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Volatile anesthetics are known to attenuate inflammatory response and tissue damage markers in acute organ injury. It is unclear whether these beneficial effects of volatile anesthetics are mediated by the ether basic structure or by characteristics of their halogenations. We describe in an in vitro model of acute inflammation in pulmonary cells that halogenation (fluorinated carbon groups) is responsible for the immunomodulatory effects. The inflammatory response after coexposure to endotoxin and sevoflurane, diethyl-ether, or various water-soluble molecules carrying trifluorinated carbon (CF(3)) groups was evaluated in pulmonary epithelial and endothelial cells and in neutrophils. In epithelial and endothelial cells, expression of inflammatory mediators to LPS stimulation was dose-dependently decreased upon exposure to sevoflurane and other molecules with CF(3) groups. This was not observed for diethyl-ether or structure-similar nonfluorinated molecules. In neutrophils, chemotactic activity, as well as expression of surface CD11b and CD62L, was positively modified by molecules carrying CF(3) groups. Cytotoxicity could be excluded. These findings for the first time reveal in an in vitro model of acute inflammation that the immunomodulatory effects are not limited to volatile anesthetics but are associated with a much broader class of CF(3) group-containing molecules. The immunomodulatory effects could now be provided in a hydrophilic, injectable formulation for the treatment of patients suffering from acute organ injury, such as acute lung injury, in environments not suitable for volatile anesthetics.

Nowadays, aerosol processes are widely used for the manufacture of nanoparticles (NPs), creating an increased occupational exposure risk of workers, laboratory personnel and scientists to airborne particles. There is evidence that possible adverse effects are linked with the accumulation of NPs in target cells, pointing out the importance of understanding the kinetics of particle internalization. In this context, the uptake kinetics of representative airborne NPs over 30 min and their internalization after 24 h post-exposure were investigated by the use of a recently established exposure system. This system combines the production of aerosolized cerium oxide (CeO(2)) NPs by flame spray synthesis with its simultaneous particle deposition from the gas-phase onto A549 lung cells, cultivated at the air-liquid interface. Particle uptake was quantified by mass spectrometry after several exposure times (0, 5, 10, 20 and 30 min). Over 35% of the deposited mass was found internalized after 10 min exposure, a value that increased to 60% after 30 min exposure. Following an additional 24 h post-incubation, a time span, after which adverse biological effects were observed in previous experiments, over 80% of total CeO(2) could be detected intracellularly. On the ultrastructural level, focal cerium aggregates were present on the apical surface of A549 cells and could also be localized intracellularly in vesicular structures. The uptake behaviour of aerosolized CeO(2) is in line with observations on cerium suspensions, where particle mass transport was identified as the rate-limiting factor for NP internalization.

The exposure of cell cultures to aerosols or nanoparticle dispersions offers an experimental access to study particle related toxicology and nanomedicine. The present article discusses the concept of dose for soluble or persistent particles with optional stabilizing shells and/or chemical or catalytic activity. We further investigate the minimal set of experiments and controls required for hands-on experiments feasible in well-equipped standard research laboratories. This article recommends strategies to implement nanotoxicity experiments into laboratory routine and shall assist aerosol scientists to engage into biological/medical questions. The most prominent differences between molecule- and particle-related health effects are additionally discussed as physical (concentration-dependent mobility due to agglomeration) and chemical effects (catalytic/chemically active surfaces, Trojan horse type toxin transport through membranes, long-term risks). In the last part we describe the implementation of these concepts within the Swiss Recommendations for Industrial Use of Nanoparticles as a first attempt to provide a regulatory framework for the risk assessment of nanoproducts.

The rapidly increasing production of engineered nanoparticles has raised questions regarding their environmental impact and their mobility to overcome biological important barriers. Nanoparticles were found to cross different mammalian barriers, which is summarized under the term translocation. The present work investigates the uptake and translocation of cerium dioxide nanoparticles into maize plants as one of the major agricultural crops. Nanoparticles were exposed either as aerosol or as suspension. Our study demonstrates that 50 μg of cerium/g of leaves was either adsorbed or incorporated into maize leaves. This amount could not be removed by a washing step and did not depend on closed or open stomata investigated under dark and light exposure conditions. However, no translocation into newly grown leaves was found when cultivating the maize plants after airborne particle exposure. The use of inductively coupled mass spectrometer allowed detection limits of less than 1 ng of cerium/g of leaf. Exposure of plants to well-characterized nanoparticle suspensions in the irrigation water resulted also in no detectable translocation. These findings may indicate that the biological barriers of plants are more resistant against nanoparticle translocation than mammalian barriers.

Metal nanoparticles have distinctly different chemical and physical properties than currently investigated oxides. Since pure metallic nanoparticles are igniting at air, carbon stabilized copper nanoparticles were used as representative material for this class. Using copper as a representative example, we compare the cytotoxicity of copper metal nanoparticles stabilized by a carbon layer to copper oxide nanoparticles using two different cell lines. Keeping the copper exposure dose constant, the two forms of copper showed a distinctly different response. Whilst copper oxide had already been reported to be highly cytotoxic, carbon-coated copper nanoparticles were much less cytotoxic and more tolerated. Measuring the two material's intra- and extracellular solubility in model buffers explained this difference on the basis of altered copper release when supplying copper metal or the corresponding oxide particles to the cells. Control experiments using pure carbon nanoparticles were used to exclude significant surface effects. Reference experiments with ionic copper solutions confirmed a similar response of cultures if exposed to copper oxide nanoparticles or ionic copper. These observations are in line with a Trojan horse-type mechanism and illustrate the dominating influence of physico-chemical parameters on the cytotoxicity of a given metal.

The chemical and catalytic activity of nanoparticles has strongly contributed to the current tremendous interest in engineered nanomaterials and often serves as a guiding principle for the design of functional materials. Since it has most recently become evident that such active materials can enter into cells or organisms, the present study investigates the level of intracellular oxidations after exposure to iron-, cobalt-, manganese-, and titania-containing silica nanoparticles and the corresponding pure oxides in vitro. The resulting oxidative stress was quantitatively measured as the release of reactive oxygen species (ROS). The use of thoroughly characterized nanoparticles of the same morphology, comparable size, shape, and degree of agglomeration allowed separation of physical (rate of particle uptake, agglomeration, sedimentation) and chemical effects (oxidations). Three sets of control experiments elucidated the role of nanoparticles as carriers for heavy metal uptake and excluded a potential interference of the biological assay with the nanomaterial. The present results indicate that the particles could efficiently enter the cells by a Trojan-horse type mechanism which provoked an up to eight times higher oxidative stress in the case of cobalt or manganese if compared to reference cultures exposed to aqueous solutions of the same metals. A systematic investigation on iron-containing nanoparticles as used in industrial fine chemical synthesis demonstrated that the presence of catalytic activity could strongly alter the damaging action of a nanomaterial. This indicates that a proactive development of nanomaterials and their risk assessment should consider chemical and catalytic properties of nanomaterials beyond a mere focus on physical properties such as size, shape, and degree of agglomeration.

Early indicators for nanoparticle-derived adverse health effects should provide a relative measure for cytotoxicity of nanomaterials in comparison to existing toxicological data. We have therefore evaluated a human mesothelioma and a rodent fibroblast cell line for in vitro cytotoxicity tests using seven industrially important nanoparticles. Their response in terms of metabolic activity and cell proliferation of cultures exposed to 0-30 ppm nanoparticles (microg g(-1)) was compared to the effects of nontoxic amorphous silica and toxic crocidolite asbestos. Solubility was found to strongly influence the cytotoxic response. The results further revealed a nanoparticle-specific cytotoxic mechanism for uncoated iron oxide and partial detoxification or recovery after treatment with zirconia, ceria, or titania. While in vitro experiments may never replace in vivo studies, the relatively simple cytotoxic tests provide a readily available pre-screening method.

The effects of an exposure to three mass-produced metal oxide nanoparticles-similar in size and specific surface area but different in redox activity and solubility-were studied in rat alveolar macrophages (MAC) and epithelial cells (AEC). We hypothesized that the cell response depends on the particle redox activity and solubility determining the amount of reactive oxygen species formation (ROS) and subsequent inflammatory response. MAC and AEC were exposed to different amounts of Mn3O4 (soluble, redox-active), CeO2 (insoluble, redox-active), and TiO2 (insoluble, redox-inert) up to 24 h. Viability and inflammatory response were monitored with and without coincubation of a free-radical scavenger (trolox). In MAC elevated ROS levels, decreased metabolic activity and attenuated inflammatory mediator secretion were observed in response to Mn3O4. Addition of trolox partially resolved these changes. In AEC, decreased metabolic activity and an attenuated inflammatory mediator secretion were found in response to CeO2 exposure without increased production of ROS, thus not sensitive to trolox administration. Interestingly, highly redox-active soluble particles did not provoke an inflammatory response. The data reveal that target and effector cells of the lung react in different ways to particle exposure making a prediction of the response depending on redox activity and intracellular solubility difficult.

An important aspect in risk assessment of nanoparticles (NPs) is to understand their environmental interactions. We used hydroponic plant cultures to study nanoparticle–plant-root interaction and translocation and exposed wheat and pumpkin to suspensions of uncoated CeO 2 –NP for 8 d (primary particle size 17–100 nm, 100 mg L −1 ) in the absence and presence of fulvic acid (FA) and gum arabic (GA) as representatives of different types of natural organic matter. The behavior of CeO 2 –NPs in the hydroponic solution was monitored regarding agglomeration, sedimentation, particle size distribution, surface charge, amounts of root association, and translocation into shoots. NP-dispersions were stable over 8 d in the presence of FA or GA, but with growing plants, changes in pH, particle agglomeration rate, and hydrodynamic diameter were observed. None of the plants exhibited reduced growth or any toxic response during the experiment. We found that CeO 2 –NPs translocated into pumpkin shoots, whereas this did not occur in wheat plants. The presence of FA and GA affected the amount of CeO 2 associated with roots (pure > FA > GA) but did not affect the translocation factor. Additionally, we could confirm via TEM and SEM that CeO 2 –NPs adhered strongly to root surfaces of both plant species.

Volatile anaesthetics are known as immunomodulatory substances in inflammatory as well as in ischemia/reperfusion processes [1,2]. We investigated in a model of acute pulmonary inflammation whether these immunomodulatory effects arise from the ether basic structure or from characteristics in their halogenation.

Attachment of EDTA-like chelators to carbon coated metal nanomagnets results in a magnetic reagent for the rapid removal of heavy metals from solutions or contaminated water by three orders of magnitude to concentrations as low as microg L(-1).

The tremendous application potential of nanosized materials stays in sharp contrast to a growing number of critical reports of their potential toxicity. Applications of in vitro methods to assess nanoparticles are severely limited through difficulties in exposing cells of the respiratory tract directly to airborne engineered nanoparticles. We present a completely new approach to expose lung cells to particles generated in situ by flame spray synthesis. Cerium oxide nanoparticles from a single run were produced and simultaneously exposed to the surface of cultured lung cells inside a glovebox. Separately collected samples were used to measure hydrodynamic particle size distribution, shape, and agglomerate morphology. Cell viability was not impaired by the conditions of the glovebox exposure. The tightness of the lung cell monolayer, the mean total lamellar body volume, and the generation of oxidative DNA damage revealed a dose-dependent cellular response to the airborne engineered nanoparticles. The direct combination of production and exposure allows studying particle toxicity in a simple and reproducible way under environmental conditions.

The rapidly increasing production of engineered nanoparticles has created a demand for particle removal from industrial and communal wastewater streams. Efficient removal is particularly important in view of increasing long-term persistence and evidence for considerable ecotoxicity of specific nanoparticles. The present work investigates the use of a model wastewater treatment plant for removal of oxide nanoparticles. While a majority of the nanoparticles could be captured through adhesion to clearing sludge, a significant fraction of the engineered nanoparticles escaped the wastewater plant’s clearing system, and up to 6 wt % of the model compound cerium oxide was found in the exit stream of the model plant. Our study demonstrates a significant influence of surface charge and the addition of dispersion stabilizing surfactants as routinely used in the preparation of nanoparticle derived products. A detailed investigation on the agglomeration of oxide nanoparticles in wastewater streams revealed a high stabilization of the particles against clearance (adsorption on the bacteria from the sludge). This unexpected finding suggests a need to investigate nanoparticle clearance in more detail and demonstrates the complex interactions between dissolved species and the nanoparticles within the continuously changing environment of the clearing sludge.

Journal of Nanoparticle Research, 9 (2), ISSN:1388-0764, ISSN:1572-896X

The urgent need for toxicological studies on carbon nanotubes (CNTs) has arisen from the rapidly emerging applications of CNTs well beyond material science and engineering. In order to provide a basis for comparison to existing epidemiological data, we have investigated CNTs at various degrees of agglomeration using an in vitro cytotoxicity study with human MSTO-211H cells. Non-cytotoxic polyoxyethylene sorbitan monooleate was found to well-disperse CNT. In the present study, the cytotoxic effects of well-dispersed CNT were compared with that of conventionally purified rope-like agglomerated CNTs and asbestos as a reference. While suspended CNT-bundles were less cytotoxic than asbestos, rope-like agglomerates induced more pronounced cytotoxic effects than asbestos fibres at the same concentrations. The study underlines the need for thorough materials characterization prior to toxicological studies and corroborates the role of agglomeration in the cytotoxic effect of nanomaterials.

Quantitative studies on the uptake of nanoparticles into biological systems should consider simultaneous agglomeration, sedimentation, and diffusion at physiologically relevant concentrations to assess the corresponding risks of nanomaterials to human health. In this paper, the transport and uptake of industrially important cerium oxide nanoparticles, into human lung fibroblasts is measured in vitro after exposing thoroughly characterized particle suspensions to a fibroblast cell culture for particles of four separate size fractions and concentrations ranging from 100 ng g(-1) to 100 microg g(-1) of fluid (100 ppb to 100 ppm). The unexpected findings at such low but physiologically relevant concentrations reveal a strong dependence of the amount of incorporated ceria on particle size, while nanoparticle number density or total particle surface area are of minor importance. These findings can be explained on the basis of a purely physical model. The rapid formation of agglomerates in the liquid is strongly favored for small particles due to a high number density while larger ones stay mainly unagglomerated. Diffusion (size fraction 25-50 nm) or sedimentation (size fraction 250-500 nm) limits the transport of nanoparticles to the fibroblast cells. The biological uptake processes on the surface of the cell are faster than the physical transport to the cell at such low concentrations. Comparison of the colloid stability of a series of oxide nanoparticles reveals that untreated oxide suspensions rapidly agglomerate in biological fluids and allows the conclusion thatthe presented transport and uptake kinetics at low concentrations may be extended to other industrially relevant materials.

The enantioselective hydrogenation of several isatine derivatives over cinchonidine modified Pt/Al2O3 was investigated. A maximum enantiomeric excess (e.e.) of 45% was found for (R)-5,7-dimethylisatin. The enantiomeric excess was limited by racemization catalyzed by the basic cinchonidine in solution, leading to low enantiomeric excess at high cinchonidine concentration. The modifier in solution also catalyzed the formation of the corresponding isatide. High cinchonidine concentration favored isatide formation, whereas low cinchonidine concentration and high hydrogen pressure favored alcohol formation. The isatide, formed from the isatin reactant and the alcohol, underwent disproportionation. Though both hydrogenation and isatide formation are fast reactions, isatide formation was considerably faster at least at the beginning of the reaction. Substitution of the isatin reactant had relatively little effect on enantiomeric excess but affected considerably the rate of racemization.

The rapidly growing applications of nanotechnology require a detailed understanding of benefits and risks, particularly in toxicology. The present study reviews the physical and chemical differences between particles and molecules when interacting with living organisms. In contrast to classical chemicals, the mobility of nanoparticles is governed by agglomeration, a clustering process that changes the characteristic size of the nanomaterials during exposure, toxicity tests or in the environment. The current status of nanotoxicology highlights non-classical toxic interactions through catalytic processes inside living cells and the enhanced heavy metal transport into the cytosol through the 'Trojan horse mechanism'. The safety of nanoparticles in consumer goods is proposed to be rendered inherently safer by substituting the currently used persistent oxides through biodegradable materials.

More than 100 million tonnes of municipal solid waste are incinerated worldwide every year1. However, little is known about the fate of nanomaterials during incineration, even though the presence of engineered nanoparticles in waste is expected to grow2. Here, we show that cerium oxide nanoparticles introduced into a full-scale waste incineration plant bind loosely to solid residues from the combustion process and can be efficiently removed from flue gas using current filter technology. The nanoparticles were introduced either directly onto the waste before incineration or into the gas stream exiting the furnace of an incinerator that processes 200,000 tonnes of waste per year. Nanoparticles that attached to the surface of the solid residues did not become a fixed part of the residues and did not demonstrate any physical or chemical changes. Our observations show that although it is possible to incinerate waste without releasing nanoparticles into the atmosphere, the residues to which they bind eventually end up in landfills or recovered raw materials, confirming that there is a clear environmental need to develop degradable nanoparticles.