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NanoSafetyCluster - Compendium 2012 The specific scientific and technical objectives are: [1] To synthesise and fully characterise a set of engineered nanoparticles with a range of physicochemical properties using industrial and laboratory methods. [2] To study the abiotic reactivity (transformations) of the synthesised nanoparticles in simulated environmental and biological media. [3] To investigate in vivo uptake of nanoparticles by aquatic species and study mechanisms and paths of internalisation. [4] To investigate in vitro uptake and reactivity of nanoparticles and to discover putative mechanisms of toxicity. [5] To consider the genotoxicity and carcinogenicity of metal nanoparticles. [6] To determine whether cellular responses between human cells, mammalian cells, cell lines and invertebrate cells or whole organisms are comparable or different with relevance to screening models. [7] To establish universal approaches to risk assessment model and risk communication. 2 Background The physicochemical properties of nano-sized particles are distinct from the properties of equivalent bulk substances. As the use of nanomaterials increases, the research into any potential risks of adverse effects on the environment and/or health must be intensified. Concerns on free engineered nanoparticles have been highlighted in several reports, including those by the Royal Society and the Royal Academy of Engineering in the UK (2004), the EPA’s Nanotechnology White Paper (2005), the European Commission’s Action Plan for Nanotechnology (2006), and the Royal Commission on Environmental Pollution (2008). All expressed unease over the apparent lack of urgency (at the time of the reports) in identifying the extent of the potential risks. Indications of the potential toxicity of engineered nanoparticles can be drawn from epidemiological studies of inhaled environmental particulate matter in humans. These show that one of the primary target organs, in this case the lung, cannot necessarily defend other body systems from the effects of inhaling very small, ultrafine, nanosized material. Consequently, the cardiovasculature is also affected. Indications from these human studies are that particles may enter the circulation and translocate to other organs and/or that there are “knock-on” systemic effects due to locally produced pro-inflammatory and pro-thrombotic mediators. Clearly, other mechanisms may exist. Studies in experimental animals suggest that inhaled nano-sized particles relocate to the brain, vasculature, liver, kidney and spleen. Similarly, intravenous nanoparticles can access multiple organs including the foetus1. Other important portals of entry of exogenous nano-substances are the skin and gastrointestinal tract. Furthermore, there is in vivo evidence that activation of specific body compartments by some nanoparticles can initiate both local and systemic reactivity. All these findings may have serious implications for human health. What is not known is which engineered particle(s) induce cellular reactivity, how and where this might occur. The rapid expansion of nanotechnology means there is a vast array of nanomaterials, many of which are already in industrial production. Because of the wide variety in physicochemical properties amongst different nanomaterials it is not possible at present to predict which elicit human and/or environmental harm. However, until the mechanistic associations between nanomaterial characteristics and putative toxicity are understood, determination of nanorisks will not move forward. Many recent toxicological studies have fallen short of this; furthermore many studies have led to contrasting results and interpretations about risks, possibly reflecting the diverse sources and nature of the test materials. This illustrates the importance of studying commercial and designer particles that have been fully characterised before, during and after toxicity studies. Of the many different types of engineered nanoparticles currently produced, industrially or in the laboratory, environmental risks from non-carbon-based nanoparticles are the least studied. This is despite the rapidly growing use of particles such as TiO 2, ZnO, SiO 2, Ag, CuO, and CdS. The chemical composition of metal nanoparticles may contribute to their having significant additional toxicity, but few studies address this. Ecotoxicological studies with engineered nanomaterials are currently limited. Most of the studies so far undertaken are simple “proof of principle” tests evaluating the possibility of either toxicity, under high concentration exposures, and/or the visual penetration of cells. There is a clear need for a more systematic approach to evaluating the processes that determine hazard, exposure and risk and for validated models predicting the release, transport, transformation, accumulation and uptake of nanoparticles in the environment and the human body. 3 What is NanoReTox The overriding objective of NanoReTox is to contribute new knowledge to what will be a global endeavour in addressing the scientific uncertainties related to the health and environmental effects of engineered nanoparticles and to provide a body of new information and a new tool that industry and governments can use to begin to assess the risks of these nanomaterials. Thus, NanoReTox aims to identify the potential risks of free engineered metal nanoparticles to the environment and human health, and address a great deal of the issues described earlier. More specifically: NanoReTox intends to examine the molecular and cellular reactivity of well characterised nanoparticles on a panel of primary human/mammalian cells and human cell lines originating from different target organs and exposure routes as an indicator of in vivo toxicity. The aim is to discover which features of nanoparticles confer reactivity with which cell types/target organs. NanoReTox will comprehensively address all physicochemical properties of industrially important metal based nanoparticles with a potential to induce toxicity (particle size, size distribution, shape, agglomeration state, crystal phase, chemical composition, surface area, surface chemistry and surface charge). By using labeled particles (with either stable isotopes or fluorescent dyes), NanoReTox will quantitatively determine the accumulated NPs in in vitro and in vivo systems. These techniques literally resolve the problem of determining nanoparticle bioavailability. 168 Compendium of Projects in the European NanoSafety Cluster
NanoReTox will compare animal models that are likely to be sensitive to nano-materials: animals that pump vast quantities of water across their gills (bivalves) or ingest plants or sediments where nanomaterials are likely to accumulate. NanoReTox will use determinations of biodynamic characteristics, including rate of uptake from water, assimilation efficiency and rate of uptake from food, as well as retention (rate constant of loss), across several species and a range of particles. This screening approach (equivalent to a biological bioavailability probe) will increase the number of particle formulations and characteristics that can be compared. The biodynamic studies will be complemented by longer term experiments with fewer particle types to verify probe results. By quantifying nanoparticle uptake using labelling, verifying the presence of particles in cells with visual or light scattering approaches, and observing responses of the organism at the cellular and whole organism level, we will assemble the lines of evidence that are necessary to determine if bioavailability and toxicity are feasible expectations for the metal nanoparticles. By systematically making such determinations using a number of different types of particles of well-defined character we will tie together nanoparticle properties with their bioavailability and toxicity in unique ways. NanoReTox will also provide comparative data between mammalian systems and non-mammalian systems by using isotopic methods in the mammalian systems. This will provide unique data regarding the relationship between particle physicochemistry, bioavailability, cellular uptake and reactivity across a range of relevant target cell systems. Finally, NanoReTox has been employing the extensive experience within the partnership, and a specific work package devoted to risk assessment and risk communication to develop appropriate criteria, considering factors that have, historically, generated surprising risks in the past. 3.1 The three principles of NanoReTox • Focus on engineered metal nanoparticles, synthesised and fully characterised by project partners (both research & industry), to provide a coherent well defined study material with controllable properties. The project will not consider natural or other non-engineered (e.g. combustion derived) nanoparticles. • Use of organisms that are not currently included in standard toxicity tests, but which have (a) greater potential to be affected by nanoparticle toxicity due to the environment where they live or their biology and (b) are potentially valuable indicators. • Minimal use of animal models in keeping with the 7th Amendment to the EU Cosmetics Directive (European Commission, 2003; Council Directive 76/768/EEC) which aims to reduce the use of experimental animal research. NanoSafetyCluster - Compendium 2012 4 Organisation of NanoReTox NanoReTox is devided into six inter-related and interconnected work packages (WPs, see graph below) and is funded for the period 2008 to 2012. Consortium Management WP9 Abiotic Reactivity WP2 Public outreach NP Synthesis and characterisation WP1 In vivo exposure, aquatic WP3 In vitro exposure, aquatic WP4 Interlinkages, comparisons WP7 Risk assessment, communication WP8 Legislators, industry In vitro exposure, mammalian WP5 4.1 WP 1: Synthesis and characterisation Carcinogenicity/genotoxicity WP6 Scientific publications This workpackage is generating sets of well-characterized nanoparticles using different methods of synthesis. The nanoparticle sets are tailored to display a range of physicochemical properties of interest. In order to establish that the nanoparticles tested by NanoReTox are representative of what is currently and in the future released in the environment, both top down (i.e. nanoparticles produced from bulk materials by milling) as well as bottom up (wet chemical, plasma and microfluidic synthesis), so that many important routes of synthesis are represented. This “inhouse” “tailored” synthesis is essential for materials of this nature, because unlike conventional chemical toxins (where a solution of a particular substance will have the same properties regardless of the way it was produced or its source) nanoparticle properties can vary substantially depending on the method of synthesis and subsequent functionalisation. This approach is complementary to that of the OECD Working Party on Manufactured Nanomaterials, by placing emphasis on the controlled variation of properties. The particles being tested are: TiO 2, SiO 2, ZnO, CuO, CdS, Ag (Figure 1) and Au. The nanomaterials studied in NanoReTox are extensively characterised using analytical and biochemical techniques such as Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Dynamic Light Scattering (DLS) and Zeta Potential Analysis (ZPA), Single Particle Tracing (SPT), Gel Filtration (GF), Fast Protein Liquid Chromatography (FPLC), Scanning Electron Microscopy (SEM), Transmitted Electron Microscopy (TEM), Atomic Force Microscopy (AFM) in both wet and dry mode, X-ray Diffraction (XRD) and surface area analysis (BET). Multicollector ICP-MS is available for analyses of labelled nanoparticle isotopic composition. Focused Ion Beam Scanning Electron Microscopy for visualising the nanomaterials produced and their inner structure. X-ray Photoelectron Spectroscopy (XPS) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF SIMS) for nanoparticle surface composition. Compendium of Projects in the European NanoSafety Cluster 169
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Compendium of Projects in the Europ
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EDITED BY Michael Riediker, PD Dr.s
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CONTENTS NanoSafetyCluster - Compen
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Project Acronym ENNSATOX ENPRA EURO
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Foreword NanoSafetyCluster - Compen
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ENNSATOX ENgineered Nanoparticle Im
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The biological membrane and its dep
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distinguishes between the interacti
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Figure 10. Schematic representation
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WP5: • Permeability of NPs in hyd
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NanoSafetyCluster - Compendium 2012
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ENPRA RISK ASSESSMENT OF ENGINEERED
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vitro findings with in vivo models;
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protocols with real biological samp
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and it was organised in the frame o
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First Name Last Name Affiliation Ad
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EURO-NanoTox European Center for Na
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silver nanoparticles, iron nanopart
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The core functions of the Center, h
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8 Directory Table 1 Directory of pe
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HINAMOX Health Impact of Engineered
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High Resolution Electron Microscopy
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integrated risk assessment. Integra
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powders: What is the difference in
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InLiveTox Intestinal, Liver and End
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- to develop and validate a novel m
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environments, IEEE Industrial Elect
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INSTANT Innovative Sensor for the f
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complementary research which will l
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7 Copyright NanoSafetyCluster - Com
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ITS-NANO Intelligent testing strate
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approach to conveying the appropria
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in the discussion. The integration
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MARINA MANAGING RISKS of NANOMATERI
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for risk analysis, these tools need
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environmental ENM toxicity, but tox
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propose it as a Method Validation F
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and SiO2-NM200 and NM203, and a SiO
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ModNanoTox Modelling nanoparticle t
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3) To model environmental exposure
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Nanodetector European Network on th
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measurement interval. Measurements
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5 Directory Table 1 Directory of pe
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NANODEVICE Novel Concepts, Methods,
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ENP in order to be sure of their sa
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4.3 Exploring the association betwe
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NanoFATE Nanoparticle Fate Assessme
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or proteins associated with particu
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sludge. Information on rates of slu
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The exposures to be conducted will
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NanoFATE progression beyond the “
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Timing, hosts and locations of (grouped) events of NanoImpactNet

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