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Compared to the classical chemicals, nanoparticles (NPs) exhibit unique properties, which lead to challenges in sample preparation and analysis. Fractionation techniques and, in particular, hollow fiber flow field flow fractionation (HF5) have recently become popular in the characterization and quantification of nanomaterials, because of their fine fractionation capability in the nanoscale-range. When dealing with NPs, a great drawback during fractionation is the loss of particles in the fractionation devices, tubing and connectors. There is a need for studies to systematically explore and assess the quality of the fractionation process. A combination of two complementary mass-based setups was used to determine particle loss in HF5. Inductively coupled plasma mass spectrometry (ICP-MS) enabled the estimation of recovery rates for NPs after HF5 separation. Reciprocally, laser ablation ICP-MS (LA-ICP-MS) permitted the evaluation of particles retained on the hollow fiber. 15 nm Au-NPs in different concentrations were evaluated in this study and showed a recovery level for Au-NPs of 50 – 65% based on the applied concentrations after a complete HF5 separation run. Detection of sample deposition on the hollow fiber by LA-ICP-MS indicated a sample loss of about 8%. These findings are important for experiments relying on fractionation of low concentrated nanoparticulate samples.

The biomolecular imaging of cell-nanoparticle (NP) interactions using time-of-flight secondary ion mass spectrometry (ToF-SIMS) represents an evolving tool in nanotoxicology. In this study we present the three dimensional (3D) distribution of nanomaterials within biomolecular agglomerates using ToF-SIMS imaging. This novel approach was used to model the resistance of human alveolar A549 cells against gold (Au) ion toxicity through intra- and extracellular biomineralization. At low Au concentrations (≤1 mM HAuCl4) 3D-ToF-SIMS imaging reveals a homogenous intracellular distribution of Au-NPs in combination with polydisperse spherical NPs biomineralized in different layers on the cell surface. However, at higher precursor concentrations (≥2 mM) supplemented with biogenic spherical NPs as seeds, cells start to biosynthesize partially embedded long aspect ratio fiber-like Au nanostructures. Most interestingly, A549 cells seem to be able to sense the enhanced Au concentration. They change the chemical composition of the extracellular NP agglomerates from threonine-O-3-phosphate aureate to an arginine-Au(I)-imine. Furthermore they adopt the extracellular mineralization process from spheres to irregular structures to nanoribbons in a dose-dependent manner with increasing Au concentrations. The results achieved regarding size, shape and chemical specificity were cross checked by SEM-EDX and single particle (sp-)ICP-MS. Our findings demonstrate the potential of ToF-SIMS 3D imaging to better understand cell-NP interactions and their impact in nanotoxicology.

Nanomaterials (NMs) can be produced in plenty of variants posing several challenges for NM hazard and risk assessment. Metabolomic profiling of NM-treated cells and tissues allows for insights into underlying Mode-of-Action (MoA) and offers several advantages in this context. It supports the description of Adverse Outcome Pathways (AOPs) and, therefore, tailored AOP-based hazard testing strategies. Moreover, it bears great potential for biomarker discovery supporting toxicity prediction. Here, we applied metabolomics profiling to cells treated with four well-selected SiO

International audience; Aluminum (Al) is one of the most common elements in the earth crust and increasingly used in food, consumer products and packaging. Its hazard potential for humans is still not completely understood. Besides the metallic form, Al also exists as mineral, including the insoluble oxide, and in soluble ionic forms. Representatives of these three species, namely a metallic and an oxidic species of Al-containing nanoparticles and soluble aluminum chloride, were applied to human intestinal cell lines as models for the intestinal barrier. We characterized physicochemical particle parameters, protein corona composition, ion release and cellular uptake. Different in vitro assays were performed to determine potential effects and molecular modes of action related to the individual chemical species. For a deeper insight into signaling processes, microarray transcriptome analyses followed by bioinformatic data analysis were employed. The particulate Al species showed different solubility in biological media. Metallic Al nanoparticles released more ions than AlO nanoparticles, while AlCl showed a mixture of dissolved and agglomerated particulate entities in biological media. The protein corona composition differed between both nanoparticle species. Cellular uptake, investigated in transwell experiments, occurred predominantly in particulate form, whereas ionic Al was not taken up by intestinal cell lines. Transcellular transport was not observed. None of the Al species showed cytotoxic effects up to 200 µg Al/mL. The transcriptome analysis indicated mainly effects on oxidative stress pathways, xenobiotic metabolism and metal homeostasis. We have shown for the first time that intestinal cellular uptake of Al occurs preferably in the particle form, while toxicological effects appear to be ion-related.

Porous tantalum components are widely used for complex acetabular reconstructions in revision hip arthroplasty. Multiple other metal alloys such as titanium-aluminum-vanadium or cobalt-chromium-molybdenum are principally used in artificial joint setups. We report a case of tantalum component failure being both cause and effect of a multiple metal exposure. Our aims were to assess and to characterize associated particle exposure and biological consequences. Metal level quantification revealed substantial in vivo exposure to particulate and dissociated tantalum, zirconium, chromium, cobalt, molybdenum, titanium, aluminum and vanadium in periprosthetic compartments. Aside from micron-sized particles, nanoparticles of a broad size range and elemental composition were obtained. Histological exams verified a spectrum of necrotic changes in the periprosthetic tissues. In the presented case tantalum release was accompanied by concomitance of particles originating from other utilized metals. We conclude that an overall in vivo exposure assessment is mandatory for realistic appraisal of metal toxicity and associated risks.

Aluminum (Al) is extensively used for the production of different consumer products, agents, as well as pharmaceuticals. Studies that demonstrate neurotoxicity and a possible link to Alzheimer&rsquo, s disease trigger concern about potential health risks due to high Al intake. Al in cosmetic products raises the question whether a possible interaction between Al and retinol (vitamin A) and cholecalciferol (vitamin D3) metabolism might exist. Understanding the uptake mechanisms of ionic or elemental Al and Al nanomaterials (Al NMs) in combination with bioactive substances are important for the assessment of possible health risk associated. Therefore, we studied the uptake and distribution of Al oxide (Al2O3) and metallic Al0 NMs in the human keratinocyte cell line HaCaT. Possible alterations of the metabolic pattern upon application of the two Al species together with vitamin A or D3 were investigated. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging and inductively coupled plasma mass spectrometry (ICP-MS) were applied to quantify the cellular uptake of Al NMs.

The knowledge about a potential in vivo uptake and subsequent toxicological effects of aluminum (Al), especially in the nanoparticulate form, is still limited. This paper focuses on a three day oral gavage study with three different Al species in Sprague Dawley rats. The Al amount was investigated in major organs in order to determine the oral bioavailability and distribution. Al-containing nanoparticles (NMs composed of Al0 and aluminum oxide (Al2O3)) were administered at three different concentrations and soluble aluminum chloride (AlCl3·6H2O) was used as a reference control at one concentration. A microwave assisted acid digestion approach followed by inductively coupled plasma mass spectrometry (ICP-MS) analysis was developed to analyse the Al burden of individual organs. Special attention was paid on how the sample matrix affected the calibration procedure. After 3 days exposure, AlCl3·6H2O treated animals showed high Al levels in liver and intestine, while upon treatment with Al0 NMs significant amounts of Al were detected only in the latter. In contrast, following Al2O3 NMs treatment, Al was detected in all investigated organs with particular high concentrations in the spleen. A rapid absorption and systemic distribution of all three Al forms tested were found after 3-day oral exposure. The identified differences between Al0 and Al2O3 NMs point out that both, particle shape and surface composition could be key factors for Al biodistribution and accumulation.

Aluminium is one of the most abundant elements in earth’s crust and its manifold uses result in an exposure of the population from many sources. Developmental toxicity, effects on the urinary tract and neurotoxicity are known effects of aluminium and its compounds. Here, we assessed the health risks resulting from total consumer exposure towards aluminium and various aluminium compounds, including contributions from foodstuffs, food additives, food contact materials (FCM), and cosmetic products. For the estimation of aluminium contents in foodstuff, data from the German “Pilot-Total-Diet-Study” were used, which was conducted as part of the European TDS-Exposure project. These were combined with consumption data from the German National Consumption Survey II to yield aluminium exposure via food for adults. It was found that the average weekly aluminium exposure resulting from food intake amounts to approx. 50% of the tolerable weekly intake (TWI) of 1 mg/kg body weight (bw)/week, derived by the European Food Safety Authority (EFSA). For children, data from the French “Infant Total Diet Study” and the “Second French Total Diet Study” were used to estimate aluminium exposure via food. As a result, the TWI can be exhausted or slightly exceeded—particularly for infants who are not exclusively breastfed and young children relying on specially adapted diets (e.g. soy-based, lactose free, hypoallergenic). When taking into account the overall aluminium exposure from foods, cosmetic products (cosmetics), pharmaceuticals and FCM from uncoated aluminium, a significant exceedance of the EFSA-derived TWI and even the PTWI of 2 mg/kg bw/week, derived by the Joint FAO/WHO Expert Committee on Food Additives, may occur. Specifically, high exposure levels were found for adolescents aged 11–14 years. Although exposure data were collected with special regard to the German population, it is also representative for European and comparable to international consumers. From a toxicological point of view, regular exceedance of the lifetime tolerable aluminium intake (TWI/PTWI) is undesirable, since this results in an increased risk for health impairments. Consequently, recommendations on how to reduce overall aluminium exposure are given.

International audience; Development and market introduction of new nanomaterials trigger the need for an adequate risk assessment of such products alongside suitable risk communication measures. Current application of classical and new nanomaterials is analyzed in context of regulatory requirements and standardization for chemicals, food and consumer products. The challenges of nanomaterial characterization as the main bottleneck of risk assessment and regulation are presented. In some areas, e.g., quantification of nanomaterials within complex matrices, the establishment and adaptation of analytical techniques such as laser ablation inductively coupled plasma mass spectrometry and others are potentially suited to meet the requirements. As an example, we here provide an approach for the reliable characterization of human exposure to nanomaterials resulting from food packaging. Furthermore, results of nanomaterial toxicity and ecotoxicity testing are discussed, with concluding key criteria such as solubility and fiber rigidity as important parameters to be considered in material development and regulation. Although an analysis of the public opinion has revealed a distinguished rating depending on the particular field of application, a rather positive perception of nanotechnology could be ascertained for the German public in general. An improvement of material characterization in both toxicological testing as well as end-product control was concluded as being the main obstacle to ensure not only safe use of materials, but also wide acceptance of this and any novel technology in the general public

Inhalation is considered a critical uptake route for NMs, demanding for sound toxicity testing using relevant test systems. This study investigates cytotoxicity and genotoxicity in EpiAirway™ 3D human bronchial models using 16 well-characterized NMs, including surface-functionalized 15 nm SiO

Long perceived as a form of exotic self-expression in some social fringe groups, tattoos have left their maverick image behind and become mainstream, particularly for young people. Historically, tattoo-related health and safety regulations have focused on rules of hygiene and prevention of infections. Meanwhile, the increasing popularity of tattooing has led to the development of many new colours, allowing tattoos to be more spectacular than ever before. However, little is known about the toxicological risks of the ingredients used. For risk assessment, safe intradermal application of these pigments needs data for toxicity and biokinetics and increased knowledge about the removal of tattoos. Other concerns are the potential for phototoxicity, substance migration, and the possible metabolic conversion of tattoo ink ingredients into toxic substances. Similar considerations apply to cleavage products that are formed during laser-assisted tattoo removal. In this Review, we summarise the issues of concern, putting them into context, and provide perspectives for the assessment of the acute and chronic health effects associated with tattooing.

Nanotechnology has emerged as one of the central technologies in the twenty-first century. This judgment becomes apparent by considering the increasing numbers of people employed in this area; the numbers of patents, of scientific publications, of products on the market; and the amounts of money invested in RD. Prospects originating from different fields of nanoapplication seem unlimited. However, nanotechnology certainly will not be able to meet all of the ambitious expectations communicated, yet has high potential to heavily affect our daily life in the years to come. This might occur in particular in the field of consumer products, for example, by introducing nanomaterials in cosmetics, textiles, or food contact materials. Another promising area is the application of nanotechnology in medicine fueling hopes to significantly improve diagnosis and treatment of all kinds of diseases. In addition, novel technologies applying nanomaterials are expected to be instrumental in waste remediation and in the production of efficient energy storage devices and thus may help to overcome world's energy problems or to revolutionize computer and data storage technologies. In this chapter, we will focus on nanomaterials. After a brief historic and general overview, current proposals of how to define nanomaterials will be summarized. Due to general limitations, there is still no single, internationally accepted definition of the term "nanomaterial." After elaborating on the status quo and the scope of nanoanalytics and its shortcomings, the current thinking about possible hazards resulting from nanoparticulate exposures, there will be an emphasis on the requirements to be fulfilled for appropriate health risk assessment and regulation of nanomaterials. With regard to reliable risk assessments, until now there is still the remaining issue to be resolved of whether or not specific challenges and unique features exist on the nanoscale that have to be tackled and distinctively addressed, given that they substantially differ from those encountered with microsized materials or regular chemicals. Based on the current knowledge, we finally provide a proposal on how risk assessment in the nanofield could be achieved and how it might look like in the near future.

Oxidative stress is more and more recognized as the underlying motif for a broad variety of diseases including cancer. Medicine faces the paramount task to develop better diagnostic tools and drug treatment prediction models in the future to significantly enhance the quality of life. Special interest will focus on earlystage disease biomarkers and biomarkers that could predict healing success at the earliest time point after the treatment started. The accelerated formation of so-called reactive oxygen species (ROS) is becoming widely regarded as the underlying process associated with many diseases like myocardial infarction, Alzheimer's, Parkinson's and kidney disease, etc. Once generated within cells and tissues, ROS can react with a variety of cellular metabolites like fatty acids, proteins or DNA. This review investigates the possibilities for various oxidized metabolites as well as proteomics, genomics and bioimaging biomarkers to serve as early-stage disease biomarkers or biomarkers for drug treatment success. We also assess the value of a step-by-step or cascade biomarker approach as a new paradigm in medical diagnostics. Examples are given for possible analytical methodology and tools as well as statistical methods that could be applied. Such an approach may straighten the road toward new medical diagnostics and treatment regimes, which ultimately could lead to a significantly enhanced medical service for patients suffering from chronic and debilitating or deadly diseases including cancer. Examples from recent research are given to show the progress and possibilities for the proposed model.

Silver nanoparticles (SNP) are the subject of worldwide commercialization because of their antimicrobial effects. Yet only little data on their mode of action exist. Further, only few techniques allow for visualization and quantification of unlabeled nanoparticles inside cells. To study SNP of different sizes and coatings within human macrophages, we introduce a novel laser postionization secondary neutral mass spectrometry (Laser-SNMS) approach and prove this method superior to the widely applied confocal Raman and transmission electron microscopy. With time-of-flight secondary ion mass spectrometry (TOF-SIMS) we further demonstrate characteristic fingerprints in the lipid pattern of the cellular membrane indicative of oxidative stress and membrane fluidity changes. Increases of protein carbonyl and heme oxygenase-1 levels in treated cells confirm the presence of oxidative stress biochemically. Intriguingly, affected phagocytosis reveals as highly sensitive end point of SNP-mediated adversity In macrophages. The cellular responses monitored are. hierarchically linked, but follow individual kinetics and are partially reversible.

The risk assessment of nano-sized materials (NM) currently suffers from great uncertainties regarding their putative toxicity for humans and the environment. An extensive amount of the respective original research literature has to be evaluated before a targeted and hypothesis-driven Environmental and Health Safety research can be stipulated. Furthermore, to comply with the European animal protection legislation in vitro testing has to be preferred whenever possible. Against this background, there is the need for tools that enable producers of NM and risk assessors for a fast and comprehensive data retrieval, thereby linking the 3Rs principle to the hazard identification of NM. Here we report on the development of a knowledge-based search engine that is tailored to the particular needs of risk assessors in the area of NM. Comprehensive retrieval of data from studies utilising in vitro as well as in vivo methods relying on the PubMed database is presented exemplarily with a titanium dioxide case study. A fast, relevant and reliable information retrieval is of paramount importance for the scientific community dedicated to develop safe NM in various product areas, and for risk assessors obliged to identify data gaps, to define additional data requirements for approval of NM and to create strategies for integrated testing using alternative methods.

Commenting on "120 Years of Nanosilver History: Implications for Policy Makers" (Environ. Sci. Technol.2011, 45, 1177-1183). The title of the article seduces readers to the impression that we can look back at more than a century of safe use of nanosilver. In this context, colloidal silver and nanosilver have been sometimes used as synonyms. Historically, the term "colloidal silver" refers to dispersed silver particles encompassing a size range of 10-1000 nm. Following scientific definitions, "colloid" stands for freely dispersed particles in a fluid (heterogenic) phase irrespective of its size distribution, while the term "nanosilver" is used for categorization by size. Of course, just the labeling as such neither necessarily implies new hazard properties nor any specific risks; however, uncertainties and data gaps at many levels call for careful consideration and usually should take effect as alert signal for regulatory toxicologists all over the world. Within the frame of this short commentary, we would like to focus on some unclarified issues related to consumer products.

In Europe, the data requirements for the hazard and exposure characterisation of chemicals are defined according to the REACH regulation and its guidance on information requirements and chemical safety assessment (Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), and its guidance documents; available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:396:0001:0849:EN:PDF ; and at: http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm ). This is the basis for any related risk assessment. The standard reference for the testing of cosmetic ingredients is the SCCP's 'Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation' (The SCCP's Notes of Guidance for the testing of cosmetic ingredients and their safety evaluation (2006); available at: http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_03j.pdf ), which refers to the OECD guidelines for the testing of chemicals (The OECD Guidelines for the Testing of Chemicals as a collection of the most relevant internationally agreed testing methods used by government, industry and independent laboratories to assess the safety of chemical products; available at: http://www.oecd.org/topic/0,2686,en_2649_34377_1_1_1_1_37407,00.html ). According to the cosmetics directive [76/768/EEC], compounds that are classified as mutagenic, carcinogenic or toxic to reproduction are banned for the use in cosmetic products. Since December 2010, the respective labelling is based on the rules of regulation (EC) No. 1272/2008 (Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, Official Journal L 353, 31/12/2008, pages 1-1355; available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:en:PDF ) on classification, labelling and packaging of substances and mixtures (CLP). There is no further impact from the CLP regulation on cosmetic products, because regulation (EC) No. 1223/2009 on cosmetic products defines its own labelling rules (Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products; available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:342:0059:0209:en:PDF ). Special notification procedures are mandatory for preservatives, colourants and UV-filters where a safety approval from the European 'Scientific Committee on Consumer Safety' (SCCS) is needed prior to marketing. The risk assessment of nanomaterials in consumer products still poses a significant challenge as highlighted by the example of UV-filters in sunscreens since nanomaterials cannot be classified as a homogenous group of chemicals but still need to be addressed in risk characterisation on a case by case basis.