Timing, hosts and locations of (grouped) events of NanoImpactNet

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NanoSafetyCluster - Compendium 2012 nanomaterials. Risk assessment will be performed in close collaboration between all consortium members. Members of our consortium possess considerable expertise in Physiologically- Based-Pharmaco-Kinetics (PBPK) modelling. These models can be extended to incorporate the variability seen in animal data and the uncertainty due to lack of knowledge, an important feature of risk assessment. PBPK models have been used in describing the distribution of the internal dose across different target organs. The target organ dose is better correlated with the biological responses than the external exposure. As acknowledged by SCENIHR (2007), there is currently no established PBPK model for the distribution of nanoparticles in the body. In this project, we plan to extend this model, based on the inhalation mode of exposure, to other exposure routes such as intravenous injection and dermal exposure, thus taking it beyond the current state-ofthe-art. (Q)SAR [(Quantitative) Structure-Activity Relationship)] is the quantitative correlation of the biological (ecological, toxicological or pharmacological) activity to the structure of chemical compounds, which allows the prediction of the so-called "drug efficacy" of a structurally related compound. (Q)SAR is highly desirable as an approach which could replace extensive animal testing. To date, few attempts at (Q)SAR modeling were made for ENs. However, a (Q)SAR-like model, linking the particle physico-chemical characteristics with the immune response to nanoparticles is highly desirable because it helps to better understand the dose-response relationship, and to mitigate hazard with better designs for manufactured nanoparticles, by supplying important information on particle characteristics. Our approach will thus combine the immune hazard data (in vitro and in vivo) and modelling generated in this project with further information on exposure obtained in the public domain and other ongoing research projects, to develop a strategy for risk assessment of nanomaterials. In synopsis, our multidisciplinary approach will contribute to the elucidation of the hazardous effects of ENs on the immune system, and will allow us to perform reliable and sound assessment of the risks to human health posed by these materials. Our studies will benefit a) citizens, because we address issues related to human health; b) researchers, because we will generate new knowledge in material production, and on mechanisms of interaction of nanomaterials with biological systems; and c) industry (including SMEs), because we plan to incorporate our characterization protocols and risk assessment guidelines into a Quality Handbook (QHB), which can provide support to interested parties. Moreover, our consortium provides a template for collaborations between European and US institutes as demonstrated by several joint publciations. 2.4 Important achievements In the following sections, some important research results are highlighted (and see list below of selected publications from our consortium). 2.4.1 Interaction of carbon nanotubes with immunecompetent cells Biopersistence, tissue distribution, immune and inflammatory responses to SWCNT are largely dependent on their recognition and uptake by phagocytozing cells. Previous studies on macrophage recognition of apoptotic cells have revealed that the exposition of the phospholipid, phosphatidylserine (PS) on the surface of apoptotic cells serves as an important recognition signal for phagocytic cells (Fadeel and Xue, Crit. Rev. Biochem. Mol. Biol., 2009). Several partners of the NANOMMUNE consortium have now shown that SWCNT coating with the “eat-me” signal, PS makes nanotubes recognizable by macrophages, including primary human monocyte-derived macrophages and dendritic cells (Konduru et al., PLoS-ONE, 2009). Aspiration of PS-coated SWCNT in mice stimulated their uptake by alveolar macrophages in vivo. These studies also demonstrated that PS-coated SWCNT triggered less pro-inflammatory cytokine secretion than non-coated nanotubes. Enzymatic biodegradation of SWCNT by the plant enzyme, horseradish peroxidase has been reported by US partners belonging to the NANOMMUNE consortium (Allen et al., J. Am. Chem. Soc., 2009). In addition, several members of our consortium have recently demonstrated a novel route of biodegradation of SWCNT through enzymatic catalysis by human neutrophil-derived myeloperoxidase (hMPO) (Kagan et al., Nat. Nanotech., 2010). Biodegradation occurred in primary human neutrophils and to a lesser extent in macrophages. Biodegradation of SWCNT was enhanced when nanotubes were pre-coated with immunoglobulin (IgG) to promote neutrophil internalization of SWCNT through Fc receptors. Furthermore, using an established mouse model of pharyngeal aspiration of SWCNT, it was shown that biodegradation attenuated the characteristic inflammatory responses to carbon nanotubes. These findings strongly indicate that novel biomedical applications of carbon nanotubes may be achievable under conditions of carefully controlled biodegradation. More recently, our consortium has reported enhanced pulmonary inflammatory and fibrotic responses to SWCNT in myeloperoxidase-deficient mice (in press). These studies were co-funded by US funding agencies. 2.4.2 Gene expression profiling of nanoparticle-exposed cells and tissues Monitoring nanomaterial-induced immune responses by changes at the transcription level may be a valuable approach in terms of providing information on signalling pathways involved. One may assume that alterations in nanomaterial-induced gene expression can be rather subtle and, hence, focusing on discovery of biological pathways rather than individual genes is likely to provide a more informative view of the underlying processes. In the NANOMMUNE consortium, both in vitro (WP3) and in vivo (WP4) models are included for the characterization of immune responses using transcriptomics. The results will be used to generate novel hypotheses for further experimental testing and to describe nanomaterial and cell-specific changes in gene expression, i.e. to define novel “nanotoxicogenomic signatures”. In the first study (unpublished), cytotoxicity testing of two commonly used nanoparticles, ZnO and TiO 2 was performed using primary human macrophages and dendritic cells as well as the leukemic Jurkat cell line. Exposure to ZnO nanoparticles triggered a dose-dependent loss of cell viability. Transcriptomics analysis using Illumina Sentrix® HumanHT-12 Expression BeadChips disclosed that the expression of different metallothionein genes was significantly upregulated in all three cell types after exposure to ZnO. These findings are in accordance with the observation that ZnO nanoparticles undergo rapid dissolution in cell culture. Further 154 Compendium of Projects in the European NanoSafety Cluster
assessment of differentially expressed genes is ongoing. In a subsequent study, comprehensive transcriptomics analysis of murine tissues (lung, spleen, and blood) harvested at various timepoints post exposure to carbon-based nanomaterials including SWCNTs and fullerenes versus asbestos fibres are performed. These studies, conducted in collaboration between US and European partners, may reveal novel patterns of global gene expression – nanotoxicogenomic signatures – following in vivo exposure. 2.4.3 Mapping the surface adsorption forces of nanomaterials Recently, US participants in NANOMMUNE developed a biological surface adsorption index (BSAI) to predict the molecular interactions of nanoparticles with proteins (Xia et al. Nat Nanotech. 2010). A set of small molecule probes that mimic amino acid residues were allowed to competitively adsorb onto a set of nanoparticles and the adsorption coefficients for the probes were measured. By assuming the adsorption was governed by five basic molecular forces, the measured adsorption coefficients were used to develop descriptors that represent the relative contributions of each of the forces, which, in turn, could be used in an in silico model to predict the adsorption of small molecules to other nanomaterials. Moreover, we have reported on the successful measurement of the BSAI nano-descriptors for 16 different types of nanomaterials in a recent study carried out jointly with European and US partners (Xia et al. ACS-NANO, 2011). The 5dimensional nano-descriptor index describing the five types of molecular interactive forces was reduced to 2-dimensional via principal component analysis, which allows different nanomaterials to be clustered by their surface adsorption properties. 2.5 Conclusions The NANOMMUNE project spans from synthesis, procurement, and physico-chemical characterization of nanomaterials, to detailed in vitro and in vivo investigations, using relevant murine and human model systems to assess adverse effects on the immune system, to mathematical modelling and risk assessment. Our project is further augmented by state-of-the-art, highthroughput global transcriptomics and oxidative lipidomics approaches, to obtain “nanotoxicogenomic” signatures, and to define novel biomarkers of immunotoxic responses. Overall, the NANOMMUNE consortium has performed a comprehensive assessment of adverse immune effects of ENs in order to understand how the benefits of the emerging nanotechnologies can be realized while minimizing potential risks to human health. The consortium has collated Standard Operating Procedures (SOPs) in a NANOMMUNE Quality Handbook which we plan to make freely available to all interested parties via the Nanosafety Cluster. 2.6 Dissemination of results Results of the NANOMMUNE consortium were disseminated as follows: NanoSafetyCluster - Compendium 2012 • A public-access website has been developed as a principal portal of dissemination of our results (at the time of writing, 3930 unique visitors have visited the website). • Members of the consortium have presented scientific findings at numerous scientific conferences, and scientific findings and reviews are published in international peerreviewed journals (currently, more than 50 peer-reviewed papers). • Members of our consortium are actively involved in the organization of international conferences on nanotoxicology, including the 3 rd International Meeting on Nanotoxicology, Edinburgh, United Kingdom, 2010 (Dr. Lang Tran); 1 st Italian-Swedish Workshop on Health Impacts of Engineered Nanomaterials, Rome, Italy, 2010 (Dr. Bengt Fadeel); 2 nd Nobel Forum Mini-Symposium on Nanotoxicology, Stockholm, Sweden, 2010 (Dr. Bengt Fadeel), and the FP7-NANOMMUNE Closing Workshop in June 2011 in Stockholm to highlight key results of the consortium (Dr. Bengt Fadeel, and Project Manager, Dr. Erika Witasp). • Members of the consortium are also involved in the organization of the Nanosafety Autumn School on San Servolo Island, Venice, Italy (Dr. Lang Tran, Dr. Bengt Fadeel); the first in November 2009, and the second edition in October 2010. The course is open to students, post docs, and participants from government agencies, industry. The third edition was organized in 2011 in the frame of FP7-MARINA. • Dr. Bengt Fadeel was the main organizer of the 6 th Key Symposium on Nanomedicine, Stockholm, Sweden, 2009 (co-organized with the Royal Swedish Academy of Sciences; several NANOMMUNE members contributed as invited speakers). • In addition, other forms of dissemination were also considered. Hence, the project coordinator, Dr. Bengt Fadeel presented the NANOMMUNE project to a broad assembly of international journalists at press briefings hosted by the European Commission at the EURONANOFORUM in Prague, Czech Republic (2009); and the 6 th World Conference of Science Journalists, London, UK (2009). 2.7 Nanosafety Cluster activities The NANOMMUNE project has participated to the European Nanosafety Cluster, eg. Prof. Bengt Fadeel was involved in the initiation of the Immunosafety Task Force with Dr. Diana Boraschi, Italy, and Dr. Alfred Duschl, Austria. The task force is integrated into the WG on Nanomaterial Hazard in the European Nanosafety Cluster. 2.8 Selected publications • Witasp E, Kupferschmidt N, Bengtsson L, Hultenby K, Smedman C, Paulie S, Garcia-Bennett AE, Fadeel B. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or Compendium of Projects in the European NanoSafety Cluster 155
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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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