The physical and chemical properties of materials exhibit extraordinary behaviors when the size of particles is reduced to the nano-scale (e.g. the colloidal gold nanoparticles range in color from red to purple depending on their particle size). These exceptional features of engineered nanomaterials (ENMs) make them ideal for several applications in almost every industrial field. As a consequence, there are now hundreds of nanotechnology-based products on the market, most of which do not carry nano-labels since the labelling of nano-scale ingredients in the products has been very recently turned into a legal obligation. The size-dependency of nano characteristics also suggests that the biological activity (i.e. toxicity) of materials may vary depending on the size of particles in the nano-range. Therefore, the safety of materials containing nano-sized particles should be carefully checked before their commercial use in order to prevent the negative consequences that may arise due to inadequate evaluation of health risk posed by potentially toxic nanoparticles (NPs). As the number of ENMs and their commercial use increase, it becomes more and more difficult to individually evaluate the toxicity of all newly developed nano- products. This motivates the development and use of alternative, cost and time efficient methods to assess the potential risks associated with exposure to ENMs. It is believed that the integration of computational methods, such as quantitative structure activity relationship analysis (QSAR), with nanotoxicology will facilitate the risk assessment of the large number of ENMs and their variants.
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The risk is assessed based upon the level of exposure to the manufactured NM, toxicity of the particle in ques- tion, route of exposure and the persistence in the organ- ism of the particular material. Hence it is crucial to identify the hazards associated with NM exposure both in vitro and in vivo, consequently assembling a know- ledge base of the human health effects associated with NM exposure . Engineered nanomaterials are manu- factured from a diverse group of substances each with an array of unique physicochemical characteristics, hence a varied range of materials need to be evaluated for a comprehensive toxicity profile allowing for a struc- ture activity relationship to be generated. It is likely that NMs will differ in the levels of toxicity induced and the mechanism by which they exert these adverse effects.
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Most human involvement with food also modifies foodstuff at the nanoscale. Traditional cooking practices and industrial food processing are intended to improve the nutritional and storage properties of many food products. The application of mechanical forces and heat changes the structure of foods at the nanoscale and, in doing so, modifies flavour, structure, texture and storage behaviour. Such processing is generally conducted and controlled at the macro-level without the intention of obtaining well defined nanostructures. Since “technology” implies human involvement, natural nanostructures are not regarded as products of nanotechnology, and they need to be differentiated from deliberately engineered nanomaterials when considering regulatory requirements and definitions. With advances in nano science and nanotechnology, industry can now acquire better control over processes which modify materials at the nanoscale and also can understand what specific nanostructures would provide better functionalities.
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Major accident regulations aim at protecting the population and the environment from possible accidental releases of chemicals. To achieve this goal, the regulations need to be reassessed in light of the development of new technologies. A currently rapidly growing new technology is nanotechnology, and engineered nanomaterials (ENM) are already produced and used in commercial products. The aim of this work was therefore to evaluate the current knowledge on human and ecotoxicology of ENM and their release and behavior in the environment in the context of major accident prevention. Nano-specific release paths are not to be expected. The established safety standards in the chemical industry are also applicable to ENM, especially the separate storage of flammable solvents and detention reservoirs. The potential of a release to the environment of ENM in powder form is larger than for suspensions; however, it can be minimized by safety measures established for conventional dusts. The considered human toxicology studies show that to date not conclusive enough answers regarding the toxicity of ENM can be made. The effects are dependent not only on the material itself but more on the functionalization, surface reactivity, size, and form. The acute ecotoxicity of ENM seems to be similar to the one of the corresponding microparticles (TiO 2 ) or the respective dissolved ions (Ag, Zn)
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experienced by the specific cell culture system under a real- istic exposure scenario. In other words, delivered dose (or the dose range) is mainly dependent on the cell type used in the study, and the administered dose should take into consideration the in vitro dosimetry. As illustrated in Table 2, our evaluation affirms that, to our knowledge, since 2007, no in vitro study in the realm of iENM toxicity con- sidered dosimetry and its implications, which can poten- tially have a profound impact on the outcome and/or the interpretation of results. In an assessment of the impact of dosimetry, Pal et al.  found that after taking dosimetry into consideration, the slopes of administered/delivered dose-response relationships changed 1:4.94 times and were ENM-dependent, which significantly changed the toxico- logical ranking of engineered nanomaterials. Moreover, the resultant overall relative ranking of ENM intrinsic toxicity matched the in vivo inflammation data much better (Fig. 7). With this in mind, an in vitro cell culture model is of great utility if it closely resembles or validates the in vivo condi- tions . Future in vitro iENM toxicity studies should consider better modeling of exposures and equivalency that are relevant between exposure scenarios and in vitro dosimetry.
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Background: It is well established that toxicological evaluation of engineered nanomaterials (NMs) is vital to ensure the health and safety of those exposed to them. Further, there is a distinct need for the development of advanced physiologically relevant in vitro techniques for NM hazard prediction due to the limited predictive power of current in vitro models and the unsustainability of conducting nano-safety evaluations in vivo. Thus, the purpose of this study was to develop alternative in vitro approaches to assess the potential of NMs to induce genotoxicity by secondary mechanisms. Results: This was first undertaken by a conditioned media-based technique, whereby cell culture media was transferred from differentiated THP-1 (dTHP-1) macrophages treated with γ -Fe 2 O 3 or Fe 3 O 4 superparamagnetic iron oxide nanoparticles
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Advancements in the field of nanotechnology, have led to a concomitant rise in the incorporation of nanomaterials in consumer products. Engineered nanomaterials today are already being used in diverse commercial products in the fields of energy, sensing, food technology, electronics, pharmaceuticals, cosmetics, and material applications and have an estimated global market value of €20 billion. This has given rise to concerns about the undesirable effects of this technology on the environment. This review presents an overview of published studies about likely impact of nanoparticles in the ecosystem, their ecotoxicology, threat to human health and the environment and lack of sufficient data in the Indian context.
Fine tuning and troubleshooting experiments to eliminate toxicity of small intestine digest It is worth noting that in initial experiments, we observed that the small intestinal digesta without ENMs (control) was highly toxic to the triculture cells, and therefore unsuit- able for iENM biokinetics or toxicity studies. Based on the osmolarity calculated for each solution used in the simulated digestion (Additional file 1: Table S2), the osmolarity of that digesta was calculated to be 654 mOsm/L; which is more than double isotonic (~280–290 mOsm/L). Since exposure of cells to such a hypertonic solution would cause a loss of water leading to cell shrinkage, crenation, and likely cell injury and death, we hypothesized that this was a potential cause of the observed toxicity. Another potential source of cell injury in the digesta was bile salts, which were present in our initial small intestinal digesta at a concentration of ~10 mM. Bile salts play a number of important roles in food digestion by facilitating the emulsification of ingested lipids, aiding the adsorption of lipase to lipid droplet surfaces, and solubilizing and transporting lipid digestion products and hydrophobic bioactive agents. However, because of their detergent properties they can also be toxic to cells when present at sufficiently high levels. Indeed, bile salts have been shown to be capable of causing injury to tissues throughout the GIT [72–74]. In a number of fine-tuning experiments, the toxicity of the final small intestine phase digesta was reduced by adding sufficient phosphate buffer (5 mM, pH 7.0) to lower the osmolarity (280 mOsm/L) and bile salt con- centration (~4 mM) to lower but still physiologically relevant levels.
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The field of nanotechnology is continually expanding, and the market for consumer products produced using this technology is expected to reach $2.4 trillion by the end of 2015 [1-3]. Nanotechnology utilizes engineered nanomaterials (ENMs), which are ultrafine particulates with at least one dimension less than 100 nm [5-7]. ENMs have a variety of chemical and physical properties that make them ideal for use in many industrial settings, including an increased surface area per unit mass, heightened strength and durability, and exceptional conductivity [2,3]. Many of the features that make ENMs useful in industry also make them potentially toxic, making it imperative to study the possible risks of ENM exposure, particularly in terms of human health [2,3]. Multi-walled carbon nanotubes (MWCNTs), are a specific class of ENMs consisting of concentric sheets of graphene rolled into cylinders . MWCNTs have a longer, fiber-like shape, very similar to that of asbestos, which increases the risk of pulmonary toxicity following exposure [2,3,14,15]. MWCNTs are believed to exert their inflammatory effects through activation of the NLRP3 inflammasome and induction of IL-1β secretion [40,41].
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A total of 2334 gene symbols were in common across all platforms with 190 experimental conditions relative to controls. The resulting data matrix consisting of gene symbols were filtered based on the number of experi- mental conditions exceeding a log2 (1.5 fold) cut-off. Although the use of fold change ranking in conjunction with a flexible (non-stringent) p-value threshold is sug- gested in order to generate reproducible differentially expressed gene lists , no numeric values as fold change or p-value cut-offs have been specifically pre- scribed. Using a pre-determined stringent cut-off for fold change to identify differentially expressed genes, espe- cially in an experiment where the objective is to deter- mine the effects following exposures to ENMs of varying potency and across several doses (including low doses where not many changes are expected), may comprom- ise sensitivity and miss some biologically relevant genes that have low fold changes. For this reason, we have used the fold change of 1.5. Furthermore, the filtering helped remove non-informative genes that could distort correlations between experimental conditions. Gene symbols that had more than 5 experimental conditions that exceeded this cut-off (in absolute value) were retained for hierarchical cluster analysis, which resulted in 945 gene symbols.
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There are numerous reports of adverse lung effects, and some reports of human deaths, from nanosized polymer fumes. Two deaths were reported among seven 18- to 47-year-old female workers exposed to polyacrylate nanoparticles for 5 to 13 months. Cotton gauze masks were the only PPE used, and were used only occasionally. The workplace had one door, no win- dows, and no exhaust ventilation for the prior 5 months . Workers presented with dyspnea on exertion, pericardial and pleural effusions, and rash with intense itching. Spirometry showed that all suffered from small airway injury and restrictive ventilatory function; three had severe lung damage. Non-specific pulmonary inflammation, fibrosis, and foreign-body granulomas of the pleura were seen. Fibrous-coated nanoparticles (~30 nm) were observed in the chest fluid and lodged in the cytoplasm, nuclei, and other cytoplasmic organelles of pulmonary epithelial and mesothelial cells. Two workers died of respiratory failure. Although presented as the first report of clinical toxicity in humans associated with long-term ENM exposure, many experts have expressed uncertainty that ENMs contributed to these outcomes [22,185,186]. Given the poor environmental conditions of the workplace and lack of effective PPE use, these outcomes could probably have been prevented.
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Additionally, M cell- targeting of ENMs should be carefully considered as another possible pathway of interaction between ENMs and the intestinal milieu which may have possible systemic implications. M cells are specialized epithelial cells of the gut-associated lymphoid tissues (GALT) that can play an immunosen- sing and surveillance role by delivering luminal antigens through the follicle-associated epithelium to the under- lying immune cells. Recent evidence has supported the critical function of endogenous and synthetic nanomin- eral chaperones in the efficient transport of molecules across the epithelial barrier of the lymphoid follicles in the small intestine [27, 31]. In this perspective, further investigation should be focused to assess whether ENMs may be involved in protecting molecules from the GI degradation, favoring an effective M-cell delivery, and a greater transfection efficacy, therefore promoting tolero- genic or stimulatory immunological responses. Overall, this may be important to define the role of ENMs in vac- cine delivery systems for priming more effective humoral and mucosal immune responses in the hosts .
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abilities of various flame-generated nanomaterials to translocate across alveolar epithelial monolayers in vitro . Furthermore, with regards to hazard ranking large panels of ENMs, a recent investigation into the toxicity of low aspect ratio ENMs reported ratios of slopes for delivered dose vs administered dose varying between 1.02 and 5.58, with the rank order of ENMs shifting not- ably for some ENMs when delivered dose was taken into account (Pal et al., submitted 2014). Furthermore, the development of reliable in vitro screening assays re- quires identification of equivalent doses between in vitro and in vivo systems. One proposed approach was recently reported that utilized the multiple-path particle dosimetry model (MPPD) to estimate the deposited and retained dose of ENMs in the alveolar regions of exposed animals. These doses were then compared with cellular responses measured at equivalent doses of ENMs delivered to cells in vitro [6,48, Teeguarden et al., submitted 2014]. Future studies are necessary to further determine the impact of dosimetry on the hazard ranking of large panels of ENMs in both cellular and whole animal systems, though prelim- inary results suggest particle delivery to cells plays a sig- nificant role in nano-bio interactions in vitro and affect hazard ranking for some ENMs and endpoints. More im- portantly, there is consensus in the nanotoxicology field that there is a need to bridge the gap between in vitro and in vivo models, which requires reporting of biological response data in vitro and in vivo on the same dose scale- the amount of material deposited to cells/tissue, rather than the administered mass dose metric currently used in nanotoxicology studies. The proposed dosimetric approach can be a valuable and easy to use tool for nano- toxicologists in their quest of understanding the toxico- logical implications of ENMs.
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All the nanomaterials used in this study were characterised by a combination of analytical techniques in order to infer primary physical and chemical properties useful to under- stand their toxicological behaviour. A comprehensive list of the main physical and chemical properties of the panel NMs has been shown (Table 1) [Reproduced and modified from 14]. Furthermore the hydrodynamic size distributions and zeta potential of the NMs dispersed in the complete renal cell medium (K-SFM) and RPMI with 10% FCS (RPMI-FCS) were determined in the 1–128 μg/ml concen- tration range by Dynamic Light Scattering (DLS) using a Malvern Metasizer nano series – Nano ZS (USA) (Table 1).
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While employing a large variety of engineered hybrid nanomaterials for meeting application-specific responses in abundance, it is quite possible to minimize or eliminate the toxic effects arising from using these synthetic materials in all-pervasive IoT applications involving human beings by employing biomolecular species derived from natural sources like plants. It is further becoming more pertinent to evolve greener methods of synthesizing these nano building blocks from natural materials of plant origin comprising of almost unlimited varieties of phytochemicals that are evolved through millions of years in Nature for minimizing their cytotoxicity . Employing biomimetically motivated green material syntheses and developing hybrid nanomaterials by conjugating nano particulate inorganic, organic and biomolecular species would enable minimizing the inorganic part required for some specific purpose in addition to increasing the biomolecular part with the appropriate combinations of polymeric components of organic origin. This would allow incorporating the features of soft materials with added advantages of green smart/intelligent compositions possessing minimum toxic properties. Ideally, once this strategy of optimizing the material composition is mastered using computer aided designs involving quantitative structure activity relation data (QSAR), already compiled for a very large number of materials at atomic and molecular levels, mimicking some features of the living organism, would not remain a far-fetched dream [11-14]. What Nature took so long might be possible to mimic with the help of supercomputers based designs in a relatively much shorter duration while synthesizing newer compositions that would be smart/intelligent as well as green in nature. This would especially turn the entire ecology smart and intelligent resulting in better living conditions. Addition of these materials in realizing components, devices, and systems for their uses in the all-pervasive applications of IoT is indeed expected to make a number of significant changes in near future as a whole .
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Using the three previously modified and standardized in vitro assays, we screened the biological effects of 23 engineered NMs in ten different cell lines. Overall, seven NMs induced cytotoxic responses in one or more cell lines tested (Figures 1,2,3,4,5,6,7) whereas all other NMs used for the in vitro screening did not show any significant effect at concentrations from 0.1 to 10 μg cm -2 (Additional file 1: Figure S3). Intracellular ROS for- mation was most frequently observed after exposure to NMs. Significant increases in cell death were not detected with any of the particle types utilized (Addi- tional file 1: Figure S3) and reduced metabolic activity was only displayed by a single cell line NIH3T3) and only when exposed to dispersions of BaSO 4 NMs
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With the advances in the fields of nanotechnology and nanomedicine, the potential for public and occupational exposure is likely to increase, so that there is an urgent need to consider any potential health consequences as- sociated with this increased exposure to nanomaterials. The potential for NM translocation to distal organs fol- lowing a variety of exposure routes is a realistic pro- spect, with the liver accumulating a large proportion of the total or translocated dose. Although advances have been made in identifying the potential nanotoxicological effects on the liver, there are still large gaps in the know- ledge currently available. Therefore, more information is required for the likely exposure routes and levels, combined with a mechanistic understanding of the fate and behaviour of the NMs to determine the biological activity of the nanomaterial in question . As a means of better understanding the mechanistics of NM me- diated hepatotoxicity, we believe that the 3D human liver microtissues utilised within this study are an extremely strong candidate for further progression of in vitro hepatic nanotoxicology.
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emission was found to be negligible in enclosed oper- ation of coating of nanomaterials, enclosed operation of mixing or grinding of nanopigments, and wet process in synthesis or centrifuge of nanomaterials. However, lim- ited amount of nanoparticle emissions could be detected in spray drying of nanomaterials as well as dry process in polishing, milling and grinding. Table 1 indicates that most of the studied factories used liquid suspension and wet process. But there were still some factories using powder in operations, which may lead to the emission of small amounts of nanomaterials. Environmental moni- toring in some of the studied plants showed that mass concentrations, surface area, and particles count of nanoparticles measured in post-operation were only slightly higher than those in pre-operation. The low con- centrations of nanoparticles may induce an increase of early reaction of antioxidant enzymes, but the concen- trations of nanoparticles were not high enough to induce oxidative damages and toxic effects of other organs. Therefore, nanomaterials handling in current negligible emission scenarios may not have health impact on workers in regards to cardiopulmonary injuries and Table 6 Generalized estimating equation analysis of ≥ 2 repeated measurements of cardiovascular disease markers over 4 years
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example, nanomaterials that are generally considered nontoxic are present in consumer products, such as cosmetics and apparel . Further, nanomedicine is a subfield dealing with applications of nanotechnology in medicine, with growing interest in drug delivery systems owing to certain nanomaterials’ having the ability to cross membrane barriers for more targeted drug therapy [5, 6]. Various studies have shown that the small size creates an advantage of greater surface area exposure at equivalent concentrations to larger materials [7, 8]. Besides the small size, studies of the effects caused by nanomaterial structural characteristics or in vivo molecular interactions show different behaviors from their well characterized bulk counterparts [9, 10]. Thus, further toxicity screening and hazard risk assessment are needed for both novel and existing materials.
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The rapid growth of nanotechnology research and the resultant potential for nanotechnology’s rapid entrance into consumer goods presents a challenge to the regulatory agencies in health, food, and environmental protection. Two of these agencies are the United States (US) Food and Drug Administration (FDA) and the Environmental Protection Agency. Nanomaterials have already reached the consumer market and rapid growth in consumer available nanomaterials is expected. Some of the materials with useful properties in the nanodomain have already been deemed as safe by regulatory agencies in the bulk form. To allow the nanomaterial into consumer goods if the bulk form has been deemed safe is to ignore the unique physical and chemical characteristics that are realized with nanomaterials. The unique physical and chemical properties that make nanomaterials attractive for materials applications may also have unintended environmental and biological side effects. In order to regulate nanomaterials that may have detrimental impacts on human and environmental health, analytical methods are needed to identify nanomaterials present in environmental and biological systems. 33,34
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