Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
Archives of Toxicology (v.86, #7)
Genotoxicity investigations on nanomaterials by Franz Oesch; Robert Landsiedel (pp. 985-994).
This review is based on the lecture presented at the April 2010 nanomaterials safety assessment Postsatellite to the 2009 EUROTOX Meeting and summarizes genotoxicity investigations on nanomaterials published in the open scientific literature (up to 2008). Special attention is paid to the relationship between particle size and positive versus negative outcome, as well as the dependence of the outcome on the test used. Salient conclusions and outstanding recommendations emerging from the information summarized in this review are as follows: recognize that nanomaterials are not all the same; therefore know and document what nanomaterial has been tested and in what form; take nanomaterials specific properties into account; in order to make your results comparable with those of others and on other nanomaterials: use or at least include in your studies standardized methods; use in vivo studies to put in vitro results into perspective; take uptake and distribution of the nanomaterial into account; and in order to become able to make extrapolations to risk for human: learn about the mechanism of nanomaterials genotoxic effects. Past experience with standard non-nanosubstances already had shown that mechanisms of genotoxic effects can be complex and their elucidation can be demanding, while there often is an immediate need to assess the genotoxic hazard. Thus, a practical and pragmatic approach to genotoxicity investigations of novel nanomaterials is the use of a battery of standard genotoxicity testing methods covering a wide range of mechanisms. Application of these standard methods to nanomaterials demands, however, adaptations, and the interpretation of results from the genotoxicity testing of nanomaterials needs additional considerations exceeding those used for standard size materials.
Keywords: Nanomaterials; Particles, mutagenicity, genotoxicity; DNA damage, test methods
Small difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials by Thomas Gebel (pp. 995-1007).
Materials that can be described as respirable granular biodurable particles without known significant specific toxicity (GBP) show a common mode of toxicological action that is characterized by inflammation and carcinogenicity in chronic inhalation studies in the rat. This study was carried out to compare the carcinogenic potency of GBP nanomaterials (primary particle diameter 1–100 nm) to GBP micromaterials (primary particle diameter >100 nm) in a pooled approach. For this purpose, the positive GBP rat inhalation carcinogenicity studies have been evaluated. Inhalation studies on diesel engine emissions have also been included due to the fact that the mode of carcinogenic action is assumed to be the same. As it is currently not clear which dose metrics may best explain carcinogenic potency, different metrics have been considered. Cumulative exposure concentrations related to mass, surface area, and primary particle volume have been included as well as cumulative lung burden metrics related to mass, surface area, and primary particle volume. In total, 36 comparisons have been conducted. Including all dose metrics, GBP nanomaterials were 1.33- to 1.69-fold (mean values) and 1.88- to 3.54-fold (median values) more potent with respect to carcinogenicity than GBP micromaterials, respectively. Nine of these 36 comparisons showed statistical significance (p < 0.05, U test), all of which related to dose metrics based on particle mass. The maximum comparative potency factor obtained for one of these 9 dose metric comparisons based on particle mass was 4.71. The studies with diesel engine emissions did not have a major impact on the potency comparison. The average duration of the carcinogenicity studies with GBP nanomaterials was 4 months longer (median values 30 vs. 26 months) than the studies with GBP micromaterials, respectively. Tumor rates increase with age and lung tumors in the rat induced by GBP materials are known to appear late, that is, mainly after study durations longer than 24 months. Taking the different study durations into account, the real potency differences were estimated to be twofold lower than the relative potency factors identified. In conclusion, the chronic rat inhalation studies with GBP materials indicate that the difference in carcinogenic potency between GBP nanomaterials and GBP micromaterials is low can be described by a factor of 2–2.5 referring to the dose metrics mass concentration.
Keywords: Nanomaterials; Carcinogenicity; Respirable granular biodurable particles without known significant specific toxicity (GBP); Chronic rat inhalation study
Application of carbon nanotubes in neurology: clinical perspectives and toxicological risks by Antonio Nunes; Khuloud Al-Jamal; Takeshi Nakajima; Marwan Hariz; Kostas Kostarelos (pp. 1009-1020).
Nanomedicine is an emerging field that proposes the application of precisely engineered nanomaterials for the prevention, diagnosis and therapy of certain diseases, including neurological pathologies. Carbon nanotubes (CNT) are a new class of nanomaterials, which have been shown to be promising in different areas of nanomedicine. In this review, the application of CNT interfacing with the central nervous system (CNS) will be described, and representative examples of neuroprosthetic devices, such as neuronal implants and electrodes will be discussed. Furthermore, the possible application of CNT-based materials as regenerative matrices of neuronal tissue and as delivery systems for the therapy of CNS will be presented.
Keywords: Carbon nanotubes; Neurology; CNS neurotoxicity; Therapy; Neuroregeneration
Toxico-/biokinetics of nanomaterials by Robert Landsiedel; Eric Fabian; Lan Ma-Hock; Wendel Wohlleben; Karin Wiench; Franz Oesch; Ben van Ravenzwaay (pp. 1021-1060).
Nanomaterials (NM) offer great technological advantages but their risks to human health are still under discussion. For toxicological testing and evaluation, information on the toxicokinetics of NM is essential as it is different from that of most other xenobiotics. This review provides an overview on the toxicokinetics of NM available to date. The toxicokinetics of NM depends on particle size and shape, protein binding, agglomeration, hydrophobicity, surface charge and protein binding. In most studies with topical skin application, unintentional permeation and systemic availability were not observed; permeation for some NM with distinct properties was observed in animals. Upon inhalation, low levels of primary model nanoparticles became systemically available, but many real-world engineered NM aggregate in aerosols, do not disintegrate in the lung, and do not become systemically available. NM are prone to lymphatic transport, and many NM are taken up by the mononuclear phagocyte system (MPS) acting as a depot. Their half-life in blood depends on their uptake by MPS rather than their elimination from the body. NM reaching the GI tract are excreted with the feces, but of some NM low levels are absorbed and become systemically available. Some quantum dots were not observably excreted in urine nor in feces. Some model quantum dots, however, were efficiently excreted by the kidneys below, but not above 5–6 nm hydrodynamic diameter, while nanotubes 20–30 nm thick and 500–2,000 nm long were abundant in urine. NM are typically not metabolized. Some NM cross the blood–brain barrier favored by a negative surface charge.
Keywords: Toxicokinetics of nanomaterials; Protein binding to nanomaterials; Agglomeration of nanomaterials; Surface charge of nanomaterials; ADME of nanomaterials
Erratum to: Toxico-/biokinetics of nanomaterials
by Robert Landsiedel; Eric Fabian; Lan Ma-Hock; Ben van Ravenzwaay; Wendel Wohlleben; Karin Wiench; Franz Oesch (pp. 1061-1061).
Nano-sized cosmetic formulations or solid nanoparticles in sunscreens: A risk to human health? by Gerhard J. Nohynek; Eric K. Dufour (pp. 1063-1075).
Personal care products (PCP) often contain micron- or nano-sized formulation components, such as nanoemulsions or microscopic vesicles. A large number of studies suggest that such vesicles do not penetrate human skin beyond the superficial layers of the stratum corneum. Nano-sized PCP formulations may enhance or reduce skin absorption of ingredients, albeit at a limited scale. Modern sunscreens contain insoluble titanium dioxide (TiO2) or zinc oxide (ZnO) nanoparticles (NP), which are efficient filters of UV light. A large number of studies suggest that insoluble NP do not penetrate into or through human skin. A number of in vivo toxicity tests, including in vivo intravenous studies, showed that TiO2 and ZnO NP are non-toxic and have an excellent skin tolerance. Cytotoxicity, genotoxicity, photo-genotoxicity, general toxicity and carcinogenicity studies on TiO2 and ZnO NP found no difference in the safety profile of micro- or nano-sized materials, all of which were found to be non-toxic. Although some published in vitro studies on insoluble nano- or micron-sized particles suggested cell uptake, oxidative cell damage or genotoxicity, these data are consistent with those from micron-sized particles and should be interpreted with caution. Data on insoluble NP, such as surgical implant-derived wear debris particles or intravenously administered magnetic resonance contrast agents suggest that toxicity of small particles is generally related to their chemistry rather than their particle size. Overall, the weight of scientific evidence suggests that insoluble NP used in sunscreens pose no or negligible risk to human health, but offer large health benefits, such as the protection of human skin against UV-induced skin ageing and cancer.
Keywords: Personal care products; Sunscreens; Nanoparticles; TiO2 ; ZnO; Skin penetration; Safety assessment
Nanostructured calcium silicate hydrate seeds accelerate concrete hardening: a combined assessment of benefits and risks by Michael Bräu; Lan Ma-Hock; Christoph Hesse; Luc Nicoleau; Volker Strauss; Silke Treumann; Karin Wiench; Robert Landsiedel; Wendel Wohlleben (pp. 1077-1087).
Nanotechnology creates new possibilities to control and improve material properties for civil infrastructure. Special focus in this area is put on Portland cement and gypsum. Together their annual production is by far larger than for any other material worldwide. Nanomodification of these materials can be done during the few hours between dissolution and hardening, especially by nucleation of the re-crystallization with suitable colloids. Here we report first results in homogeneous seeding of the precipitation of calcium silicate hydrates within a real Portland cement composition. The occupational safety during the production phase and during mixing of concrete paste is addressed in detail by in vivo testing. We perform 5-day inhalation with 21-day recovery in rats and analyze organ-specific toxicity and 71 endpoints from bronchoalveolar lavage (BALF) and blood. In BALF parameters, no test-related changes were observed, indicating the generally low toxicity of the test material. Some mild lesions were observed in larynx level. In the lungs, all animals of the 50 mg/m³ concentration group revealed a minimal to mild increase in alveolar macrophages, which recovered back to control level.
Keywords: Nanomaterials; Construction; Concrete; Occupational safety; Inhalation
A novel type of silver nanoparticles and their advantages in toxicity testing in cell culture systems by A. Haase; A. Mantion; P. Graf; J. Plendl; A. F. Thuenemann; W. Meier; A. Taubert; A. Luch (pp. 1089-1098).
Silver nanoparticles (SNPs) are among the most commercialized nanoparticles worldwide. Often SNP are used because of their antibacterial properties. Besides that they possess unique optic and catalytic features, making them highly interesting for the creation of novel and advanced functional materials. Despite its widespread use only little data exist in terms of possible adverse effects of SNP on human health. Conventional synthesis routes usually yield products of varying quality and property. It thus may become puzzling to compare biological data from different studies due to the great variety in sizes, coatings or shapes of the particles applied. Here, we applied a novel synthesis approach to obtain SNP of well-defined colloidal and structural properties. Being stabilized by a covalently linked small peptide, these particles are nicely homogenous, with narrow size distribution, and form monodisperse suspensions in aqueous solutions. We applied these peptide-coated SNP in two different sizes of 20 or 40 nm (Ag20Pep and Ag40Pep) and analyzed responses of THP-1-derived human macrophages while being exposed against these particles. Gold nanoparticles of similar size and coating (Au20Pep) were used for comparison. The cytotoxicity of particles was assessed by WST-1 and LDH assays, and the uptake into the cells was confirmed via transmission electron microscopy. In summary, our data demonstrate that this novel type of SNP is well suited to serve as model system for nanoparticles to be tested in toxicological studies in vitro.
Keywords: Silver nanoparticles; Peptide coating; Nanotoxicity
In vivo visualisation of nanoparticle entry into central nervous system tissue by Petra Henrich-Noack; Sylvia Prilloff; Nadine Voigt; Jing Jin; Werner Hintz; Jürgen Tomas; Bernhard A. Sabel (pp. 1099-1105).
Because the potential neurotoxicity of nanoparticles is a significant issue, characterisation of nanoparticle entry into the brain is essential. Here, we describe an in vivo confocal neuroimaging method (ICON) of visualising the entry of fluorescent particles into the parenchyma of the central nervous system (CNS) in live animals using the retina as a model. Rats received intravenous injections of fluorescence-labelled polybutyl cyanoacrylate nanoparticles that had been synthesised by a standard miniemulsion polymerisation process. We performed live recording with ICON from before and up to 9 days after particle injection and took photomicrographs of the retina. In addition, selective retrograde labelling of the retinal ganglion cells was achieved by stereotaxic injection of a fluorescent dye into the superior colliculus. Using ICON, we observed vascular kinetics of nanoparticles (wash-in within seconds), their passage to the retina parenchyma (within minutes) and their distribution (mainly cellular) under in vivo conditions. For the detection of cell loss—which is important for the evaluation of toxic effects—in another experiment, we semi-quantitatively analysed the selectively labelled retinal neurons. Our results suggest that the dye per se does not lead to neuronal death. With ICON, it is possible to study nanoparticle kinetics in the retina as a model of the blood-brain barrier. Imaging data can be acquired within seconds after the injection, and the long-term fate of cellular uptake can be followed for many days to study the cellular/extracellular distribution of the nanoparticles. ICON is thus an effective and meaningful tool to investigate nanoparticle/CNS interactions.
Keywords: Polybutyl cyanoacrylate nanoparticles; Blood-brain barrier; Blood-retina barrier; In vivo confocal neuroimaging; Brain
Cytotoxicity of peptide-coated silver nanoparticles on the human intestinal cell line Caco-2 by Linda Böhmert; Birgit Niemann; Andreas F. Thünemann; Alfonso Lampen (pp. 1107-1115).
Silver nanoparticles are used in a wide range of consumer products such as clothing, cosmetics, household goods, articles of daily use and pesticides. Moreover, the use of a nanoscaled silver hydrosol has been requested in the European Union for even nutritional purposes. However, despite the wide applications of silver nanoparticles, there is a lack of information concerning their impact on human health. In order to investigate the effects of silver nanoparticles on human intestinal cells, we used the Caco-2 cell line and peptide-coated silver nanoparticles with defined colloidal, structural and interfacial properties. The particles display core diameter of 20 and 40 nm and were coated with the small peptide l-cysteine l-lysine l-lysine. Cell viability and proliferation were measured using Promegas CellTiter-Blue® Cell Viability assay, DAPI staining and impedance measurements. Apoptosis was determined by Annexin-V/7AAD staining and FACS analysis, membrane damage with Promegas LDH assay and reactive oxygen species by dichlorofluorescein assay. Exposure of proliferating Caco-2 cells to silver nanoparticle induced decreasing adherence capacity and cytotoxicity, whereby the formation of reactive oxygen species could be the mode of action. The effects were dependent on particle size (20, 40 nm), doses (5–100 μg/mL) and time of incubation (4–48 h). Apoptosis or membrane damage was not detected.
Keywords: Oral uptake; Intestinal cells; Peptide-coated silver nanoparticles; Cytotoxicity
Biological interactions and toxicity of nanomaterials in the respiratory tract and various approaches of aerosol generation for toxicity testing by Otto Creutzenberg (pp. 1117-1122).
After deposition in the respiratory tract, nanoparticles exhibit acute, neutrophil-driven inflammatory and oxidative reactions, fibrotic responses and in chronic studies under overload conditions carcinogenic effects, more severely than the microscaled materials of the same chemistry. Besides these effects also known to be induced by microsized particles, nanoparticles principally can translocate from the site of exposure to circulation and become systemically available. This may either increase the toxic outcome (e.g. cardio-vascular effects and potential responses in remote organs) or facilitate an elimination of nanomaterials. For example, in combination with partial dissolution, a strong lung response after a short-term inhalative exposure may be followed by a rapid recovery effect. Mechanistically, in vitro and in vivo tests demonstrated that nanoparticles induce inflammation and oxidative stress after interaction with macrophages and lung epithelial cells; consequently, a cytotoxic and genotoxic potential may exist. The deposition, retention and clearance behaviour of inhaled nanomaterials and the toxic effects observed are decisively dependent on the particle agglomeration status of the aerosol. Two principally different experimental approaches are used for inhalative exposure to nanoparticles: either (1) a basic research-oriented approach using very small aerosol mass concentrations or particle formulations that result in at least partially nanoscaled aerosols; in this way, the potential hazard and the translocation potential for individual nanoparticles can be followed effectively; or (2) exposure scenarios mimicking the occupational situation (risk-oriented) with mostly agglomerated nanoparticles; consequently, the probable risk deriving from incidental/accidental exposure can be assessed more adequately.
Keywords: Nanoparticles; Agglomeration; Translocation; Exposure scenario
Interference of engineered nanoparticles with in vitro toxicity assays by Alexandra Kroll; Mike Hendrik Pillukat; Daniela Hahn; Jürgen Schnekenburger (pp. 1123-1136).
Accurate in vitro assessment of nanoparticle cytotoxicity requires a careful selection of the test systems. Due to high adsorption capacity and optical activity, engineered nanoparticles are highly potential in influencing classical cytotoxicity assays. Here, four common in vitro assays for oxidative stress, cell viability, cell death and inflammatory cytokine production (DCF, MTT, LDH and IL-8 ELISA) were assessed for validity using 24 well-characterized engineered nanoparticles. For all nanoparticles, the possible interference with the optical detection methods, the ability to convert the substrates, the influence on enzymatic activity and the potential to bind proinflammatory cytokines were analyzed in detail. Results varied considerably depending on the assay system used. All nanoparticles tested were found to interfere with the optical measurement at concentrations of 50 μg cm−2 and above when DCF, MTT and LDH assays were performed. Except for Carbon Black, particle interference could be prevented by altering assay protocols and lowering particle concentrations to 10 μg cm−2. Carbon Black was also found to oxidize H2DCF-DA in a cell-free system, whereas only ZnO nanoparticles significantly decreased LDH activity. A dramatic loss of immunoreactive IL-8 was observed for only one of the three TiO2 particle types tested. Our results demonstrate that engineered nanoparticles interfere with classic cytotoxicity assays in a highly concentration-, particle- and assay-specific manner. These findings strongly suggest that each in vitro test system has to be evaluated for each single nanoparticle type to accurately assess the nanoparticle toxicity.
Keywords: Engineered nanoparticles; Cytotoxicity assays; Interference; Cytokine adsorption
Hazard identification of inhaled nanomaterials: making use of short-term inhalation studies by Christoph L. Klein; Karin Wiench; Martin Wiemann; Lan Ma-Hock; Ben van Ravenzwaay; Robert Landsiedel (pp. 1137-1151).
A major health concern for nanomaterials is their potential toxic effect after inhalation of dusts. Correspondingly, the core element of tier 1 in the currently proposed integrated testing strategy (ITS) is a short-term rat inhalation study (STIS) for this route of exposure. STIS comprises a comprehensive scheme of biological effects and marker determination in order to generate appropriate information on early key elements of pathogenesis, such as inflammatory reactions in the lung and indications of effects in other organs. Within the STIS information on the persistence, progression and/or regression of effects is obtained. The STIS also addresses organ burden in the lung and potential translocation to other tissues. Up to now, STIS was performed in research projects and routine testing of nanomaterials. Meanwhile, rat STIS results for more than 20 nanomaterials are available including the representative nanomaterials listed by the Organization for Economic Cooperation and Development (OECD) working party on manufactured nanomaterials (WPMN), which has endorsed a list of representative manufactured nanomaterials (MN) as well as a set of relevant endpoints to be addressed. Here, results of STIS carried out with different nanomaterials are discussed as case studies. The ranking of different nanomaterials potential to induce adverse effects and the ranking of the respective NOAEC are the same among the STIS and the corresponding subchronic and chronic studies. In another case study, a translocation of a coated silica nanomaterial was judged critical for its safety assessment. Thus, STIS enables application of the proposed ITS, as long as reliable and relevant in vitro methods for the tier 1 testing are still missing. Compared to traditional subacute and subchronic inhalation testing (according to OECD test guidelines 412 and 413), STIS uses less animals and resources and offers additional information on organ burden and progression or regression of potential effects.
Keywords: Short term inhalation study; Nanomaterial; Test strategy