Public Health Nanotechnology
by
Anupam Dhasmana, Sumbul Firdaus, Mohtashim Lohani, Mohammed Yahya Areeshi, Peter Langer, Qamar Rahman
  • LAST MODIFIED: 28 November 2016
  • DOI: 10.1093/obo/9780199756797-0154

Introduction

Nanotechnology is defined as the study of structures of size ranging between 1 and 100 nanometers in at least one of their dimensions. It is an emerging interdisciplinary field of research and development, integrating multiple areas of science such as chemistry, engineering, physical sciences, molecular engineering, biology, and biotechnology. Nanotechnology is the design, production, characterization, and application of structures, devices, and systems by controlling shape and size at nanometer scale. These structures of the nanometer range, with novel properties and functions, are termed as nanoparticles (NPs). Nanoparticles may be dry, suspended in a gas (nanoaerosol), suspended in a liquid (as a nanocolloid or nanohydrosol), or embedded in a matrix (as a nanocomposite). Nanoparticles exist in several forms, such as nanotubes, nanoplates, and nanofibers. Nanoparticles are predicted to play a significant role in medical science and technology in the coming decades due to their special electronic, mechanical, and chemical properties. The applications of NPs for drug delivery, pharmaceutical, and many industrial and commercial practices are expected to increase considerably. Out of surplus of size-dependent physical properties of nanomaterials, these unlimited advantages of nanoparticles lead to their mass production, making exposure to them unavoidable. Human exposure to these nanoparticles raises alarm about their potential risk to human health. The influence of nanosciences and technology has been expanded from their medical, technological, industrial, and environmental applications to fields such as engineering, biology, chemistry, materials science, and communications. The presence of nanoparticles is not in itself a threat, but nanoparticles have the ability to harm human and other life by interacting through various mechanisms. It is only certain aspects that can make them risky—in particular, their mobility and their increased reactivity. In addition, various strict guidelines are required regarding which defensive measures are warranted in order to support the improvement of “green nanosciences and technologies” and other potential modern technologies, while at the same time reducing the potential for negative unexpected consequences in the form of unfavorable effects on human and environmental health.

Sources of Nanoparticles

Nanoparticles are defined as materials with at least one dimension in the 1–100-nanometer (nm) range and may be naturally present in the atmosphere in the form of some viral particles and proteins or as byproducts of photochemical and volcanic activities. Nanoparticles may be manufactured/engineered intentionally, or they may be unintentionally produced anthropogenically via engine exhaust (Smita, et al. 2012). They may be used for various purposes, such as a catalyst in chemistry, as drug delivery devices in nanobiotechnology, or as imaging agents and consumer products. They are also used in engineering and information technology (Aguilera-Granja, et al. 1993). The utility of nanoparticles has increased in almost every field due to their enhanced size-dependent properties as compared to larger particles of the same material. Electrical, optical, and chemical properties are very different at “nano” scale as compared to those exhibited by larger particles; a maximum number of nanomaterial atoms are at the surface, and, due to this very high reactivity, nanoparticles are used in decontamination and detoxification (Deng, et al. 2011). Large-scale materials have a lower percentage of atoms at the surface.

  • Aguilera-Granja, Faustino, Jesús Dorantes-Dávila, José L. Morán-López, and Juan Ortíz-Saavedra. 1993. Electronic structure of some semiconductor fullerenes. Nanostructured Materials 3.1–6: 469–477.

    DOI: 10.1016/0965-9773(93)90114-QSave Citation »Export Citation »E-mail Citation »

    Fullerenes have useful properties in the material sciences, such as in nano-microscopic-engineered semiconductors.

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    • Deng, Qixin, Chaozhang Huang, Wei Xie, et al. 2011. Significant reduction of harmful compounds in tobacco smoke by the use of titanate nanosheets and nanotubes. Chemical Communications 47.21: 6153–6155.

      DOI: 10.1039/C1CC10794ASave Citation »Export Citation »E-mail Citation »

      Titanate nanosheets (TNS) and titanate nanotubes (TNT) have also been synthesized and used as additives for removing harmful compounds from cigarette smoke.

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      • Smita, Suchi, Shailendra K. Gupta, Alena Bartonova, Maria Dusinska, Arno C. Gutleb, and Qamar Rahman. 2012. Nanoparticles in the environment: Assessment using the causal diagram approach. Environmental Health 11.S1: S13.

        DOI: 10.1186/1476-069X-11Save Citation »Export Citation »E-mail Citation »

        Man-made engineered nanoparticles (ENPs) are unknowingly or purposely released in the environment during various industrial and mechanical processes. In the fireplace at home, fullerenes such as buckyballs or buckytubes are formed when wood is burned. In industrial processes, coal, oil, and gas boilers release tons of nanoparticles unintentionally.

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        Classification of Nanoparticles

        Nanoparticles may be classified either as naturally existing nanoparticles or manufactured nanoparticles. Naturally existing nanoparticles exist in nature in the form of carbon soot. They may rise from volcanic eruptions, lightening discharge, forest fire, and other such sources. Manufactured nanoparticles are produced manually, either intentionally or unintentionally; internal-combustion engine exhaust, jet airplanes, power plants, metal fumes (e.g., from smelting or welding), and polymer fumes are examples of unintentionally produced nanoparticles. Conversely, nanoparticles of controlled size and shape and with designed functionality, such as quantum dots/rods, metal oxides, fullerenes, nanotubes, nanowires, and nanoshells, are produced intentionally for their potential applications in various fields such as cosmetics, medicine, electronics, optics, and pharmacology; these are referred to as intentionally manufactured nanoparticles or engineered nanoparticles (ENPs).

        Dimension

        Nanoparticles can also be classified as zero dimensional (0-D), one dimensional (1-D), two-dimensional (2-D), and three-dimensional (3-D). Zero-dimensional nanoparticles are a special form of spherical nanocrystals from 1 to 10 nanometers (nm) in diameter, which includes nanodots and quantum dots. They have been developed as semiconductors, insulators, metals, magnetic materials, and metallic oxides. Quantum dots are used to track DNA molecules in cells and as biosensors for detecting agents of biological warfare, and they are efficient alternatives to conventional lighting sources. One-dimensional nanoparticles include thin films and manufactured surfaces or coatings and can be used for corrosion or wear and scratch resistance, as dirt repellents, or as antibacterial and antimicrobial agents. Two-dimensional nanoparticles include nanotubes, nanowires, nanofibers, and nanopolymers. Carbon nanotubes are a different form of carbon molecule, wound in a hexagonal network of carbon atoms; these hollow cylinders can have diameters as small as 0.7 nm and can reach several millimeters in length (Hett 2004), and each end of a carbon nanotube can be opened and closed by a fullerene half molecule. These nanotubes may have a single layer (like a straw) or several layers (like a poster rolled in a tube) of coaxial cylinders of increasing diameters in a common axis (Iijima 1991). Three-dimensional nanoparticles comprise fullerenes, dendrimers, and quantum dots. Fullerenes are allotropes of carbon in the form of spherical cages containing twenty to more than one hundred carbon atoms. Fullerenes have novel physical properties and can be subjected to extreme pressures, tending to regain their original shape when the pressure is released. Fullerene products include drug-delivering vehicles and electronic circuits. Dendrimers correspond to a new class of controlled-structure polymers with nanometric dimensions. They are considered to be the basic elements for large-scale synthesis of organic and inorganic nanostructures (with dimensions between 1 to 100 nm) and have unique properties. Because they are compatible with organic structures such as DNA, they can also be fabricated to interact with metallic nanocrystals and nanotubes or to possess an encapsulation capacity (Tomalia 2004). They may have conventional applications or may be used for drug delivery or environmental and water cleaning.

        • Hett, Annabelle. 2004. Nanotechnology: Small matter, many unknowns. Risk Perception. Zurich, Switzerland: Swiss Re.

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          The structural dimension of fullerene is discussed. These hollow cylinders can have diameters as small as 0.7 nm and reach several millimeters in length.

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          • Iijima, Sumio. 1991. Helical microtubules of graphitic carbon. Nature 354.6348: 56–58.

            DOI: 10.1038/354056a0Save Citation »Export Citation »E-mail Citation »

            The morphology and geometry of graphitic carbon is discussed; these nanotubes may have a single layer (like a straw) or several layers.

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            • Tomalia, Donald A. 2004. Birth of new macromolecular architecture: Dendrimers as quantized building blocks for nanoscale synthetic organic chemistry. Aldrichimica Acta 37.2: 39–57.

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              Nanoparticles have different shapes, types, compositions, and interactions with biomolecules.

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              Applications of Nanoparticles

              Nanoparticles have become a highly significant topic of research since the late 20th century due to their extraordinary functional properties, and they have been increasingly used in the manufacturing industry as well as in biomedical technology. The benefits of nanotechnology are due to the novel properties of nanomaterials, such as volume-to-surface ratio, as well as to the capability of researchers to organize and control their properties with greater precision and complexity. Nanoparticles are therefore expected to play an important role in medical science and technology in the coming decades. A number of novel technologies are based on binding between nanoparticles and DNA, and their interactions have been developed and used in molecular diagnosis, gene therapy, sensing, drug delivery, and artificial implants (Curtis and Wilkinson 2001; Sachlos, et al. 2006; Vaseashta and Dimova-Malinovska 2005; Chan and Nie 1998). Polymeric micelle nanoparticles are used to deliver drugs to tumors, and polymer-coated iron oxide nanoparticles are employed to break up clusters of bacteria, possibly allowing more-effective treatment of chronic bacterial infections. These approaches offer an opportunity for the development of efficient and low-cost technologies for high-sensitivity disease diagnosis and DNA detection (Buxton, et al. 2003; Yezhelyev, et al. 2006). Researchers at Rice University have showed that cerium oxide nanoparticles act as an antioxidant to remove oxygen-free radicals that are present in a patient’s bloodstream; such free radicals potentially could lead to a traumatic injury. The nanoparticles absorb the oxygen-free radicals and then release the oxygen in a less dangerous state, freeing up the nanoparticle to absorb more free radicals. Nanoparticles have varied applications in manufacturing, and materials composed of ceramic silicon carbide nanoparticles, when dispersed in magnesium, produce a strong, lightweight material that can be used in prosthetics and has been demonstrated to be effective both with self-healing capability and the ability to sense pressure. Zinc oxide nanoparticles can be dispersed in industrial coatings to protect wood, plastic, and textiles from exposure to ultraviolet (UV) rays, and silicon dioxide crystalline nanoparticles can be used to fill gaps between carbon fibers, thereby strengthening tennis rackets, for example. Silver nanoparticles are used in fabric to kill bacteria, thereby making clothing odor-resistant. Nanoparticles also have environmental applications; for example, iron nanoparticles are used to clean up carbon tetrachloride pollution in groundwater, and iron oxide nanoparticles are used to clean arsenic from water wells. Researchers are using gold nanoparticles embedded in a porous manganese oxide as a room temperature catalyst to break down volatile organic pollutants in air.

              • Buxton, Denis B., Stephen C. Lee, Samuel A. Wickline, and Mauro Ferrari. 2003. Recommendations of the National Heart, Lung, and Blood Institute Nanotechnology Working Group. Circulation 108.22: 2737–2742.

                DOI: 10.1161/01.CIR.0000096493058.E8Save Citation »Export Citation »E-mail Citation »

                The use of nanoparticles is recommended as a new application for diagnosis and therapy of cardiovascular, lung, and blood-related diseases and sleep disorders.

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                • Chan, Warren C. W., and Shuming Nie. 1998. Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 281.5385: 2016–2018.

                  DOI: 10.1126/science.281.5385.2016Save Citation »Export Citation »E-mail Citation »

                  Semiconductor quantum dots have a covalent-attachment property to biomolecules for ultrasensitive detection at the single-dot level. This kind of quality can be used for diagnostic purposes during sandwich immunoassay, nucleic-acid hybridization, and single native biomolecules, such as cytokines and viral RNA detection.

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                  • Curtis, Adam, and Chris Wilkinson. 2001. Nanotechniques and approaches in biotechnology. Trends in Biotechnology 19.3: 97–101.

                    DOI: 10.1016/S0167-7799(00)01536-5Save Citation »Export Citation »E-mail Citation »

                    The objective of this article is to explore the surface-directed properties of nanobiotechnologies, given that they were closer to commercial realization at the time, such as for use in tissue engineering, control of biofouling, and cell culture.

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                    • Sachlos, Eleftherios, Duce Gotora, and Jan T. Czernuszka. 2006. Collagen scaffolds reinforced with biomimetic composite nano-sized carbonate-substituted hydroxyapatite crystals and shaped by rapid prototyping to contain internal microchannels. Tissue Engineering 12.9: 2479–2487.

                      DOI: 10.1089/ten.2006.12.2479Save Citation »Export Citation »E-mail Citation »

                      It is proposed that biomimetic, composite, nanosized, carbonate-substituted hydroxyapatite crystals will play an important role in next-generation tissue-engineering scaffolds, being made to accommodate blood vessels and nutrient channels to support cell survival deep in the interior of the scaffolds.

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                      • Vaseashta, Ashok, and Doriana Dimova-Malinovska. 2005. Nanostructured and nanoscale devices, sensors and detectors. In Special issue: International Conference on Nanotechnology in Environmental Protection and Pollution. Science and Technology of Advanced Materials 6.3–4: 312–318.

                        DOI: 10.1016/j.stam.2005.02.018Save Citation »Export Citation »E-mail Citation »

                        The aim of this study is the detection of chemical and biological agents by using nanostructured materials in nanodevices and nanosensors.

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                        • Yezhelyev, Maksym V., Xiaohu Gao, Yun Xing, Ahmad Al-Hajj, Shuming Nie, and Ruth M. O’Regan. 2006. Emerging use of nanoparticles in diagnosis and treatment of breast cancer. Lancet: Oncology 7.8: 657–667.

                          DOI: 10.1016/S1470-2045(06)70793-8Save Citation »Export Citation »E-mail Citation »

                          In breast cancer diagnosis, three crucial biomarkers can be detected and accurately quantified in single-tumor sections by the use of nanoparticles conjugated to antibodies.

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                          Future Applications of Nanoparticles

                          In the future, techniques based on nanoparticle-DNA binding may have potential implications in medical biotechnology. In addition to the understanding of chemical and structural properties such as biocompatibility, water solubility, and biodegradability, the basics of positive molecular-binding reactions between nanoparticles and DNA are of major significance. It is necessary to understand the interactions within cellular membranes or compartmental molecules of the cell. The growth in the course of applications of nanoparticle-based technology in medicine and medical biotechnology continues to be a significant factor for research in medical practice, and it is expected to trigger more innovations in this field. The industrial use of engineered nanoparticles (such as in the manufacturing of household goods) is expected to increase as well, enabling them to interact with biological molecules and potentially damage the cells in vivo (Fischer and Chan 2007). The functionalization of nanoparticles can provide target-specific interaction and thus can be utilized in varied applications from industrial (Barth, et al. 2005) to environmental (Gehrke, et al. 2015) to biomedical uses (Salata 2004). Nanoparticles are predicted to play an important role in medical science and technology in the coming decades due to their special electronic, mechanical, and chemical properties. The applications of nanoparticles for drug delivery, pharmaceutical, and many industrial and commercial practices are expected to increase considerably (Duncan 2011). For example, carbon black is commonly used as a pigment, as a reinforcing phase in automotive tires and belts, and as a food color. A number of novel technologies based on nanoparticle-DNA binding and their interactions have been invented and are used in molecular diagnosis, gene therapy, sensing (Alivisatos, et al. 2005), and imaging. In the future, nanoparticles may help the current state of medicine in several ways, such as by providing highly selective and targeted therapeutics (i.e., with increased efficacy and minimal side effects compared to current therapeutics), by increasing the efficiency of diagnostic and prognostic tools, and by affecting the development of drugs.

                          • Alivisatos, A. Paul, Weiwei Gu, and Carolyn Larabell. 2005. Quantum dots as cellular probes. Annual Review of Biomedical Engineering 7:55–76.

                            DOI: 10.1146/annurev.bioeng.7.060804.100432Save Citation »Export Citation »E-mail Citation »

                            Discusses the recent applications of quantum dot at the cellular level like cell tracking, immunolabelling and fluorescence imaging.

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                            • Barth, Johannes V., Giovanni Costantini, and Klaus Kern. 2005. Engineering atomic and molecular nanostructures at surfaces. Nature 437.7059: 671–679.

                              DOI: 10.1038/nature04166Save Citation »Export Citation »E-mail Citation »

                              Engineered nanostructures show some fundamental properties in fabrication, such as control over the shape, composition, and mesoscale organization of the surface structures, which helps create a wide range of surface nanostructures from metallic, semiconducting, and molecular materials.

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                              • Duncan, Timothy V. 2011. Applications of nanotechnology in food packaging and food safety: Barrier materials, antimicrobials and sensors. Journal of Colloid and Interface Science 363.1: 1–24.

                                DOI: 10.1016/j.jcis.2011.07.017Save Citation »Export Citation »E-mail Citation »

                                The applications of nanoparticles in food technology are reviewed, such as polymer/clay nanocomposites as high-barrier packaging materials, silver nanoparticles as effective antimicrobial agents, and nanosensors and nanomaterial-based assays for the recognition of food-relevant analytes.

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                                • Fischer, Hans C., and Warren C. W. Chan. 2007. Nanotoxicity: The growing need for in vivo study. In Special issue: Chemical biotechnology / pharmaceutical biotechnology. Current Opinion in Biotechnology 18.6: 565–571.

                                  DOI: 10.1016/j.copbio.2007.11.008Save Citation »Export Citation »E-mail Citation »

                                  Nanotoxicology is a growing field in science, dealing with overexposure to nanoparticles, which induces toxic biological responses by interacting with biological systems.

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                                  • Gehrke, Ilka, Andreas Geiser, and Annette Somborn-Schulz. 2015. Innovations in nanotechnology for water treatment. Nanotechnology, Science and Applications 8:1–17.

                                    DOI: 10.2147/NSA.S43773Save Citation »Export Citation »E-mail Citation »

                                    An overview of modern advances in nanotechnologies for water and wastewater treatment processes, using nanoparticles such as nanoadsorbents, nanometals, nanomembranes, and photocatalysts.

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                                    • Salata, Oleg V. 2004. Applications of nanoparticles in biology and medicine. Journal of Nanobiotechnology 2:3.

                                      DOI: 10.1186/1477-3155-2-3Save Citation »Export Citation »E-mail Citation »

                                      Advancements in the use of nanoparticles in the field of tissue engineering, including in cancer therapy, multicolor optical coding for biological assays, manipulation of cells and biomolecules, and protein detection.

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                                      Production and Exposure of Nanoparticles

                                      Nanoparticles are increasingly being used in industry, medicine, diagnostics, and pharmacology, among other fields, but their unlimited use leads to their overproduction. It is has been estimated that thousands of kilograms (kg) of nanosized materials are being produced per year through accidental anthropogenic sources (e.g., combustion or nucleation). On the other hand, even when nanoparticles are manufactured by using appropriate techniques, they are released in air, which may lead to the contamination of soil and food products (Luther 2004). Single-walled and multiwalled nanotubes had a worldwide production of 2,954 kg in 2003, and the Carbon Nanotechnology Research Institute, in Japan, proposed an increase in the production of carbon nanotubes (CNTs) from about 1,000 kg in 2003 to 120,000 kg per year by 2008, and it was predicted that production rates would accelerate exponentially in the next few years after that. Considering the tons of engineered nonomaterial planned for production, it is likely that some of these materials will enter the environment during the product’s life cycle (i.e., manufacture, use, and disposal).

                                      • Luther, Wolfgang. 2004. Industrial application of nanomaterials: Chances and risks technological analysis. Future Technologies 54:1–112.

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                                        Risk assessment in the production and use of nanoparticles, including discussion of the development of preventive measures and a practice code.

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                                        Toxicity of Nanoparticles

                                        Research on the toxicity of nanoparticles has revealed that nanoparticles may adversely affect biological systems because of their size, strong mobility, and reactivity. Upon exposure to these nanoparticles, some of these products may enter the human body and become toxic at the cellular, subcellular, and molecular level in the tissues and organs (Vishwakarma, et al. 2010). Nanoparticle uptake by the cell membrane is followed by the activation of mechanisms of reactive oxygen species generation, which induces biomolecular damage in the cell (Unfried, et al. 2007). These particles may or may not be carcinogenic or allergic, but even inert nanoparticles can show harmful effects due to the presence of some absorbed toxic species or to the formation of toxic products following reactions with body fluids. Their potential toxic effects on the environment and human health are therefore a major concern. Workers engaged in manufacturing and handling of nanoparticles are more vulnerable to these diseases, which poses new challenges for doctors in diagnosis and treatment. A large number of consumer products containing nanoparticles, such as cosmetics, sunscreens, sports clothes, personal care products, food packaging, paints, and pharmaceuticals, even tires and auto parts, are already in the market, and various medical procedures using nanoparticles also can lead to adverse effects (Niemeyer 2001; Zhang, et al. 2015). The lack of awareness about the harmful effects of these products has more of an impact on consumers’ health than on that of workers. These particles may end up in the environment, settling in the soil, being taken up by some plants, and then being accumulated in bodies, because of their small size.

                                        • Niemeyer, Christof, M. 2001. Nanoparticles, proteins, and nucleic acids: Biotechnology meets materials science. Angewandte Chemie 40.22: 4128–4158.

                                          DOI: 10.1002/1521-3773(20011119)40:22<4128::AID-ANIE4128>3.3.CO;2-JSave Citation »Export Citation »E-mail Citation »

                                          This review is focused on the current approach to nanomaterials and their application in the fields of molecular biotechnology and interdisciplinary chemistry.

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                                          • Unfried, Klaus, Catrin Albrecht, Lars-Oliver Klotz, Anna Von Mikecz, Susanne Grether-Beck, and Roel P. F. Schins. 2007. Cellular responses to nanoparticles: Target structures and mechanisms. Nanotoxicology 1.1: 51–72.

                                            DOI: 10.1080/00222930701314932Save Citation »Export Citation »E-mail Citation »

                                            Nanoparticles interact with various biomolecular and submolecular machineries of the cell, activating a large amount of signaling cascades, which then causes the disruption of normal cellular physiology.

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                                            • Vishwakarma, Vinita, Subhranshu Sekhar Samal, and N. Manoharan. 2010. Safety and risk associated with nanoparticles—A review. Journal of Minerals and Materials Characterization and Engineering 9.5: 455–459.

                                              DOI: 10.4236/jmmce.2010.95031Save Citation »Export Citation »E-mail Citation »

                                              The emerging field of nanotechnology has created a risk for the environment and human health. The existence of nanoparticles has been known for many years. In spite of this, the toxicology of nanoparticles is poorly understood because there are not sufficient methods to test nanoparticles for health, safety, and environmental impacts, especially in the size range lower than 50 nanometers.

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                                              • Zhang, Yuanyuan, Yu-Rui Leu, Robert J. Aitken, and Michael Riediker. 2015. Inventory of engineered nanoparticle-containing consumer products available in the Singapore retail market and likelihood of release into the aquatic environment. International Journal of Environmental Research and Public Health 12.8: 8717–8743.

                                                DOI: 10.3390/ijerph120808717Save Citation »Export Citation »E-mail Citation »

                                                The concentration of human-produced nanoparticles in the studied products, the quantity of daily use of these products, their release factor, and their market share were in the range of several hundred tons per year. Because these quantities are likely to increase, it will be important to further study the fate of engineered nanoparticles that reach the aquatic environment in Singapore.

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                                                Interaction of Nanoparticles in the Human Body

                                                Although the revolutionary growth of nanoparticles will be an overall benefit for humans, this growth will also lead to large-scale production of nanoparticles and nanostructures. This ever-increasing development of nanoparticles is likely to amplify environmental toxicity, as well as hazards to humans through inhalation and ingestion of nanoparticles in the workplace. These engineered nanoparticles will induce adverse effects in the human body system (Zhao, et al. 2012). The impact of the interactions of nanoparticles with the body depends on their size, chemical composition, surface structure, solubility, shape, and accumulation. A University of California at Berkeley proposal showed that lower-sized less than 10 nanometer) nanoparticles behave more like a gas and can easily pass through skin and lung tissue to penetrate cell membranes. Therefore, they may easily enter the human body through the food or water we consume, both accidently or intentionally via the nose and lungs, just like other aerosols, and also through the skin (Papp, et al. 2008). Some nanoparticles readily travel throughout the body, deposit in target organs, penetrate cell membranes, lodge in mitochondria, and may trigger injurious responses (Oberdörster, et al. 2002). Because the sizes of the nanoparticles and biological molecules are comparable, the nanoparticles can easily invade the natural defense system of humans or other species and ultimately enter the cells to affect cellular functions (Gramowski, et al. 2010). On the basis of related research on the effects of smoking on lung tissue, the foreign particles inhaled into the lungs have the potential to do great damage (Ryu, et al. 2001), and studies have revealed that inhaled nanoparticles not only cause lung damage but also can move into the bloodstream, potentially causing cardiac damage. Other observations indicate that inhaled nanoparticles in humans caused damage both to the point of entry and to the brain itself. According to a report by the Royal Society, the UK national science academy, nanotubes are structurally similar to asbestos fibers, which can cause lung fibrosis when inhaled in large amounts over long periods (as noted in DelVecchio 2006). The unique properties of nanoparticles, such as the large surface area, anomalous interface, complicated reactivity, and quantum effects, can also lead to changes in physicochemical properties, which naturally alter the biological activities in vivo (Zhao and Nalwa 2006). It has already been revealed that nanoparticles used in the medical field may induce cytotoxic effect, as had previously been shown in eukaryotic and prokaryotic cells (Brunner, et al. 2006; Feris, et al. 2010). Engineered nanoparticles could interact with biological molecules and have the potential to damage cells in vivo (Fischer and Chan 2007). All these findings lead to a great concern about the toxicological effects of engineered nanomaterials and nanoparticles.

                                                • Brunner, Tobias J., Peter Wick, Pius Manser, et al. 2006. In vitro cytotoxicity of oxide nanoparticles: Comparison to asbestos, silica, and the effect of particle solubility. Environmental Science & Technology 40.14: 4374–4381.

                                                  DOI: 10.1021/es052069iSave Citation »Export Citation »E-mail Citation »

                                                  Evaluation of a human mesothelioma and a rodent fibroblast cell line for in vitro cytotoxicity, by testing seven industrially important nanoparticles.

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                                                  • DelVecchio, Rick. 2006. Berkeley considering need for nano safety. San Francisco Chronicle, 24 November.

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                                                    Nanotubes are structurally similar to asbestos fibers, which can cause lung fibrosis when inhaled in large amounts over long periods.

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                                                    • Feris, Kevin, Caitlin Otto, Juliette Tinker, et al. 2010. Electrostatic interactions affect nanoparticle-mediated toxicity to gram-negative bacterium Pseudomonas aeruginosa PAO1. Langmuir 26.6: 4429–4436.

                                                      DOI: 10.1021/la903491zSave Citation »Export Citation »E-mail Citation »

                                                      Nanoparticles used in the medical field may induce cytotoxic effect, as has already been shown in eukaryotic and prokaryotic cells.

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                                                      • Fischer, Hans C., and Warren C. W. Chan. 2007. Nanotoxicity: The growing need for in vivo study. In Special issue: Chemical biotechnology / pharmaceutical biotechnology. Current Opinion in Biotechnology 18.6: 565–571.

                                                        DOI: 10.1016/j.copbio.2007.11.008Save Citation »Export Citation »E-mail Citation »

                                                        Engineered nanoparticles could interact with biological molecules and have the potential to damage cells in vivo.

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                                                        • Gramowski, Alexandra, Juliane Flossdorf, Kunal Bhattacharya, et al. 2010. Nanoparticles induce changes of the electrical activity of neuronal networks on microelectrode array neurochips. Environmental Health Perspectives 118.10: 1363–1369.

                                                          DOI: 10.1289/ehp.0901661Save Citation »Export Citation »E-mail Citation »

                                                          Nanoparticles can easily invade the natural defense system of the human body or that of other species, ultimately entering the cells and affecting cellular functions.

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                                                          • Oberdörster, Günter, Zachary Sharp, Viorel Atudorei, et al. 2002. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. Journal of Toxicology and Environmental Health, Part A 65.20: 1531–1543.

                                                            DOI: 10.1080/00984100290071658Save Citation »Export Citation »E-mail Citation »

                                                            Nanoparticles readily travel throughout the body, deposit in target organs, and lodge in mitochondria, possibly triggering injurious responses.

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                                                            • Papp, Thilo, Dietmar Schiffmann, Dieter Weiss, Vince Castranova, Val Vallyathan, and Qamar Rahman. 2008. Human health implications of nanomaterial exposure. Nanotoxicology 2.1: 9–27.

                                                              DOI: 10.1080/17435390701847935Save Citation »Export Citation »E-mail Citation »

                                                              Nanoparticles may easily enter the human body through the food or water we consume, both accidently or intentionally via the nose and lungs (just like other aerosols), and also through the skin.

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                                                              • Ryu, Jay H., Thomas V. Colby, Thomas E. Hartman, and Robert Vassallo. 2001. Smoking-related interstitial lung diseases: A concise review. European Respiratory Journal 17.1: 122–132.

                                                                DOI: 10.1183/09031936.01.17101220Save Citation »Export Citation »E-mail Citation »

                                                                Foreign particles inhaled into the lungs have the potential to do great damage.

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                                                                • Zhao, Yuliang, and Hari Singh Nalwa, eds. 2006. Nanotoxicology: Interactions of nanomaterials with biological systems. Nanotechnology Book 19. Stevenson Ranch, CA: American Scientific.

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                                                                  This book about nanotoxicology contains chapters evaluating the safety of nanotechnology, covering the main aspects of dealing with the risks and implications of exposure to nanomaterials, especially the potential dangers of nanoparticles to human health and safety and the environment.

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                                                                  • Zhao, Yuliang, Bing Wang, Weiyue Feng, and Chunli Bai. 2012. Nanotoxicology: Toxicological and biological activities of nanomaterials. In Encyclopedia of life support systems: Nanoscience and nanotechnologies. Edited by Valeri Nikolayevich Harkin, Chunli Bai, and Sae-Chul Kim. Paris: EOLSS.

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                                                                    Nanoparticles have a very strong tendency to interact with biomolecules, which may induce toxicity in humans.

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                                                                    Carbon-Based Nanoparticles

                                                                    Carbon nanomaterials are divided into two categories: fullerenes and carbon nanotubes (CNTs). Single-wall carbon nanotubes (SWNTs) and multiwall nanotubes (MWNTs) are the two main members in the CNT family. SWNTs are formed by rolling graphene into a cylindrical shape, with a diameter of about 0.7–10.0 nanometers (nm) and a length of about 10 nm up to 1 micrometer (μg). Similarly, MWNTs can be considered equal to the spacing of adjacent graphene layers in graphite. With the nested-tubes structure, MWNTs are concentric rings of SWNTs with different diameters (see Iijima 1991, cited under Classification of Nanoparticles: Dimension). They are allotropes but have individual spatial structures. C60 is the most distinctive fullerene, built up by twelve isolated pentagons and twenty hexagons and having a diameter of about 0.7 nm (Talyzin, et al. 2014). Carbon-based nanomaterials have attracted a great deal of attention from scientists in many fields of research and development, due to their novel electronic, mechanical, and chemical properties. So, the applications of carbon nanoparticles (CNPs) are expectedly increasing in almost every field, such as pharmacology and drug delivery, and many industrial and commercial practices. Some of the common applications of CNPs are in the form of a reinforcing phase in automotive tires, belts, or food coloring.

                                                                    • Talyzin, Alexandr V., Serhiy Luzan, Ilya V. Anoshkin, et al. 2014. Hydrogen-driven cage unzipping of C60 into nano-graphenes. Journal of Physical Chemistry 118.12: 6504∓6513.

                                                                      DOI: 10.1021/jp500377sSave Citation »Export Citation »E-mail Citation »

                                                                      C60 is the most distinctive fullerene, built up by twelve isolated pentagons and twenty hexagons and having a diameter of about 0.7 nm.

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                                                                      Toxicity of Carbon Nanomaterials

                                                                      The benefits of CNP engineered or released from industrial and human activities, as noted in Carbon-Based Nanoparticles, may cause significant risk to the environment and, in particular, public health (Panessa-Warren, et al. 2006; Ramón-Azcón, et al. 2014). Therefore, CNP exposure is a major concern because of the possibility of respiratory risks and cardiovascular morbidity and mortality (Peters and Pope 2002). A number of reports indicate that ultrafine CNP and carbon nanotubes cause lung injury via inhalation and injection (Donaldson, et al. 2004; Donaldson, et al. 2006; Oberdörster, et al. 2005), and some reports have already shown that CNPs affect human cells, resulting in lipid membrane peroxidation, gene down-regulation of adhesive proteins, and increased cell death, including necrosis and apoptosis (Poulsen, et al. 2015).

                                                                      • Donaldson, Ken, Robert Aitken, Lang Tran, et al. 2006. Carbon nanotubes: A review of their properties in relation to pulmonary toxicology and workplace safety. Toxicological Sciences 92.1: 5–22.

                                                                        DOI: 10.1093/toxsci/kfj130Save Citation »Export Citation »E-mail Citation »

                                                                        CNTs seem to have a special ability to stimulate mesenchymal cell growth and to cause granuloma formation and fibrogenesis. CNTs have more adverse effects than the same mass of nanoparticle carbon and quartz.

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                                                                        • Donaldson, Ken, Vicki Stone, C. Lang Tran, Wolfgang Kreyling, and Paul J. A. Borm. 2004. Nanotoxicology. Occupational & Environmental Medicine 61.9: 727–728.

                                                                          DOI: 10.1136/oem.2004.013243Save Citation »Export Citation »E-mail Citation »

                                                                          Nanoparticles may have adverse effects at their portal of entry (e.g., the lungs), but some nanoparticles may also escape the normal defenses and translocate from their portal of entry to have diverse effects in other target organs.

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                                                                          • Oberdörster, Günter, Eva Oberdörster, and Jan Oberdörster. 2005. Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 113.7: 823–839.

                                                                            DOI: 10.1289/ehp.7339Save Citation »Export Citation »E-mail Citation »

                                                                            Ultrafine CNP and carbon nanotubes cause lung injury via inhalation and injection.

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                                                                            • Panessa-Warren, Barbara J., John B. Warren, Stanislaus S. Wong, and James A. Misewich. 2006. Biological cellular response to carbon nanoparticle toxicity. Journal of Physics: Condensed Matter 18.33: S2185–S2201.

                                                                              DOI: 10.1088/0953-8984/18/33/S34Save Citation »Export Citation »E-mail Citation »

                                                                              Reports about cytotoxicity of nanoparticles developed for biomedical applications.

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                                                                              • Peters, Annette, and C. Arden Pope III. 2002. Cardiopulmonary mortality and air pollution. Lancet 360.9341: 1184–1185.

                                                                                DOI: 10.1016/S0140-6736(02)11289-XSave Citation »Export Citation »E-mail Citation »

                                                                                Provides incomplete but intriguing results suggesting that particle-induced pulmonary and systemic inflammation, accelerated atherosclerosis, and altered cardiac autonomic function may be part of the pathophysiological pathways linking particulate air pollution with cardiovascular mortality.

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                                                                                • Poulsen, Sarah S., Anne T. Saber, Andrew Williams, et al. 2015. MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicology and Applied Pharmacology 284.1: 16–32.

                                                                                  DOI: 10.1016/j.taap.2014.12.011Save Citation »Export Citation »E-mail Citation »

                                                                                  Toxico-genomic analysis of female C57BL/6 mouse lungs following a single intratracheal instillation of 0, 18, 54, or 162 μg/mouse of a small, curled (CNTSmall, 0.8 ± 0.1 μm in length) or large, thick MWCNT (CNTLarge, 4 ± 0.4 μm in length).

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                                                                                  • Ramón-Azcón, Javier, Samad Ahadian, Raquel Obregón, Hitoshi Shiku, Murugan Ramalingam, and Tomokazu Matsue. 2014. Applications of carbon nanotubes in stem cell research. Journal of Biomedical Nanotechnology 10.10: 2539–2561.

                                                                                    DOI: 10.1166/jbn.2014.1899Save Citation »Export Citation »E-mail Citation »

                                                                                    CNTs can also be used for stem cell labeling due to their high optical absorbance in the near-infrared regime.

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                                                                                    Carbon-Nanomaterials-Induced Toxicity in Genetic and Protein Levels

                                                                                    It has been determined that the interactions of CNP with DNA may potentially lead to abnormal effect, mutagenesis, or DNA damage (Nel, et al. 2006). In vitro studies suggest that DNA molecules may interact with carbon nanomaterials, with unusual responses. It has been reported that C60 and its derivatives inhibit the replication of simian immunodeficiency virus (SIV) in vitro and the activity of Moloney murine leukemia virus (M-MuLV) reverse transcriptase (Nacsa, et al. 1997). Further, these CNPs have enhanced the amplification efficiency for long polymerase chain reactions (PCR) (Zhang, et al. 2007). Nanosized carbon and titanium dioxide (TiO2) nanoparticles may impair the ability of the alveolar macrophage (AM) for phagocytosis and chemotaxis. Molecular dynamics (MD) simulations were conducted in order to understand possible conformational changes that the carbon nanotube may induce on the structure of a protein, human serum albumin (Shen, et al. 2008), and it was found that α-helical secondary structure of the protein was mostly unchanged whereas the random coils that connect these α-helices were strongly affected. This leads to the alteration in the tertiary structure of the protein, mostly due to the orientation and conformational changes of the protein structure to fit the arrangement of carbon atoms on the nanotube surface. It can affect the overall structure and function of proteins by hydrophobic interactions and π-stacking between the aromatic residues and hexagonal carbon arrangement on some carbonaceous nanoparticles. The interactions of CNP with DNA have been studied only by simulation (Gao and Kong 2004; Zhao, et al. 2005), so in vivo or in vitro interaction of CNP with DNA and their potential impacts on DNA are yet to be explored.

                                                                                    • Gao, Huajian, and Yong Kong. 2004. Simulation of DNA-nanotube interactions. Annual Review of Materials Research 34:123–150.

                                                                                      DOI: 10.1146/annurev.matsci.34.040203.120402Save Citation »Export Citation »E-mail Citation »

                                                                                      The encapsulated CNT-DNA molecular complex can be further exploited for applications such as DNA-modulated molecular electronics, molecular sensors, electronic DNA sequencing, and nanotechnology of gene delivery systems.

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                                                                                      • Nacsa, János, Judit Segesdi, Ágnes Gyuris, et al. 1997. Antiretroviral effects of nonderivatized C60 in vitro. Fullerenes, Nanotubes, and Carbon Nanostructures 5.5: 969–976.

                                                                                        DOI: 10.1080/15363839708013310Save Citation »Export Citation »E-mail Citation »

                                                                                        C60 and its derivatives inhibit the replication of SIV in vitro and the activity of M-MuLV reverse transcriptase.

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                                                                                        • Nel, Andre, Tian Xia, Lutz Mädler, and Ning Li. 2006. Toxic potential of materials at the nanolevel. Science 311.5761: 622–627.

                                                                                          DOI: 10.1126/science.1114397Save Citation »Export Citation »E-mail Citation »

                                                                                          Interactions of CNP with DNA may potentially lead to abnormal effect, mutagenesis, or DNA damage.

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                                                                                          • Shen, Jia-Wei, Tao Wu, Qi Wang, and Yu Kang. 2008. Induced stepwise conformational change of human serum albumin on carbon nanotube surfaces. Biomaterials 29.28: 3847–3855.

                                                                                            DOI: 10.1016/j.biomaterials.2008.06.013Save Citation »Export Citation »E-mail Citation »

                                                                                            MD simulations were carried out in order to understand possible conformational changes that the carbon nanotube may induce on the structure of a protein, human serum albumin.

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                                                                                            • Zhang, Zhizhou, Mingchun Wang, and Hongjie An. 2007. An aqueous suspension of carbon nanopowder enhances the efficiency of a polymerase chain reaction. Nanotechnology 18.35: 355706.

                                                                                              DOI: 10.2144/000112692Save Citation »Export Citation »E-mail Citation »

                                                                                              CNPs have enhanced the amplification efficiency for long PCR reactions.

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                                                                                              • Zhao, Xiongce, Alberto Striolo, and Peter T. Cummings. 2005. C60 binds to and deforms nucleotides. Biophysical Journal 89.6: 3856–3862.

                                                                                                DOI: 10.1529/biophysj.105.064410Save Citation »Export Citation »E-mail Citation »

                                                                                                Fullerene binds to single-strand DNA very strongly and distort the nucleotide bases. But with A-form double-strand DNA, fullerenes infiltrate from the end of the double helix, form stable hybrids, and disturb the H-bonds & hydrophilic interactions between the nucleotides.

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                                                                                                Fullerenes

                                                                                                Fullerenes are spherical cage-like structures with a diameter of about 1 nanometer (nm). They exist in different molecular weights ranging from C20 to C720, among which the most common form, C60, is also known as Buckminster fullerene. Fullerenes may be produced naturally as they are released from combustion processes such as forest fires (Powell and Kanarek 2006).

                                                                                                • Powell, Maria C., and Marty S. Kanarek. 2006. Nanomaterial health effects—part 1: Background and current knowledge. Wisconsin Medical Journal 105.2: 16–20.

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                                                                                                  Discusses fullerenes are naturally occurring nanoparticles can be produced from the combustion processes like forest fires.

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                                                                                                  Applications

                                                                                                  Fullerenes have been found to be useful in chemical and material science applications, such as semiconductors and microscopic engineering and polymers (see Aguilera-Granja, et al. 1993, cited under Sources of Nanoparticles, and Spence 1999). Biomedical applications include antioxidant, antiviral, antibiotic, and anticancerous activities; enzyme inhibition; cell signaling; and DNA cleavage, as well as imaging and nuclear medicine (Tsao, et al. 1999 and Bogdanovic, et al. 2016).

                                                                                                  • Bogdanovic G., Djordjevic A. 2016. Carbon nanomaterials: Biologically active fullerene derivatives. Srpski Arhivza celokupno lekarstvo, 144.3–4: 222–231.

                                                                                                    DOI: 10.2298/SARH1604222BSave Citation »Export Citation »E-mail Citation »

                                                                                                    Discusses the role of fullerene in different cellular processes like cytotoxic & genotoxic responses.

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                                                                                                    • Spence, John C. H. 1999. The future of atomic resolution electron microscopy for materials science. Materials Science and Engineering R: Reports 26.1–2: 1–49.

                                                                                                      DOI: 10.1016/S0927-796X(99)00005-4Save Citation »Export Citation »E-mail Citation »

                                                                                                      Discusses the role of fullerenes in imaging of dislocation kink, superconductors, atomic-resolution imaging, surfaces, glasses, catalysts, and magnetic materials. The role fullerenes is discussed in the study of atomic defects, colossal magnetoresistance, ceramic interfaces & quasicrystals.

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                                                                                                      • Tsao, Nina, Puthuparampil P. Kanakamma, Tien-Yau Luh, Chen-Kung Chou, and Huan-Yao Lei. 1999. Inhibition of Escherichia coli-induced meningitis by carboxyfullerence. Antimicrobial Agents and Chemotherapy 43.9: 2273–2277.

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                                                                                                        Discusses carboxyfullerence (C60) have ability to inhibit meningitis induced by E. coli.

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                                                                                                        Toxicity of Fullerene

                                                                                                        Assessing the toxicity of fullerenes is essential for demarcating the risk to human health. Previous data clearly show that pristine C60 has no acute or subacute toxicity in a large variety of living organisms, but chemical modifications may change the general properties of pristine fullerene, making them toxic (e.g., polyvinylpyrrolidone, or PVP, forms a charge transfer complex with fullerenes). The identification of hazards related to fullerene exposure is difficult and complicated because a variety of fullerene derivatives exist, a diverse group of moieties can be attached to the fullerene surface, and various preparation processes can be utilized to make fullerenes water soluble. It is also known that C60 is an efficient singlet oxygen sensitizer under light exposure (Krusic, et al. 1991). In the presence of oxygen, fullerene and some of its derivatives can be extremely toxic through singlet oxygen formation, which can damage important biological molecules such as DNA, lipids, and proteins. The first toxicity study of C60 was conducted in the United States (Tucson, Arizona), as documented in Nelson, et al. 1993. Fullerenes do not remain at the site of exposure (lungs and gut) but can cross the cell barriers and be transported through blood. Identification of potential targets of fullerene toxicity within the body, and their in vitro toxicity assessments at particular target sites on the delivery of fullerenes to target organs (such as the liver or kidneys), requires their transfer into blood from their exposure site. This is necessary to access different sites within the body. However, few previous studies revealed the absorption of fullerene into blood from their exposure site (Yamago, et al. 1995). Fullerene may pass into the blood from the gut (Yamago, et al. 1995) and then may accumulate in the kidney, liver (Shipelin, et al. 2015), and spleen (Chen, et al. 1998). Metabolism of fullerene may occur following its accumulation within the liver but its metabolites are still unknown, and then it might be eliminated through urine and feces (Mori, et al. 2006; Yamago, et al. 1995). Molecular-dynamics studies have shown that the translocation of fullerene across the lipid membrane due to the ability of C60 to create a cavity (termed transient micropores) within the membrane helps C60 molecules penetrate into the membrane.

                                                                                                        • Chen, Hans H., Chi Yu, Tzuu H. Ueng, et al. 1998. Acute and subacute toxicity study of water-soluble polyalkylsulfonated C60 in rats. Toxicologic Pathology 26.1: 143–151.

                                                                                                          DOI: 10.1177/019262339802600117Save Citation »Export Citation »E-mail Citation »

                                                                                                          Rats injected with the compound intraperitoneally or intravenously immediately eliminated the compound through the kidney; the kidney appeared to be the primary target organ.

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                                                                                                          • Krusic, Paul J., Edel Wasserman, Petra N. Keizer, and John R. Morton. 1991. Radical reactions of C60. Science 254.5035: 1183–1185.

                                                                                                            DOI: 10.1126/science.254.5035.1183Save Citation »Export Citation »E-mail Citation »

                                                                                                            C60 is an efficient singlet oxygen sensitizer under light exposure.

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                                                                                                            • Mori, Tomohisa, Hiroya Takada, Shinobu Ito, Kenji Matsubayashi, Nobuhiko Miwa, and Toshiko Sawaguchi. 2006. Preclinical studies on safety of fullerene upon acute oral administration and evaluation for no mutagenesis. Toxicology 225.1: 48–54.

                                                                                                              DOI: 10.1016/j.tox.2006.05.001Save Citation »Export Citation »E-mail Citation »

                                                                                                              Determines the acute oral median lethal dose and evaluates the acute toxicity of fullerenes when administrated as a single dose to Sprague-Dawley rats.

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                                                                                                              • Nelson, Mark A., Frederick Domann, G. Tim Bowden, Stephen B. Hooser, Quintus Fernando, and Dean E. Carter. 1993. Effects of acute and subchronic exposure of topically applied fullerene extracts on the mouse skin. Toxicology and Industrial Health 9.4: 623–630.

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                                                                                                                Toxicity study of C60 was conducted in the Tucson, Arizona.

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                                                                                                                • Shipelin, Vladimir A., T. A. Smirnova, Ivan V. Gmoshinskii, and Victor A. Tutelyan. 2015. Analysis of toxicity biomarkers of fullerene C₆₀ nanoparticles by confocal fluorescent microscopy. Bulletin of Experimental Biology and Medicine 158.4: 443–449.

                                                                                                                  DOI: 10.1007/s10517-015-2781-4Save Citation »Export Citation »E-mail Citation »

                                                                                                                  Discusses the accumulation of cytoplasmic granules presumably identified as Kupffer macrophages, without any signs of visible inflammation or necrotic areas. This phenomenon can reflect the early stages of toxic reaction being a sensitive bioindicator of the damage produced by administered fullerene C60 in the hepatic tissue.

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                                                                                                                  • Yamago, Shigeru, Hidetoshi Tokuyama, Eiichi Nakamura, et al. 1995. In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity. Chemistry & Biology 2.6: 385–389.

                                                                                                                    DOI: 10.1016/1074-5521(95)90219-8Save Citation »Export Citation »E-mail Citation »

                                                                                                                    Reveals the absorption of fullerene into blood from its exposure site, possibly passing into the blood from the gut and then accumulating in the kidney and liver before being eliminated through urine and feces.

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                                                                                                                    Toxicity of Fullerene Derivatives

                                                                                                                    Some of the fullerene derivatives such as C60(OH)20 barely penetrate the membrane as they are absorbed onto the membrane surface, due to their hydrophilic nature (Qiao, et al. 2007). C60(OH)20 does not interact with the lipid core of the membrane, preventing its penetration into the membrane, but shows strong interactions with the head groups of the membrane surface, causing a “pinch” to form in the plasma membrane. Belgorodsky, et al. 2006 shows that cyclodextrin-capped fullerenes are able to form stable complexes with bovine serum albumin (BSA), which helps facilitate fullerene transport within the body. Computational models were used to reveal the interactions between fullerenes (in a pristine and carboxylated form) and proteins (namely, human serum albumin, BSA, human immunodeficiency virus [HIV] protease, and a fullerene-specific antibody), all of which had been previously confirmed to interact with fullerene molecules (Benyamini, et al. 2006). The binding sites for fullerenes within the proteins were recognized and confirmed to have similarities between the different proteins, such as BSA and HIV proteases. However, the design of the fullerene molecule is a fundamental factor for its interactions with proteins. The fullerene derivatives that were used were designed in such a way so as to support such interactions, and the applicability of the response to fullerenes as a whole requires analysis. However, the mechanism of the absorption, distribution, metabolism, and excretion (ADME) profile of fullerenes is yet to be explored, and therefore it is necessary to investigate the toxicity of fullerene. The ability of fullerenes to interact with biological molecules such as proteins, DNA, and RNA is of major concern because they not only have the ability to alter the normal structure and function of these biological moieties, and to enable fullerene transport within the body (as interactions of fullerenes with serum proteins are evident), they are also potentially able to modify the behavior of the particles.

                                                                                                                    • Belgorodsky, Bogdan, Ludmila Fadeev, Jenny Kolsenik, and Michael Gozin. 2006. Formation of a soluble stable complex between pristine C60-fullerene and a native blood protein. Chembiochem 7.11: 1783–1789.

                                                                                                                      DOI: 10.1002/cbic.200600237Save Citation »Export Citation »E-mail Citation »

                                                                                                                      Cyclodextrin-capped fullerenes were able to form stable complexes with BSA, which help facilitate fullerene transport within the body.

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                                                                                                                      • Benyamini, Hadar, Alexandra Shulman-Peleg, Haim J. Wolfson, Bogdan Belgorodsky, Ludmila Fadeev, and Michael Gozin. 2006. Interaction of C60-fullerene and carboxyfullerene with proteins: Docking and binding site alignment. Bioconjugate Chemistry 17.2: 378–386.

                                                                                                                        DOI: 10.1021/bc050299gSave Citation »Export Citation »E-mail Citation »

                                                                                                                        Computational models were used to reveal the interactions between fullerenes and proteins (e.g., human serum albumin, BSA, HIV protease), all of which had been previously confirmed to interact with fullerene molecules.

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                                                                                                                        • Qiao, Rui, Aaron P. Roberts, Andrew S. Mount, Stephen J. Klaine, and Pu Chun Ke. 2007. Translocation of C60 and its derivatives across a lipid bilayer. Nano Letters 7.3: 614–619.

                                                                                                                          DOI: 10.1021/nl062515fSave Citation »Export Citation »E-mail Citation »

                                                                                                                          The simulation results showed that whereas the pristine C60 molecule can readily “jump” into the bilayer and translocate the membrane within a few milliseconds, the C60(OH)20 molecule can barely penetrate the bilayer.

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                                                                                                                          Engineered Nanoparticles

                                                                                                                          Engineered nanoparticles are intentionally produced, but ultrafine particles (often referred to as incidental nanoparticles) are normally byproducts of processes such as combustion and vaporization. Designed nanoparticles with specific properties or compositions (e.g., shape, size, surface properties, and chemistry) are known as engineered nanoparticles. The potential health risk of exposure to these nanoparticles is generally associated with the magnitude and duration of exposure, the persistence of the material in the body, the inherent toxicity of the material, and the susceptibility or health status of the exposed person. More data are needed on the health risks associated with exposure to engineered nanomaterials. Results of the existing studies on animals and humans, focusing on the exposure and response to ultrafine or other respirable particles, provide a basis for preliminary estimates of the possible adverse health effects from exposure to similar engineered materials on a nanoscale. Experimental studies in rodents and cell cultures have shown that the toxicity of ultrafine particles or nanoparticles is greater than that of the same mass of larger particles of similar chemical composition (Oberdörster, et al. 1992; Oberdörster, et al. 1994a; Oberdörster, et al. 1994b; Tran, et al. 2000; Brown, et al. 2001; Barlow, et al. 2005; Duffin, et al. 2007). Along with particle surface area, other particle characteristics may affect toxicity, including surface functionalization or coatings, solubility, shape, and the ability to generate oxidant species and to adsorb biological proteins or bind to receptors (Duffin, et al. 2002; also see Oberdörster, et al. 2005 and Donaldson, et al. 2006, both cited under Toxicity of Carbon Nanomaterials). There are many unknowns as to whether the unique properties of engineered nanomaterials pose health concerns. The potential health risk following exposure to a substance is generally associated with magnitude and duration of the exposure, persistence of the material in the body, inherent toxicity of the material, and susceptibility or health status of the person.

                                                                                                                          • Barlow, Peter G., Ken Donaldson, Janis MacCallum, Anna Clouter, and Vicki Stone. 2005. Serum exposed to nanoparticle carbon black displays increased potential to induce macrophage migration. Toxicology Letters 155.3: 397–401.

                                                                                                                            DOI: 10.1186/1743-8977-2-11Save Citation »Export Citation »E-mail Citation »

                                                                                                                            High doses of nanoparticle carbon black have the capability to cause chemotactic factor generation in serum by reactive oxygen species (ROS) generation, although ROS alone, in the form of tert-butyl hydroperoxide (tBHP), are insufficient to generate chemotactic factors in serum.

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                                                                                                                            • Brown, David M., Martin R. Wilson, William MacNee, Vicki Stone, and Ken Donaldson. 2001. Size-dependent proinflammatory effects of ultrafine polystyrene particles: A role for surface area and oxidative stress in the enhanced activity of ultrafines. Toxicology and Applied Pharmacology 175.3: 191–199.

                                                                                                                              DOI: 10.1006/taap.2001.9240Save Citation »Export Citation »E-mail Citation »

                                                                                                                              In the animal model, demonstration showed that there was a significantly greater neutrophil influx into the rat lung after instillation of 64 nanometer (nm) polystyrene particles compared with 202 and 535 nm particles, and that this was mirrored in other parameters of lung inflammation, such as increased protein and lactate dehydrogenase in bronchoalveolar lavage.

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                                                                                                                              • Duffin, Rodger, Lang Tran, David Brown, Vicki Stone, and Ken Donaldson. 2007. Proinflammogenic effects of low-toxicity and metal nanoparticles in vivo and in vitro: Highlighting the role of particle surface area and surface reactivity. Inhalation Toxicology 19.10: 849–856.

                                                                                                                                DOI: 10.1080/08958370701479323Save Citation »Export Citation »E-mail Citation »

                                                                                                                                Instillation studies revealed the importance of surface area alone as the biologically effective dose for low-toxicity dusts, and surface area times surface reactivity as the biologically effective dose for insoluble particles with a reactive surface.

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                                                                                                                                • Duffin, Rodger, C. Lang Tran, Anna Clouter, et al. 2002. The importance of surface area and specific reactivity in the acute pulmonary inflammatory response to particles. Annals of Occupational Hygiene 46.S1: 242–245.

                                                                                                                                  DOI: 10.1093/annhyg/46.suppl_1.242Save Citation »Export Citation »E-mail Citation »

                                                                                                                                  Particle characteristics may affect toxicity, such as surface functionalization or coatings, solubility, or shape.

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                                                                                                                                  • Oberdörster, Günter, Juraj Ferin, Robert Gelein, Sidney C. Soderholm, and Jacob Finkelstein. 1992. Role of the alveolar macrophage in lung injury: Studies with ultrafine particles. Environmental Health Perspectives 97 (July): 193–199.

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                                                                                                                                    The increased pulmonary toxicity of ultrafine particles is related to their larger surface area and their increased interstitial access.

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                                                                                                                                    • Oberdörster, Günter, Juraj Ferin, and Bruce E. Lehnert. 1994a. Correlation between particle size, in vivo particle persistence, and lung injury. In Special issue: Biopersistence of respirable synthetic fibers and minerals. Environmental Health Perspectives 102.S5: 173–179.

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                                                                                                                                      Discusses the respiratory damages induced by the ultrafine particles and nanoparticles.

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                                                                                                                                      • Oberdörster, Günter, Juraj Ferin, Sidney Soderholm, et al. 1994b. Increased pulmonary toxicity of inhaled ultrafine particles: Due to lung overload alone? Annals of Occupational Hygiene 38.S1: 295–302.

                                                                                                                                        DOI: 10.1093/annhyg/38.inhaled_particles_VII.295Save Citation »Export Citation »E-mail Citation »

                                                                                                                                        The toxicity of ultrafine particles or nanoparticles is greater than that of the same mass of larger particles of similar chemical composition.

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                                                                                                                                        • Tran, C. Lang, Duncan Buchanan, Richard T. Cullen, Alison Searl, A. D. Jones, and Ken Donaldson. 2000. Inhalation of poorly soluble particles II: Influence of particle surface area on inflammation and clearance. Inhalation Toxicology 12.12: 1113–1126.

                                                                                                                                          DOI: 10.1080/08958370050166796Save Citation »Export Citation »E-mail Citation »

                                                                                                                                          Ultrafine particles may also affect a greater surface area in the lung, causing more inflammation than larger particles.

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                                                                                                                                          Handling of Nanoparticles

                                                                                                                                          A few organizations, such as National Institute of Occupational Safety and Health, have started an active program for studying the safe handling of nanomaterials in the workplace. How are workers potentially exposed to nanomaterials, and, if so, what are the characteristics and levels of exposure and how do these affect workers’ health? What work practices, personal protective equipment (PPE), and engineering controls are available, and how effective are they for controlling exposures to nanomaterials (Schulte and Salamanca-Buentello 2007)? During manufacture and handling of these materials, there may be a chance of release and exposure of nanoparticles to workers, which may enter their body through inhalation, dermal contact, or ingestion routes (Dreher 2004). Only limited information on the risks of handling these materials is available, so workers should implement strict control procedures and engineering safety features to limit exposure when working with nanoparticles and should not be allowed to eat or drink in the laboratory. While handling nanomaterials, they should use laboratory safety measures such as PPE, including gloves, lab coats, safety glasses, face shields, and closed-toe shoes, to avoid skin contact with nanoparticles or nanoparticle-containing solutions (Feder 2004). If it is necessary to handle nanoparticle powders within an exhaust laminar-flow hood, workers must wear appropriate respiratory protection. The use of fume exhaust hoods to expel fumes from tube furnaces or chemical-reaction vessels is crucial. Laboratory personnel should be trained and made aware of the risk associated with workplace hazards, through periodically reviewing Material Safety Data Sheets (MSDS), labeling, and signage. Disposal of nanoparticles also reflects on the safety of the environment, and such disposal should be done in accordance with guidelines for handling hazardous chemical waste.

                                                                                                                                          • Dreher, Kevin L. 2004. Health and environmental impact of nanotechnology: Toxicological assessment of manufactured nanoparticles. Toxicological Sciences 77.1: 3–5.

                                                                                                                                            DOI: 10.1093/toxsci/kfh041Save Citation »Export Citation »E-mail Citation »

                                                                                                                                            During manufacture and handling of nanomaterials, there is a chance of release of and human exposure to nanoparticles, which may enter workers’ bodies through inhalation, dermal contact, or ingestion routes.

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                                                                                                                                            • Feder, Barnaby J. 2004. Health concerns in nanotechnology. New York Times, 29 March.

                                                                                                                                              DOI: 10.4236/jmmce.2010.95031Save Citation »Export Citation »E-mail Citation »

                                                                                                                                              Nanoparticles can enter the brain and destroy lipid cells, the most common form of brain tissue. Eva Oberdörster, an environmental toxicologist, reported that buckminsterfullerenes (buckyballs) also altered the behavior of genes in liver cells of the juvenile largemouth bass.

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                                                                                                                                              • Schulte, Paul A., and Fabio Salamanca-Buentello. 2007. Ethical and scientific issues of nanotechnology in the workplace. Environmental Health Perspectives 115.1: 5–12.

                                                                                                                                                DOI: 10.1289/ehp.9456Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                Discusses the potential health effects of occupational exposure to nanoparticles, contending that a need exists for guidance in decision making about hazards, risks, and controls.

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                                                                                                                                                Ethics

                                                                                                                                                Due to the lack of research on the potential health effects of occupational exposure to nanoparticles, there is an urgent need to study such health effects, ideally leading to the regulation of any hazards and risks, and the implementation of effective controls. Identification of the ethical issues involved may be valuable in such regulation and decision making, particularly in regard to employees, workers, investors, and health authorities. Because the aim of occupational safety and health is the prevention of injury and disease in workers, the situations that have ethical implications that most affect workers have been identified. As these ethical issues are identified and explored, options for decision makers can be developed. Additionally, societal discussions about workplace risks of nanotechnologies may be enhanced by placing special emphasis on small businesses and the adoption of a global perspective.

                                                                                                                                                • Schulte, Paul A., and Fabio Salamanca-Buentello. 2007. Ethical and scientific issues of nanotechnology in the workplace. Environmental Health Perspectives 115.1: 5–12.

                                                                                                                                                  DOI: 10.1289/ehp.9456Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                  Relevant ethical issues involve the determination of hazards and risks, autonomy, justice, privacy, and promoting respect for persons.

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