Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy

The rapid proliferation of many different engineered nanomaterials (defined as materials designed and produced to have structural features with at least one dimension of 100 nanometers or less) presents a dilemma to regulators regarding hazard identification. The International Life Sciences Institute Research Foundation/Risk Science Institute convened an expert working group to develop a screening strategy for the hazard identification of engineered nanomaterials. The working group report presents the elements of a screening strategy rather than a detailed testing protocol. Based on an evaluation of the limited data currently available, the report presents a broad data gathering strategy applicable to this early stage in the development of a risk assessment process for nanomaterials. Oral, dermal, inhalation, and injection routes of exposure are included recognizing that, depending on use patterns, exposure to nanomaterials may occur by any of these routes. The three key elements of the toxicity screening strategy are: Physicochemical Characteristics, In Vitro Assays (cellular and non-cellular), and In Vivo Assays. There is a strong likelihood that biological activity of nanoparticles will depend on physicochemical parameters not routinely considered in toxicity screening studies. Physicochemical properties that may be important in understanding the toxic effects of test materials include particle size and size distribution, agglomeration state, shape, crystal structure, chemical composition, surface area, surface chemistry, surface charge, and porosity. In vitro techniques allow specific biological and mechanistic pathways to be isolated and tested under controlled conditions, in ways that are not feasible in in vivo tests. Tests are suggested for portal-of-entry toxicity for lungs, skin, and the mucosal membranes, and target organ toxicity for endothelium, blood, spleen, liver, nervous system, heart, and kidney. Non-cellular assessment of nanoparticle durability, protein interactions, complement activation, and pro-oxidant activity is also considered. Tier 1 in vivo assays are proposed for pulmonary, oral, skin and injection exposures, and Tier 2 evaluations for pulmonary exposures are also proposed. Tier 1 evaluations include markers of inflammation, oxidant stress, and cell proliferation in portal-of-entry and selected remote organs and tissues. Tier 2 evaluations for pulmonary exposures could include deposition, translocation, and toxicokinetics and biopersistence studies; effects of multiple exposures; potential effects on the reproductive system, placenta, and fetus; alternative animal models; and mechanistic studies

Assessment of the potential in vivo ecotoxicity of Double-Walled Carbon Nanotubes (DWNTs) in water, using the amphibian Ambystoma mexicanum

Because of their specific properties (mechanical, electrical, etc), carbon nanotubes (CNTs) are being assessed for inclusion in many manufactured products. Due to their massive production and number of potential applications, the impact of CNTs on the environment must be taken into consideration. The present investigation evaluates the ecotoxic potential of CNTs in the amphibian larvae (Ambystoma mexicanum). Acute toxicity and genotoxicity were analysed after 12 days of exposure in laboratory conditions. The genotoxic effects were analysed by scoring the micronucleated erythrocytes in the circulating blood of the larvae according to the French standard micronucleus assay. The results obtained in the present study demonstrated that CNTs are neither acutely toxic nor genotoxic to larvae whatever the CNTs concentration in the water, although black masses of CNTs were observed inside the gut. In the increasing economical context of CNTs, complementary studies must be undertaken, especially including mechanistic and environmental investigations

Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat

Nanomaterial of titanium dioxide (TiO2) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO2 particles up to 90 days after intratracheal instillation. TiO2 induced a transient response of proinflammatory and T-cell-activating cytokines (interleukin [IL]-1α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1-2 days after exposure, accompanied byaninfluxofeosinophilsand neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4+ helper T-cells, but we also demonstrated presence of CD8+T-cells, B-cells, and CD25+T-cells. In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO2 nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations

Pulmonary and systemic responses of highly pure and well-dispersed single-wall carbon nanotubes after intratracheal instillation in rats

The present study was conducted to assess the pulmonary and systemic responses in rats after intratracheal instillation of highly pure, well-dispersed, and well-characterized SWCNTs. Exposure to SWCNTs up to 2mg/kg did not produce mortality, changes in clinical signs, or body weights during the observation period. Dose-dependent changes were observed in the lung weight, BALF inflammatory cells, and biochemical parameters such as LDH value, protein content, IL-1β and IL-6 activity, and histopathology. In the 0.04 mg/kg SWCNT-exposed group, almost no changes were observed during the observation period. In the 0.2 mg/kg SWCNT-exposed group, pulmonary inflammatory responses were observed after instillation. In the 1 mg/kg and 2 mg/kg SWCNT-exposed group, acute lung inflammation and subsequent granuloma accompanied by increased lung weights were observed. Furthermore, the histopathological findings in the lungs of rats exposed to SWCNTs showed inflammatory responses related with the vital reaction to the foreign substance that was instilled intratracheally, and there were no fibrosis, atypical lesion, or tumor-related findings even at the highest dose (2 mg/kg) of SWCNT-exposed groups up to 6 months after instillation. For all groups, histopathological changes due to the instillation exposure of SWCNTs were observed only in the lungs and lung-associated lymph nodes and not in the other tissues examined (i.e. the liver, kidney, spleen, and cerebrum)

Toxicity of lunar dust

The formation, composition and physical properties of lunar dust are incompletely characterised with regard to human health. While the physical and chemical determinants of dust toxicity for materials such as asbestos, quartz, volcanic ashes and urban particulate matter have been the focus of substantial research efforts, lunar dust properties, and therefore lunar dust toxicity may differ substantially. In this contribution, past and ongoing work on dust toxicity is reviewed, and major knowledge gaps that prevent an accurate assessment of lunar dust toxicity are identified. Finally, a range of studies using ground-based, low-gravity, and in situ measurements is recommended to address the identified knowledge gaps. Because none of the curated lunar samples exist in a pristine state that preserves the surface reactive chemical aspects thought to be present on the lunar surface, studies using this material carry with them considerable uncertainty in terms of fidelity. As a consequence, in situ data on lunar dust properties will be required to provide ground truth for ground-based studies quantifying the toxicity of dust exposure and the associated health risks during future manned lunar missions.Comment: 62 pages, 9 figures, 2 tables, accepted for publication in Planetary and Space Scienc

Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment

Comparison of dust released from sanding conventional and nanoparticle-doped wall and wood coatings

Introduction of engineered nanoparticles (ENPs) into traditional surface coatings (e.g., paints, lacquers, fillers) may result in new exposures to both workers and consumers and possibly also a new risk to their health. During finishing and renovation, such products may also be a substantial source of exposure to ENPs or aggregates thereof. This study investigates the particle size distributions (5.6 nm–19.8 μm) and the total number of dust particles generated during sanding of ENP-doped paints, lacquers, and fillers as compared to their conventional counterparts. In all products, the dust emissions from sanding were found to consist of five size modes: three modes under 1 μm and two modes around 1 and 2 μm. Corrected for the emission from the sanding machine, the sanding dust, was dominated by 100–300 nm size particles, whereas the mass and surface area spectra were dominated by the micrometer modes. Adding ENPs to the studied products only vaguely affected the geometric mean diameters of the particle modes in the sanding dust when compared to their reference products. However, we observed considerable differences in the number concentrations in the different size modes, but still without revealing a clear effect of ENPs on dust emissions from sanding

Phylogenetic Analysis of Pelecaniformes (Aves) Based on Osteological Data: Implications for Waterbird Phylogeny and Fossil Calibration Studies

) were also assessed. The antiquity of these taxa and their purported status as stem members of extant families makes them valuable for studies of higher-level avian diversification. (sister taxon to Phalacrocoracidae). These relationships are invariant when ‘backbone’ constraints based on recent avian phylogenies are imposed.Relationships of extant pelecaniforms inferred from morphology are more congruent with molecular phylogenies than previously assumed, though notable conflicts remain. The phylogenetic position of the Plotopteridae implies that wing-propelled diving evolved independently in plotopterids and penguins, representing a remarkable case of convergent evolution. Despite robust support for the placement of fossil taxa representing key calibration points, the successive outgroup relationships of several “stem fossil + crown family” clades are variable and poorly supported across recent studies of avian phylogeny. Thus, the impact these fossils have on inferred patterns of temporal diversification depends heavily on the resolution of deep nodes in avian phylogeny

Formation of Nano-Bio-Complex as Nanomaterials Dispersed in a Biological Solution for Understanding Nanobiological Interactions

Information on how cells interface with nanomaterials in biological environments has important implications for the practice of nanomedicine and safety consideration of nanomaterials. However, our current understanding of nanobiological interactions is still very limited. Here, we report the direct observation of nanomaterial bio-complex formation (other than protein corona) from nanomaterials dispersed in biologically relevant solutions. We observed highly selective binding of the components of cell culture medium and phosphate buffered saline to ZnO and CuO nanoparticles, independent of protein molecules. Our discoveries may provide new insights into the understanding of how cells interact with nanomaterials