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NanoSafetyCluster - Compendium 2012 DNA level? 3) Do nanoparticles interfere with cell proliferation? 4) Do nanoparticles induce cell transformation? 5) Do the genotoxic effects of nanoparticles vary between individuals and between species? 6) Which physicochemical properties of nanoparticles render them more/less genotoxic. The chosen cell models in this WP have been fully characterised and are based on human leukocyte cultures (obtained from healthy volunteers), and on cell lines relevant to occupational and environmental exposure (Figure 3). The A549 (human lung epithelial) cells will model the inhalation processes and the RAW264.7 murine macrophage cell line will model the inflammatory process. In vivo studies will concentrate in zebrafish liver as this small tropical fish species is a well-known model for hepatocarcinogenesis. In addition, possible carcinogenic effects arealso studied in mussels, where haemic or haemocytic neoplasia and gonadal neoplasia have been reported. Figure 3. Top: Genotoxicity endpoints evaluated by CBMN Cytome assay in primary human lymphocytes after treatment with nanoparticles. Bottom: damage evaluated by Comet assay in primary human lymphocytes after treatment with nanoparticles. 4.7 WP 7: Interpretative comparison and interlinkage of reactivity, bioavailability and health effects Using data collected in all previous WPs, this WP compares species, particles of differing nature, as well as human and aquatic organism responses. A variety of datasets will be produced. This work package provides a specific effort dedicated to finding commonalities among the different studies so as to maximize generalizations and applications to risk assessment. For example, many properties of cells are biologically conservative: that is, many similar mechanisms characterize the functioning of cells of all life forms. If there are commonalities in the way humans and other organisms react to nanoparticles then universal methods might be developed to both detect and better understand nanorisks. Specific questions addressed will include: 1) Do organisms differ from humans or among species in their stress responses and/or sensitivity? 2) Can we use abiotic reactivity to predict toxicity? 3) Is in vitro dose response to metal nanoparticles indicative of in vivo responses? 4) Is there a pattern of cellular reactivity and/or toxicity related to physicochemical properties, i.e. a hierarchy of activity? 4.8 WP 8: Risk model and communication Risk assessment: Ultimately a formal assessment of nanoparticle risks is essential. NanoReTox, in one study, addresses multiple nanoparticle formulations, in multiple media, using multiple species (including humans) and employing in vitro and in vivo approaches. The goal of WP8 is to incorporate this broad set of data from a single study into a risk assessment. Though there is increasing attention toward studying human health risks from nanoparticles, a common framework for conducting risk assessments is lacking. Information on environmental risks associated with nanoparticles, and particularly metallic nanoparticles, is scarce. An important outcome of the project will be development of a conceptual model to guide evaluation of hazards and risks from nanoparticles. Because our studies build a basis for evaluating risks, assessing what our results mean in a systematic way is necessary. The model will be developed to be applicable to the body of evidence that will surely grow quickly as knowledge of nano-materials grows. Risk communication: The profile of nanotechnology and any associated risk is high in the media; so inadvertent miscommunication is possible. Another goal of NanoReTox is to develop a risk communication strategy that will guide how we release our results, but more important help recipients of our results (government, industry) communicate risks in a balanced, robust manner. It is essential to “get the risks from nanoparticles right” because the technology offers many potential benefits. The costs of over-stating or under-stating risks could be high. Although general risk assessment procedures are well known, there are many unique attributes of nanoparticles that may require new or adjusted methodologies. Communicating new results in an unbiased, balanced and value free way is critical to public credibility. Communicating risks appropriately also requires a holistic view of the issues, as well as a careful, rational and transparent approach. 4.9 WP 9: Project management All aspects of project mangement are covered by this WP, including reporting, quality control, progress meetings, 172 Compendium of Projects in the European NanoSafety Cluster
financial/administrative coordination cost control, deadlines, contacts with the EU and dissemination. 5 NanoReTox Results During its first three years, NanoReTox has produced the following key results: 5.1 Results from WP1 and WP2 WP1 has produced a range of well-characterised sets of ZnO, CuO, TiO 2, SiO 2, Ag, Au and CdS nanoparticles. Some of the particles were produced by the industry partners and some tailored to show properties that vary systematically, so that robust links to toxicity can be made. Reproducible protocols for all the syntheses have been developed and the produced sets of nanoparticles were thoroughly characterised and tested in a variety of (eco)toxicity experiments in subsequent WPs. WP2 tested the stability of the above particles in a variety of conditions, with the aim to understand their behaviour in biological/environmental media as well as their overall physicochemical response to changes of conditions such as temperature, pH and ionic strength. Major findings include: a) dissolution results, which indicated increased ion release of metal ions from CuO and ZnO nanoparticles compared to their bulk counterparts, while TiO 2 remains relatively insoluble; b) the effect of temperature which appears to be reversible, i.e. an increase in size is observed while the samples are heated, suggesting aggregation, but temperature decrease is sufficient to redisperse the particles; c) the behaviour of nanoparticles in different media shows different patterns depending on the composition of the nanoparticles and the type of stabilisation; however a common feature is aggregation even at modest increases in ionic strength; the presence of organics, humic acid or albumin, induces moderate aggregation. 5.2 Results from WP3 and WP4 The main objective of these two WPs was to test nanoparticle toxicity on a selection of aquatic organisms and conditions in vivo and in vitro. In WP3 (in vivo), a wide range of species belonging to different taxonomic groups and with different biological traits were tested: Bivalve molluscs (Scrobicularia plana, Mytilus galloprovincialis, Macoma balthica), a gastropod (Peringia ulvae), two species of polychaetes (Nereis diversicolor, Capitella teleta) as representatives of the estuarine and marine environment and three freshwater species, two gastropods (Potamopyrgus antipodarum, Lynamaea stagnalis) and zebrafish (Danio rerio, embryos). The experiments included food, water- and sedimentexposure treatments. Toxicity endpoints included both subindividual-level effects (biomarkers) and individual-level effects (mortality/survival, hatching, reproduction, malformations, behaviour, feeding rate). A number of particles from a variety of sources and a wide range of doses have already been tested (CuO, Ag, Au, TiO 2, ZnO) and produced the following findings: (1) a set of preliminary indications of ecotoxicity (oxidative-stress, genotoxicity, cytotoxicity, behaviour impairments, malformations, mortality, reproduction, hatching), as a function of nanoparticle NanoSafetyCluster - Compendium 2012 properties, (2) demonstration that all of the metal forms (ionic, NPs, bulk) were bioavailable and bioaccumulated by some organisms, even of aggregated NPs in seawater; (3) demonstration that metal containing NPs yield bioavailable metals, more so than bulk or micron sized particles; (4) usually in water-exposure treatment, ionic forms were more bioavailable and/or toxic than NPs. Bioavailability of Ag from citrate-capped Ag NPs in Peringia ulvae was 2 fold less bioavailable than dissolved Ag. In Zebrafish embryos, ionic silver was the most toxic compound, (5) a detectable release in exposure medium of Ag from lactose-AgNPs has been shown whereas no detectable release of metal was observed with citrate-Ag NPs or CuO NPs (6) a particle size-related differences in bioavailablity and toxicity effects has been observed in the case of Ag NPs; the smallest ones were the most toxic in Zebrafish embryos. For mollusks, uptake rates in P. antipodarum were faster for the smaller-sized Cu particles. In contrast, the biggest Au NPs induced higher bioaccumulation than smaller ones in S. plana. However, AgNPs-size did not affect bioaccumulation in both polychaetes species (N. diversicolor, C. teleta), (6) differences in bioavailability and toxicity according to the routes of exposure: the response of biomarkers of defence in S. plana was more important after dietary than after waterborne exposure to Ag. In the snail (L. stagnalis) 67 Zn was assimilated from 67 ZnO NPs mixed with diatoms food and the mixture inhibits ingestion rates in animals at higher Zn concentrations, (7) the stable isotope tracing approach is suitable to explore ecotoxicity effects of NPs ( 67 ZnO) in environmentally realistic conditions (8) establishing of interspecies differences in bioaccumulation and toxicity effects that may be particle specific, however the species most sensitive to one type are not necessary most sensitive to another type. 5.3 Results from WP5 and WP6 In vitro models were used to examine cellular responses to nanoparticles. The work was based on the hypothesis that the cellular reactivity of the particles will critically depend both on the target tissue and the function of the cell type within that tissue. Cellular and molecular reactivity of selected metal nanoparticles were investigated in a) primary mammalian and human cells and b) in a panel of established human cell lines. .A relatively wide range of tissue sources have been covered, to include the lung, skin, immune blood cells, gut, kidney and liver. A wide range of doses of the nanoparticles were studied, between 0.1 and 100μg/ml for all the studies except those on the human skin organ model, where the doses were increased to 100,000 μg/ml topically, and 800μg/ml systemically, to represent that used in sunscreen products. Key findings include: a) In studies of lung and skin models (Imperial and DSL), which investigated cytotoxicity (MTT assay), oxidative stress (ROS and glutathione levels) and release of pro-inflammatory mediators (IL-6, IL-8, MCP-1 and TNFα), TiO 2 was found to have very little adverse reactivity, regardless of whether it was in the bulk form (BAN, BRU), mixed bulk and nanoparticles (INT), or nanoparticles (TiO 2 1-4, TiO 2 10, 50 and 100nm, P25). In studies of lung and skin cells with Au 5, 15 and 40nm, again, the particles had no significant adverse effects with respect to the above indices. b) In a colony forming efficiency assay, CFE, 5 cell lines were studied, A549, Balb/3T3, MDCK, HepG2 and Caco-2 representing lung, kidney, liver and gut. TiO 2 10, 50 and 100nm, and Au 5, 15 and 40nm, were studied. There was no effect of the TiO2, regardless of size. Neither was there any effect of Au 15 and 40. Interestingly, Au 5 caused a striking dose-related loss of Compendium of Projects in the European NanoSafety Cluster 173
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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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