9,546 research outputs found

    Varieties of Exploratory Experimentation in Nanotoxicology

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    There has been relatively little effort to provide a systematic overview of different forms of exploratory experimentation (EE). The present paper examines the growing subdiscipline of nanotoxicology and suggests that it illustrates at least four ways that researchers can engage in EE: searching for regularities; developing new techniques, simulation models, and instrumentation; collecting and analyzing large swaths of data using new experimental strategies (e.g., computer-based simulation and “high-throughput” instrumentation); and structuring an entire disciplinary field around exploratory research agendas. In order to distinguish these and other activities more effectively, the paper proposes a taxonomy that includes three dimensions along which types of EE vary: (1) the aim of the experimental activity, (2) the role of theory in the activity, and (3) the methods or strategies employed for varying experimental parameters

    Nanotoxicology

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    As the production and use of nanomaterials (NMs) in medicine and many other applications develops, so the need to understand the potential risks posed by NMs to human health (and the environment) increases (Aitken et al. 2006). At the nanoscale (1-100 nm), materials exhibit properties that are different to larger or bulk materials. These new properties are exploited by researchers and industry to generate new products; however, the same properties can also inuence how the NM behaves in biological systems, including affecting toxicity. Nanotoxicology is a relatively new eld of research that aims to assess the human and environmental hazard of nanomaterials. In recent years, this new discipline has seen a rapid expansion in the number of studies concerned with assessing the safety of engineered NMs (Figure 20.1)

    Investigations into the bioavailability of manufactured nanoparticles in fish

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    The field of nanotoxicology has emerged as a discipline in parallel with the rapid expansion of nanotechnology and the use of nanomaterials in modern life. Assessing the potential impacts of manufactured nanoparticles (MNPs) on the environment and human health is critical to the sustainable development of the nano-industry. Current knowledge on the ecological implications of nanotoxicology has major uncertainties surrounding the fate and behaviour of nanomaterials in the exposure environment. Bioavailability, uptake and partitioning of nanomaterials to organisms are key determinates to toxicity, yet these foundations of basic data are only now just starting to emerge in any useful and coherent manner for aquatic animals. This thesis work set out to address this gap in knowledge and further our understanding of these important principles for fish. In an attempt to develop a high through-put screening system for toxicity of MNPs, studies assessing the utility of primary isolated rainbow trout (Oncorhynchus mykiss) hepatocytes found they showed very limited responses to a range of MNPs. There was a lack of any evidence for either lipid peroxidation or xenobiotic detoxification activity. In these studies isolated trout hepatocytes were found to be unresponsive to the induction of these biological responses after exposure to positive controls. The findings demonstrated that the MNPs tested showed low toxicity generally and that fish hepatocytes do not provide a useful system for the screening of potential toxic effects of MNPs. In this cell culture work, coherent anti-Stokes Raman scattering (CARS) microscopy was applied to demonstrate that the particles supplied in the culture medium did cross the cell membrane and enter into the exposed cells. In the second phase of the work in this thesis CARS was investigated as an experimental technique for tracing a wide range of metal and metal oxide MNPs into cells and tissues. CARS was applied to evaluate initial detection of different MNPs and investigate the imaging capability on a range of cells, tissues and organisms. Finally, CARS was applied to assess localisation ability of MNPs within biological matrices. MNPs were shown to be taken into trout hepatocytes using a 3D reconstruction to determine the origin of the MNP signal within the cell. Uptake of MNPs was established into trout gill and kidney tissue, corophium and daphnia species and were shown to have different partitioning in zebrafish embryos. In summary CARS showed great potential for tracing particle uptake and bio-distribution both in vitro and in vivo. Particular benefits include imaging MNPs in living organisms, without the need for labelling or fixing the material. Limitations of the CARS technique are also discussed. In chapter 4, the consequences of the presence of natural organic matter (NOM) were investigated on the uptake of MNPs into fish. Carp (Cyprinus carpio) were exposed to cerium dioxide (CeO2) MNPs in combination with NOM over 28 days. Elevated levels of uptake of cerium were measured in the brain, gill and kidney tissue by induction coupled plasma mass spectroscopy (ICP-MS) for fish exposed to 50 ÎŒg/l CeO2 MNPs in combination with 250 ÎŒg/l of NOM. There were no such effects of the NOM enhancing uptake for the bulk CeO2 particles. Detailed studies on the behaviour of the CeO2 MNPs in the exposure medium demonstrated the highly complex and dynamic nature of the interactions with NOM. This study discusses some of the difficulties in the techniques, analysis and interpretation of data derived from studies of this nature. The finding that NOM may enhance MNP uptake presents a potential issue for current risk assessment criteria for MNPs that do not consider natural conditions. The final experimental chapter considered maternal transfer as a potentially important route for exposure of embryos and early life stage animals to MNPs in live bearing animals. In this work guppies (Poecilia reticulata) were exposed to 7 nm silver citrate stabilised particles and citrate stabilised bulk sized particles, dosed via the diet for a full gestation cycle. Maternal transfer of Ag to the larvae was significantly higher for the nanoparticulate treatment compared with the bulk and control treatments and larval burden was significantly higher compared with the maternal sires. However, there was no impact of Ag on larval survival, birth weights, or on indices of body condition in the exposed adults. The enhanced uptake of nano Ag compared to bulk Ag particles into the guppy offspring emphasises the potential for exposure to sensitive early life stages of organisms, which to date has not been widely considered and suggests greater research is needed in this area. Collectively, the studies conducted in this thesis contribute to the science base of nanotoxicology, specifically in areas where data are especially lacking and with a focus on bioavailability. These studies have identified that fish hepatocytes do not offer an effective screen for MNPs, and the data produced further suggests that the MNPs tested are not toxic in that form. Working with CARS I have helped advance the understanding on its utility for nanotoxicology studies, with regards to its application and limitation for uptake analyses. The study of MNPs in combination with NOM has identified the fundamental change that real life exposure scenarios may instigate for toxicity assessments of MNPs, with significant impact on risk assessment criteria. Finally, I’ve established that maternal transfer is an exposure route for MNPs that requires further study, with evidence of transfer to sensitive life stages in a non-mammalian system.DEFR

    Nanotoxicology

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    Pulmonary exposure to carbon nanotubes (CNTs) induces fibrosing lesions in the lungs that manifest rapid-onset inflammatory and fibrotic responses, leading to chronic fibrosis in animals and health concerns in exposed humans. The mechanisms underlying CNT-induced fibrogenic effects remain undefined. Macrophages are known to play important roles in immune regulation and fibrosis development through their distinct subsets. Here we investigated macrophage polarization and activation in mouse lungs exposed to multi-walled CNTs (MWCNTs). Male C57BL/6J mice were treated with MWCNTs (XNRI MWNT-7) at 40\u2009\u3bcg per mouse ( 3c1.86\u2009mg/kg body weight) by oropharyngeal aspiration. The treatment stimulated prominent acute inflammatory and fibrotic responses. Moreover, it induced pronounced enrichment and polarization of macrophages with significantly increased M1 and M2 populations in a time-dependent manner. Induction of M1 polarization was apparent on day 1 with a peak on day 3, but declined rapidly thereafter. On the other hand, the M2 polarization was induced on day 1 modestly, but was remarkably elevated on day 3 and maintained at a high level through day 7. M1 and M2 macrophages were functionally activated by MWCNTs as indicated by the expression of their distinctive functional markers, such as iNOS and ARG1, with time courses parallel to M1 and M2 polarization, respectively. Molecular analysis revealed MWCNTs boosted specific STAT and IRF signaling pathways to regulate M1 and M2 polarization in the lungs. These findings suggest a new mechanistic connection between inflammation and fibrosis induced by MWCNTs through the polarization and activation of macrophages during MWCNT-induced lung pathologic response.CC999999/Intramural CDC HHS/United States2019-03-12T00:00:00Z29338488PMC64135116076vault:3172

    Nanotoxicology

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    Carbon nanotubes (CNTs) are nanomaterials with unique physicochemical properties that are targets of great interest for industrial and commercial applications. Notwithstanding, some characteristics of CNTs are associated with adverse outcomes from exposure to pathogenic particulates, raising concerns over health risks in exposed workers and consumers. Indeed, certain forms of CNTs induce a range of harmful effects in laboratory animals, among which inflammation, fibrosis, and cancer are consistently observed for some CNTs. Inflammation, fibrosis, and malignancy are complex pathological processes that, in summation, underlie a major portion of human disease. Moreover, the functional interrelationship among them in disease pathogenesis has been increasingly recognized. The CNT-induced adverse effects resemble certain human disease conditions, such as pneumoconiosis, idiopathic pulmonary fibrosis (IPF), and mesothelioma, to some extent. Progress has been made in understanding CNT-induced pathologic conditions in recent years, demonstrating a close interconnection among inflammation, fibrosis, and cancer. Mechanistically, a number of mediators, signaling pathways, and cellular processes are identified as major mechanisms that underlie the interplay among inflammation, fibrosis, and malignancy, and serve as pathogenic bases for these disease conditions in CNT-exposed animals. These studies indicate that CNT-induced pathological effects, in particular, inflammation, fibrosis, and cancer, are mechanistically, and in some cases, causatively, interrelated. These findings generate new insights into CNT adverse effects and pathogenesis and provide new targets for exposure monitoring and drug development against inflammation, fibrosis, and cancer caused by inhaled nanomaterials.CC999999/Intramural CDC HHS/United States2019-11-01T00:00:00Z31537143PMC6803058691

    Nanotoxicology

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    Carbon nanotubes (CNT) have been developed into new materials with a variety of industrial and commercial applications. In contrast, the physicochemical properties of CNT at the nanoscale render them the potency to generate toxic effects. Indeed, the potential health impacts of CNT have drawn a great deal of attention in recent years, owing to their identified toxicological and pathological consequences including cytotoxicity, inflammation, fibrosis, genotoxicity, tumorigenesis, and immunotoxicity. Understanding the mechanisms by which CNT induce toxicity and pathology is thus urgently needed for accurate risk assessment of CNT exposure in humans, and for safe and responsible development and commercialization of nanotechnology. Here, we summarize and discuss recent advances in this area with a focus on the molecular interactions between CNT and mammalian systems, and the signaling pathways important for the development of CNT toxicity such as the NF-\uce\ubaB, NLRP3 inflammasome, TGF-\uce\ub21, MAPK, and p53 signaling cascades. With the current mechanistic evidence summarized in this review, we expect to provide new insights into CNT toxicology at the molecular level and offer new clues to the prevention of health effects resulting from CNT exposure. Moreover, we disclose questions and issues that remain in this rapidly advancing field of nanotoxicology, which would facilitate ascertaining future research directions.CC999999/Intramural CDC HHS/United States2016-01-11T00:00:00Z25676622PMC470767

    Nanotoxicology

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    The current study tests the hypothesis that multi-walled carbon nanotubes (MWCNT) with different surface chemistries exhibit different bioactivity profiles in vivo. In addition, the study examined the potential contribution of the NLRP3 inflammasome in MWCNT-induced lung pathology. Unmodified (BMWCNT) and MWCNT that were surface functionalised with -COOH (FMWCNT), were instilled into C57BL/6 mice. The mice were then examined for biomarkers of inflammation and injury, as well as examined histologically for development of pulmonary disease as a function of dose and time. Biomarkers for pulmonary inflammation included cytokines, mediators and the presence of inflammatory cells (IL-1\uce\ub2, IL-18, IL-33, cathepsin B and neutrophils) and markers of injury (albumin and lactate dehydrogenase). The results show that surface modification by the addition of the -COOH group to the MWCNT, significantly reduced the bioactivity and pathogenicity. The results of this study also suggest that in vivo pathogenicity of the BMWCNT and FMWCNT correlates with activation of the NLRP3 inflammasome in the lung.1RC2ES018742-01/ES/NIEHS NIH HHS/United StatesCC999999/Intramural CDC HHS/United StatesRC2 ES-018742/ES/NIEHS NIH HHS/United States2015-12-04T00:00:00Z23432020PMC466941

    Deriving a Provisional Tolerable Intake for Intravenous Exposure to Silver Nanoparticles Released from Medical Devices

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    Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL05) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 ÎŒg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general

    The impact of species and cell type on the nanosafety profile of iron oxide nanoparticles in neural cells

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    Background: While nanotechnology is advancing rapidly, nanosafety tends to lag behind since general mechanistic insights into cell-nanoparticle (NP) interactions remain rare. To tackle this issue, standardization of nanosafety assessment is imperative. In this regard, we believe that the cell type selection should not be overlooked since the applicability of cell lines could be questioned given their altered phenotype. Hence, we evaluated the impact of the cell type on in vitro nanosafety evaluations in a human and murine neuroblastoma cell line, neural progenitor cell line and in neural stem cells. Acute toxicity was evaluated for gold, silver and iron oxide (IO) NPs, and the latter were additionally subjected to a multiparametric analysis to assess sublethal effects. Results: The stem cells and murine neuroblastoma cell line respectively showed most and least acute cytotoxicity. Using high content imaging, we observed cell type-and species-specific responses to the IONPs on the level of reactive oxygen species production, calcium homeostasis, mitochondrial integrity and cell morphology, indicating that cellular homeostasis is impaired in distinct ways. Conclusions: Our data reveal cell type-specific toxicity profiles and demonstrate that a single cell line or toxicity end point will not provide sufficient information on in vitro nanosafety. We propose to identify a set of standard cell lines for screening purposes and to select cell types for detailed nanosafety studies based on the intended application and/or expected exposure

    Nanotechnology and the future of diabetes management

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