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      Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy


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          The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents the elements of a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics, In Vitro Assays (cellular and non-cellular), and In Vivo Assays.

          There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity.

          In vitro techniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible in in vivo tests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered.

          Tier 1 in vivo assays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies.

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          Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

          Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.
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            Probing the Cytotoxicity of Semiconductor Quantum Dots

            With their bright, photostable fluorescence, semiconductor quantum dots show promise as alternatives to organic dyes for biological labeling. Questions about their potential cytotoxicity, however, remain unanswered. While cytotoxicity of bulk cadmium selenide (CdSe) is well documented, a number of groups have suggested that CdSe QDs are cytocompatible, at least with some immortalized cell lines. Using primary hepatocytes as a liver model, we found that CdSe-core QDs were indeed acutely toxic under certain conditions. Specifically, we found that the cytotoxicity of QDs was modulated by processing parameters during synthesis, exposure to ultraviolet light, and surface coatings. Our data further suggests that cytotoxicity correlates with the liberation of free Cd2+ ions due to deterioration of the CdSe lattice. When appropriately coated, CdSe-core QDs can be rendered non-toxic and used to track cell migration and reorganization in vitro. Our results inform design criteria for the use of QDs in vitro and especially in vivo where deterioration over time may occur.
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              Long-circulating and target-specific nanoparticles: theory to practice.

              The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

                Author and article information

                Part Fibre Toxicol
                Particle and Fibre Toxicology
                BioMed Central (London )
                6 October 2005
                : 2
                : 8
                [1 ]Department of Environmental Medicine, University of Rochester, 601 Elmwood Avenue, P.O. Box EHSC, Rochester, NY 14642, USA
                [2 ]Project on Emerging Nanotechnologies, Woodrow Wilson International Center for Scholars, 1300 Pennsylvania Avenue, N.W., Washington, DC 20004-3027, USA
                [3 ]MRC/University of Edinburgh Centre for Inflammation Research, ELEGI Colt Laboratory Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
                [4 ]Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA
                [5 ]Risk Science Institute, ILSI Research Foundation, International Life Sciences Institute, One Thomas Circle, N.W., Suite 900, Washington, DC 20005-5802, USA
                [6 ]Center for Biological and Environmental Nanotechnology, MS-63, P.O. Box 1892, Rice University, Houston, TX 77251-1892, USA
                [7 ]Respiratory/Inhalation Toxicology, Central Product Safety, Procter & Gamble Company, PO Box 538707, Cincinnati, OH 45253-8707, USA
                [8 ]Office of Research and Development, United States Environmental Protection Agency, Ariel Rios Building, Mail Code: 8722F, 1200 Pennsylvania Avenue, N.W., Washington, DC 20460, USA
                [9 ]Project on Emerging Nanotechnologies, Woodrow Wilson International Center for Scholars, 1300 Pennsylvania Avenue, N.W., Washington, DC 20004-3027, USA
                [10 ]Institute for Inhalation Biology & Focus Network: Aerosols and Health, GSF National Research Centre for Environment and Health, Ingolstadter Landstrasse 1, 85764 Neuherberg, Munich, Germany
                [11 ]Risk Assessment Division, Office of Pollution Prevention & Toxics, United States Environmental Protection Agency, 7403M, 1200 Pennsylvania Avenue, N.W., Washington, DC 20460, USA
                [12 ]Center for Chemical Toxicology and Research Pharmacokinetics, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA
                [13 ]DuPont Haskell Laboratory for Health and Environmental Sciences, P.O. Box 50, 1090 Elkton Road, Newark, DE 19714-0050, USA
                [14 ]Department of Chemical Engineering, University of Rochester, Gavett Hall 253, Rochester, NY 14627, USA
                Copyright © 2005 Oberdörster et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 3 October 2005
                : 6 October 2005



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