces can affect cells without necessarily having large surface areas&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0355" class="elsevierStylePara elsevierViewall">Shape&#44; biopersistence&#44; presence of transition metals and the power to generate reactive oxygen species also explain the potential for lung damage&#46; In fact&#44; some of the main experimental studies in rodents and cell cultures have shown that the toxicity of UFPs or NPs is greater than that of the same mass of larger particles with a similar chemical composition&#44; posing specifically a higher respiratory and systemic health threat&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">At equivalent mass doses&#44; insoluble ultrafine particles cause more damage than larger particles of a similar composition in terms of pulmonary inflammation&#44; tissue damage&#44; and lung tumours&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0365" class="elsevierStylePara elsevierViewall">From the alveoli&#44; NPs have the potential to enter the bloodstream from the lungs and even translocate to other organs&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> For instance&#44; biokinetic studies show that inhaled NPs can translocate <span class="elsevierStyleItalic">via</span> olfactory neurons from the nose to the Central Nervous System&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">The biokinetics of NPs in the body varies&#44; depending on the portal of entry&#46; The same NPs entering the lung &#40;<span class="elsevierStyleItalic">via</span> inhalation or intratracheal instillation&#41; or intravenously&#44; interact with different biological media and will receive different secondary coatings&#44; affecting nanoparticle biodistribution to target organs&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0375" class="elsevierStylePara elsevierViewall">At present&#44; carrying out risk assessment of NPs can only be done sensibly on a case-by-case basis&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0380" class="elsevierStylePara elsevierViewall">Most of the studies about the effects of respiratory exposure to NPs involve pulmonary models and are performed through instillation&#44; aspiration and inhalation of carbon nanotubes &#40;the most studied NPs&#41; in rodent species&#46;</p><p id="par0385" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes some of the main <span class="elsevierStyleItalic">in vivo</span> investigations regarding the respiratory effects of carbon nanotubes&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0390" class="elsevierStylePara elsevierViewall">Many of the most pressing health and safety concerns regarding NPs and nanotechnologies come from the lack of knowledge about levels of occupational and other types of exposure during their production and use&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Among the particles with potential respiratory risks&#44; CNTs are one of the specialized structures of engineered NPs that are widespread&#46; Discovered more than 20 years ago&#44; they have increasing potential uses in biomedical&#44; aeronautic&#44; and industrial fields due to their unique conductive and electrochemical properties&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">As seen before&#44; CNTs are classified according to their structure&#58; single-walled carbon nanotubes &#40;SWCNT&#41; and multi-walled carbon nanotubes &#40;MWCNT&#41;&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">Nanotubes can have features of both NP and conventional fibres&#46; The literature currently available suggests that CNT may have toxic effects beyond those predictable for their mass exposure&#46; For instance&#44; they have more adverse effects than the same mass of NP carbon and quartz&#44; a commonly used comparator amongst harmful inhalable particles&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">CNTs can induce oxidative stress and inflammation&#44; and several studies imply that they could cause granuloma formation and fibrogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">In occupational contexts&#44; CNTs should be considered in the same way as other biopersistent fibres in the workplace&#44; with implications for at least similar approaches to control and assessment&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0420" class="elsevierStylePara elsevierViewall">It would appear that the main mechanism of engineered nanomaterial toxicity is related to oxidative stress&#44; caused by the activation of responsive transcription factors&#46; Chronic inflammation and oxidative stress observed during and after exposure can induce adverse health effects such as fibrosis&#44; genotoxicity and cancer caused by fibres or secondary mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">One of the first studies on the subject of CNTs exposure was performed by Lam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In this study mice were instilled intratracheally with 0&#44; 0&#46;1&#44; or 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg of carbon nanotubes&#44; a carbon black negative control&#44; or a quartz positive control&#44; and lung pathology studied 7 or 90 days after exposure&#46; All nanotube products induced dose-dependent epithelioid granulomas and&#44; in some cases&#44; interstitial inflammation&#44; which was more pronounced in the 90-day group&#46; Some animals had peribronchial inflammation and necrosis&#44; extending to the alveolar septa&#46; On a same weight basis&#44; when CNTs reach the lungs&#44; they are much more toxic than carbon black and can be more toxic than quartz&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Inhalation studies are able to provide more information and reproducibility of occupational and environmental risks&#46; However&#44; instillation studies are less complex and cheaper&#44; so they could represent a form of screening for the potential harm and toxicity of NPs&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">In the experiments where intratracheal instillation of NPs was performed&#44; more pronounced and severe effects were observed&#44; when compared with inhalation studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#44;63</span></a></p><p id="par0440" class="elsevierStylePara elsevierViewall">CNTs have toxicologically significant structural and chemical similarities to asbestos&#44; and experiments have shown that they cause pulmonary inflammation&#44; granuloma formation and fibrosis after entering the respiratory system of rodents&#44; as observed after exposure to asbestos&#46; Some studies confirm for MWCNTs a well established asbestos-like pathogenicity that is associated with long fibres&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">59&#44;64</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">In addition&#44; the impact of some impurities&#44; such as metals&#44; present in some MWCNTs cannot be underestimated in the forms in which the lung could be affected&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a></p><p id="par0450" class="elsevierStylePara elsevierViewall">According to Pacurari et al&#46;&#44; the fibrous characteristics of MWCNT&#44; their durability and their ability to generate reactive oxygen species at low levels in cellular systems may contribute to the initiation and progression of asbestos-like pathological responses&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p><p id="par0455" class="elsevierStylePara elsevierViewall">Shvedova et al&#46; demonstrated that SWCNT inhalation resulted in mutations of K-ras gene locus in the lung of C57BL&#47;6 mice&#46; This is one of the mutated genes that can be implicated in pulmonary tumourigenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">Aerosolized inhalation in animal studies supports a common sequence of biological events following single CNT exposure&#58; important acute phase inflammation similar to a foreign body response&#44; followed by formation of multifocal granulomas&#44; and early onset fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">MWCNTs and other carbon NPs in fine &#40;&#60;2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; particulate matter &#40;PM&#41; aggregates have been related to the combustion of methane&#44; propane&#44; and natural-gas flames of some stoves&#59; indeed&#44; indoor and outdoor fine PM samples were reported to contain significant fractions of MWCNTs&#46;</p><p id="par0470" class="elsevierStylePara elsevierViewall">A very recent study from Teeguarden et al&#46; used high sensitivity based proteomics &#8211; HPLC&#8211;FTICR&#8211;MS &#40;high performance liquid chromatography&#47;Fourier transform ion cyclotron resonance mass spectrometry&#41; to assess some of the major differences in exposure to three materials &#8211; SWCNT&#44; asbestos&#44; and ultrafine carbon black &#40;UFCB&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Rodent exposure to SWCNT led to a significantly greater inflammatory response&#44; when compared with crocidolite asbestos and UFCB&#44; with an increase in polymorphonuclear neutrophils &#40;PMNs&#41; and total cell count of bronchoalveolar lavage fluid &#40;BALF&#41;&#46; Also&#44; moderate multifocal inflammation was present in all lungs from SWCNT exposed mice&#44; with granuloma formation near bronchioles and adjacent alveoli consisting of round clusters of large macrophages and multinucleated giant cells&#46; Statistically significant differences in some cytokines &#40;TARC&#44; IL-12 and MDC&#41; were also seen&#44; proving the high inflammogenic potential of SWCNT&#46; In addition&#44; the proteomic analysis conducted by the authors supports the conclusion that lung tissue and lung infiltrate responses were generally greater on a mass dose basis for SWCNT&#46;</p><p id="par0475" class="elsevierStylePara elsevierViewall">The potential for particles to cause fibrotic reactions within the lung depends on the particle size&#44; composition&#44; surface activity&#44; and retained dose&#46; Particles containing certain transition metals have a greater capacity to generate reactive oxygen species&#44; in addition to those already generated by inflammatory neutrophils and activated alveolar macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="par0480" class="elsevierStylePara elsevierViewall">Recently&#44; Wang at al&#46; demonstrated that chronic exposure to SWCNT can produce malignant transformation of human lung epithelial cells&#46; Also&#44; SWCNT-transformed cells injected in immunodeficient mice led to tumour growth at the injection site in mice receiving SWCNT-transformed BEAS-2B cells&#44; whereas mice receiving control BEAS-2B cells did not develop tumours&#44; showing also the potential role of p53 in this process&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><p id="par0485" class="elsevierStylePara elsevierViewall">Like other areas of knowledge regarding nanotechnologies&#44; studies of the carcinogenic potential of carbon nanotubes are still in the early stages&#44; but there are some data suggesting that these structures are not risk free&#44; and can be widely dependent on several other physico-chemical and biological characteristics&#44; and also specific composition and type and size of impurities&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0490" class="elsevierStylePara elsevierViewall">Also&#44; <span class="elsevierStyleItalic">fullerenes</span> &#40;NPs with identical dimensions in all directions&#41; following exposure <span class="elsevierStyleItalic">via</span> the pulmonary route are capable of eliciting localized responses that are pro- or anti-inflammatory in nature&#44; with the type of response initiated likely to be reliant on the fullerene in question&#44; exposure method and the dose used&#46; However&#44; inhalation studies regarding the effects of fullerenes are still limited&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0495" class="elsevierStylePara elsevierViewall">Fullerene toxicity probably involves an oxidant response&#44; suggesting the potential of fullerenes to cause oxidative stress and related consequences &#40;such as inflammation or genotoxicity&#41;&#46; Generally&#44; the greater the water solubility exhibited by a fullerene sample&#44; the lower the toxicity associated with exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall">In addition&#44; recent studies in murine models prove that titanium dioxide &#40;TiO<span class="elsevierStyleInf">2</span>&#41; or gold &#40;Au&#41; NPs can interfere with the modulation of the asthmatic response regarding diisocyanate induced asthma&#44; as they can aggravate pulmonary inflammation and airway hyperreactivity&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p><p id="par0505" class="elsevierStylePara elsevierViewall">There is still a shortage of publications addressing the <span class="elsevierStyleItalic">in vivo</span>&#44; real world effects of nanoparticle exposure&#46; However&#44; some of these are very worrying&#59; for instance&#44; Chinese workers exposed to polyacrylate consisting of NPs in a print plant have shown shortness of breath&#44; and the same clinical findings of pleural effusion and pericardial effusion&#46; The study of these workers revealed nonspecific pulmonary inflammation&#44; pulmonary fibrosis and foreign-body granulomas of the pleura&#59; BALF elicited increased lymphocytes and neutrophil leukocytes&#46; Two young patients subsequently died from respiratory failure&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions and future trends</span><p id="par0510" class="elsevierStylePara elsevierViewall">Respiratory exposure to NPs can cause important adverse respiratory effects&#44; such as multifocal granulomas&#44; peribronchial inflammation&#44; progressive interstitial fibrosis&#44; chronic inflammatory responses&#44; collagen deposition&#44; oxidative stress&#44; pleural lesions and gene mutations&#44; at least in experimental animal studies&#46;</p><p id="par0515" class="elsevierStylePara elsevierViewall">At this point in time&#44; it is fundamental to know more about the toxicological effects of NPs&#44; to address the increased concern of potentially harmful public and occupational exposures&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0520" class="elsevierStylePara elsevierViewall">A very wide range of endpoints have to be considered when testing potential risks derived from NPs&#46; Hazards should be tested according to their potential routes within the human body&#46;</p><p id="par0525" class="elsevierStylePara elsevierViewall">According to Oberd&#246;rster in a recent paper regarding the safety assessment for nanotechnology&#44; although many of the current engineered nanomaterials with a potential for human exposure are not likely to induce significant adverse effects&#44; some could cause an asbestos-type disaster if it is not controlled&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0530" class="elsevierStylePara elsevierViewall">There is&#44; therefore&#44; an urgent need for the development of criteria for extrapolating toxicological data in biological systems in order to predict the risk of adverse outcomes in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a></p><p id="par0535" class="elsevierStylePara elsevierViewall">Not only traditional tests&#44; but also newer models reflecting the permanent evolution of nanotoxicology as an emerging field&#44; should be used to shed light on the mechanisms of NP toxicity&#46; The combination of <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> tests should contribute to hazard assessment in the future&#46; A multidisciplinary team approach is fundamental to addressing respiratory human risks related with Nanotechnology&#46;</p><p id="par0540" class="elsevierStylePara elsevierViewall">At present&#44; there are several extremely relevant attempts currently under way in order to formulate a science-based risk management research framework&#46; One of them is the US&#46; National Nanotechnology Initiative&#47;Environmental&#44; Health&#44; and Safety Research Strategy&#59; the main research needs to include&#44; among other points&#44; the development of measurement tools for the determination of physico-chemical properties of engineered nanomaterials &#40;ENMs&#41;&#44; their detection and monitoring in realistic exposure media and conditions during the life cycle&#44; the evaluation of transformations of ENMs in relevant media&#44; the further assessment of biological responses&#44; the better understanding of the processes and factors that determine exposures to nanomaterials&#44; the identification of population groups exposed to ENMs and their health surveillance&#44; and the development of appropriate&#44; reliable&#44; and reproducible assays and models to predict human responses to ENMs&#46;</p><p id="par0545" class="elsevierStylePara elsevierViewall">With appropriate strategies that integrate risk assessment into decision-making frameworks for risk management&#44; and incorporate and standardize risk communication within the risk management framework&#44; better esults should be expected in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall">Now is the time to promote&#44; on a global scale&#44; an in-depth discussion and evaluation of the human and environmental risks of these new materials&#59; as stated by Maynard et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> these resources are &#8220;merely the vanguard of a new era of complex materials&#44; where novel and dynamic functionality is engineered into multifaceted substances&#46; If we are to meet the challenge of ensuring the safe use of this new generation of substances&#44; it is time to move beyond &#8220;nano&#8221; toxicology and toward a new toxicology of sophisticated materials&#46;&#8221;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethic disclosures</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p id="par0555" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p id="par0560" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p id="par0565" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appears in this article&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0570" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Nanomedicine and the lung"
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          "titulo" => "Environmental challenges of exposure to nanoparticles"
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        "titulo" => "Abstract"
        "resumen" => "<span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The recently emergent field of Nanotechnology involves the production and use of structures at the nanoscale&#46; Research at atomic&#44; molecular or macromolecular levels&#44; has led to new materials&#44; systems and structures on a scale consisting of particles less than 100<span class="elsevierStyleHsp" style=""></span>nm and showing unique and unusual physical&#44; chemical and biological properties&#44; which has enabled new applications in diverse fields&#44; creating a multimillion-dollar high-tech industry&#46; Nanotechnologies have a wide variety of uses from nanomedicine&#44; consumer goods&#44; electronics&#44; communications and computing to environmental applications&#44; efficient energy sources&#44; agriculture&#44; water purification&#44; textiles&#44; and aerospace industry&#44; among many others&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The different characteristics of nanoparticles such as size&#44; shape&#44; surface charge&#44; chemical properties&#44; solubility and degree of agglomeration will determine their effects on biological systems and human health&#44; and the likelihood of respiratory hazards&#46; There are a number of new studies about the potential occupational and environmental effects of nanoparticles and general precautionary measures are now fully justified&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Adverse respiratory effects include multifocal granulomas&#44; peribronchial inflammation&#44; progressive interstitial fibrosis&#44; chronic inflammatory responses&#44; collagen deposition and oxidative stress&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The authors present an overview of the most important studies about respiratory nanotoxicology and the effects of nanoparticles and engineered nanomaterials on the respiratory system&#46;</p></span>"
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        "resumen" => "<span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O campo recentemente emergente da nanotecnologia envolve a produ&#231;&#227;o e o uso de estruturas em nanoescala&#46; A pesquisa a n&#237;veis at&#243;micos&#44; moleculares e macro moleculares conduziu a novos materiais&#44; sistemas e estruturas numa escala constitu&#237;da por part&#237;culas menores que 100<span class="elsevierStyleHsp" style=""></span>nm&#44; apresentando propriedades f&#237;sicas&#44; qu&#237;micas e biol&#243;gicas &#250;nicas e incomuns&#44; o que tem permitido novas aplica&#231;&#245;es em diversos campos&#44; criando uma ind&#250;stria de alta tecnologia multimilion&#225;ria&#46; As nanotecnologias t&#234;m uma vasta variedade de usos&#44; desde a nano medicina&#44; bens de consumo&#44; eletr&#243;nica&#44; comunica&#231;&#245;es e inform&#225;tica&#44; at&#233; &#224;s aplica&#231;&#245;es ambientais&#44; fontes de efici&#234;ncia energ&#233;tica&#44; agricultura&#44; purifica&#231;&#227;o de &#225;gua&#44; t&#234;xteis e ind&#250;stria aeroespacial&#44; entre muitos outros&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">As diferentes caracter&#237;sticas das nanopart&#237;culas&#44; tais como tamanho&#44; forma&#44; carga de superf&#237;cie&#44; propriedades qu&#237;micas&#44; solubilidade e grau de aglomera&#231;&#227;o&#44; determinar&#227;o os efeitos sobre os sistemas biol&#243;gicos e na sa&#250;de humana e a probabilidade de riscos respirat&#243;rios&#46; Existem alguns novos estudos sobre os potenciais efeitos ocupacionais e ambientais das nanopart&#237;culas&#44; sendo totalmente justificadas as medidas gerais de precau&#231;&#227;o&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Os efeitos respirat&#243;rios adversos incluem granulomas multifocais&#44; inflama&#231;&#227;o peribr&#244;nquica&#44; fibrose intersticial progressiva&#44; respostas inflamat&#243;rias cr&#243;nicas&#44; deposi&#231;&#227;o de colag&#233;nio e stress oxidativo&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Os autores apresentam um resumo dos mais importantes estudos sobre nanotoxicologia respirat&#243;ria e dos efeitos das nanopart&#237;culas e dos nanomateriais artificiais sobre o sistema respirat&#243;rio&#46;</p></span>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Animal species&#44; agent and method of administration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal instillation of CNT containing soot on guinea pigs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No induction of any abnormalities of pulmonary function or measurable inflammation&#46; No lung pathology was performed in this study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Huczko et al&#46; &#40;2001&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal instillation of different SWCNT samples &#40;three SWCNT products made by different methods and containing different types and amounts of residual metals&#41; on mice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">All nanotube products induced dose-dependent persistent epithelioid granulomas&#46; The lungs of some animals also revealed peribronchial inflammation and necrosis extending into the alveolar septa&#46; The lungs of mice treated with carbon black were normal&#44; whereas those treated with high-dose quartz revealed mild to moderate inflammation&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Lam e al&#46; &#40;2004&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal instillation of SWCNT on Sprague-Dawley rats&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pulmonary exposures to SWCNT in rats produced a non-dose-dependent series of multifocal granulomas&#44; which were evidence of a foreign tissue body reaction and were non uniform in distribution and not progressive beyond 1 month post exposure&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Warheit et al&#46; &#40;2004&#41;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intrapharyngeal aspiration of purified SWCNT on mice &#40;C57CL&#47;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Acute inflammation&#44; early onset of formation of granulomas&#44; and progressive fibrosis&#46; SWCNT-induced granulomas&#44; mainly associated with hypertrophied epithelial cells surrounding the dust aggregates&#44; and diffusive interstitial fibrosis and alveolar wall thickening&#46; Lung lesions were dose-dependent and progressive&#46; Bronchial alveolar lavage fluid &#40;BALF&#41; increases in total protein concentration&#44; cell counts&#44; concentration of transforming growth factor beta &#40;TGF-&#946;&#41;&#44; lactate dehydrogenase &#40;LDH&#41;&#44; and &#947; - glutamyltranspeptidase activities&#44; and glutathione depletion &#40;biomarkers of inflammation&#44; oxidative stress&#44; and cytotoxicity&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shvedova et al&#46; &#40;2005&#41;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal instillation of MWCNT on Sprague-Dawley Rats&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Inflammation&#44; collagen rich granulomas&#44; and fibrosis&#46; Hydroxyproline and soluble collagen&#44; increased in the lung tissues in a dose-dependent fashion&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Muller et al&#46; &#40;2005&#41;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intrapharyngeal instillation of SWCNT on mice &#40;C57CL&#47;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Activation of heme-oxygenase-1 &#40;HO-1&#41;&#44; a marker of oxidative insult&#44; in lung&#44; aorta&#44; and heart tissue&#46; Aortic mtDNA damage at 7&#44; 28&#44; and 60 days after exposure&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Li et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal Instillation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>inhalation of MWCNT on Kunming mice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Difference in lung pathological lesions induced by instilled and inhaled MWCNTs probably due to different size and distribution of aggregations of MWCNTs in lung&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Li et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Whole-body inhalation of MWCNT on mice &#40;C57CL&#47;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The experiment did not result in significant lung inflammation or tissue damage&#44; but caused systemic immune function alterations&#46; BALF demonstrated particle-laden macrophages&#46; Nonmonotonic systemic immunosuppression&#46; Decreased NK cell function&#46; No changes in gene expression were observed in lung&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mitchell et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Intratracheal instillation of SWCNT on mice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alveolar macrophage activation&#44; several chronic inflammatory responses&#44; and severe pulmonary granuloma formation&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Chou et al&#46; &#40;2008&#41;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Whole-body inhalation of SWCNT on mice &#40;C57CL&#47;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Development of multifocal granulomatous pneumonia and interstitial fibrosis&#46; SWCNT inhalation caused more inflammatory response&#44; oxidative stress&#44; collagen deposition&#44; fibrosis and mutations of K-ras gene when compared with aspiration&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shvedova et al&#46; &#40;2008&#41;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Wistar rats&#46; MWCNT&#8211;Acute inhalation study&#46; Positive control&#58; alpha quartz&#46; Negative control&#58; air&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pulmonary inflammogenicity following exposure to MWCNT was concentration-dependent with evidence of regression over time&#46; Alpha-quartz &#40;positive controls&#41; resulted in progressive changes over time&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ellinger-Ziegelbauer et al&#46; &#40;2009&#41;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Wistar rats&#46; 90-day inhalation toxicity study with MWCNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pronounced multifocal granulomatous inflammation&#44; diffuse histiocytic and neutrophilic inflammation&#44; and intra-alveolar lipoproteinosis were observed in lung and lung-associated lymph nodes&#44; incidence and severity related&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ma-Hock et al&#46; &#40;2009&#41;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Wistar rats&#46; MWCNT &#8211; Acute inhalation with 3 months postexposure period&#59; Repeated inhalation exposure with 6 months postexposure period&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sustained pulmonary inflammation related to pulmonary overload of NPs resulting probably from stasis of clearance&#46; Macrophages with enlarged and&#47;or foamy appearance&#59; increased influx of inflammatory cells and septal thickening&#44; slight to moderate inflammation&#44; focally with granulomatous appearance&#59; interstitial fibrosis&#46; Thickening of the visceral pleura&#46; Inflammation did not decrease in severity with increasing post-exposure duration&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pauluhn &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">C57BL&#47;6 mice&#46; Repeated pharyngeal aspiration of SWCNTs&#44; crocidolite&#44; and ultrafine carbon black&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The incidence and severity of inflammatory and fibrotic responses were greatest in mice treated with SWCNTs&#46; The proteomic analysis suggested that lung tissue and lung infiltrate responses to SWCNT and crocidolite asbestos were similar&#44; but as for several histopathological endpoints&#44; the response was generally greater on a mass dose basis for SWCNT&#44; when compared with asbestos or ultrafine carbon black&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Teeguarden et al&#46; &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">SWCNT-transformed cells injected in immunodeficient mice&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">One week post-injection&#44; tumours were formed at the injection site in mice receiving B-SWCNT cells&#44; whereas mice receiving control BEAS-2B cells did not develop tumours&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wang et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                      "Libro" => array:3 [
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                            0 => "A&#46;A&#46; Shvedova"
                            1 => "E&#46;R&#46; Kisin"
                            2 => "D&#46; Porter"
                            3 => "P&#46; Schulte"
                            4 => "V&#46;E&#46; Kagan"
                            5 => "B&#46; Fadeel"
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                  "host" => array:1 [
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                      "doi" => "10.1016/j.pharmthera.2008.10.009"
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                      "titulo" => "Nanomedicine and nanotoxicology&#58; two sides of the same coin"
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                            0 => "V&#46;E&#46; Kagan"
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Article information

ISSN: 08732159
Original language: English

DOI:10.1016/j.rppneu.2012.09.003

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	18	11	29
2024 October	55	46	101
2024 September	52	41	93
2024 August	61	29	90
2024 July	47	30	77
2024 June	31	29	60
2024 May	46	24	70
2024 April	47	35	82
2024 March	46	17	63
2024 February	35	23	58
2024 January	23	25	48
2023 December	40	21	61
2023 November	36	33	69
2023 October	38	26	64
2023 September	29	32	61
2023 August	41	25	66
2023 July	52	21	73
2023 June	49	16	65
2023 May	74	22	96
2023 April	60	13	73
2023 March	105	21	126
2023 February	73	21	94
2023 January	33	13	46
2022 December	81	26	107
2022 November	77	37	114
2022 October	59	39	98
2022 September	28	31	59
2022 August	48	40	88
2022 July	38	40	78
2022 June	41	27	68
2022 May	35	40	75
2022 April	31	28	59
2022 March	31	40	71
2022 February	27	28	55
2022 January	23	35	58
2021 December	28	31	59
2021 November	33	39	72
2021 October	27	37	64
2021 September	24	24	48
2021 August	22	26	48
2021 July	22	17	39
2021 June	24	14	38
2021 May	37	33	70
2021 April	142	54	196
2021 March	161	26	187
2021 February	50	18	68
2021 January	41	20	61
2020 December	36	13	49
2020 November	47	20	67
2020 October	36	18	54
2020 September	57	24	81
2020 August	80	30	110
2020 July	122	28	150
2020 June	104	16	120
2020 May	90	25	115
2020 April	91	10	101
2020 March	67	16	83
2020 February	71	20	91
2020 January	83	23	106
2019 December	90	22	112
2019 November	94	25	119
2019 October	94	26	120
2019 September	73	17	90
2019 August	138	24	162
2019 July	154	19	173
2019 June	188	15	203
2019 May	185	19	204
2019 April	169	28	197
2019 March	165	21	186
2019 February	165	21	186
2019 January	153	13	166
2018 December	96	9	105
2018 November	25	0	25
2018 October	54	10	64
2018 September	32	4	36
2018 August	47	40	87
2018 July	41	26	67
2018 June	67	19	86
2018 May	106	29	135
2018 April	152	28	180
2018 March	141	23	164
2018 February	98	9	107
2018 January	156	28	184
2017 December	247	13	260
2017 November	100	23	123
2017 October	46	19	65
2017 September	58	25	83
2017 August	33	12	45
2017 July	32	23	55
2017 June	51	38	89
2017 May	60	30	90
2017 April	15	10	25
2017 March	33	35	68
2017 February	14	9	23
2017 January	20	11	31
2016 December	27	18	45
2016 November	25	12	37
2016 October	25	26	51
2016 September	18	9	27
2016 August	9	3	12
2016 July	12	7	19
2016 June	9	5	14
2016 May	37	0	37
2016 April	30	1	31
2016 March	67	24	91
2016 February	62	21	83
2016 January	66	23	89
2015 December	67	24	91
2015 November	55	14	69
2015 October	66	10	76
2015 September	70	14	84
2015 August	61	6	67
2015 July	69	11	80
2015 June	72	8	80
2015 May	82	14	96
2015 April	143	21	164
2015 March	152	4	156
2015 February	130	4	134
2015 January	148	11	159
2014 December	136	22	158
2014 November	144	14	158
2014 October	142	13	155
2014 September	180	21	201
2014 August	159	10	169
2014 July	148	18	166
2014 June	135	13	148
2014 May	156	21	177
2014 April	180	16	196
2014 March	218	27	245
2014 February	175	26	201
2014 January	195	25	220
2013 December	149	21	170
2013 November	143	21	164
2013 October	144	29	173
2013 September	131	27	158
2013 August	124	32	156
2013 July	172	57	229
2013 June	127	26	153
2013 May	125	32	157
2013 April	122	70	192
2013 March	136	71	207
2013 February	136	70	206
2013 January	120	62	182

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