10 research outputs found

    WS22D nanosheets in 3D nanoflowers

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    In this work it has been established that 3D nanoflowers of WS2 synthesized by chemical vapour deposition are composed of few layer WS2 along the edges of the petals. An experimental study to understand the evolution of these nanostructures shows the nucleation and growth along with the compositional changes they undergo

    Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: an international workshop report

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    Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, “Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements”, explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations

    Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity

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    New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances

    An investigation of the carbon nanotube – lipid interface and its impact upon lung function

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    Multiwalled carbon nanotubes (MWCNTs) are now synthesized on a scale of thousands of tonnes per year, creating a considerable inhalation risk for the people that work with them. However, significant knowledge gaps on MWCNT pulmonary toxicity still remain due to the complex composition of the air-lung interface, particularly the influence of the pulmonary surfactant (PS) which coats the surface of the lung, plus a lack of insight into the impact of MWCNT physicochemical properties on their toxicity. The aims of this thesis were two-fold. Firstly, the Langmuir Blodgett trough was used to investigate the impact of MWCNT inhalation on the biophysical behaviour of PS lipids at the air-water interface. Changes were found to be length-dependant. ‘Short’ MWCNTs (1.1 ”m, SD = 0.61) reduced the maximum interfacial film pressure by 10 mN/m (14%) in dipalmitoylphosphatidylcholine (DPPC) and PS, at an interfacial MWCNT-PS lipid mass ratio range of 50:1 to 1:1. ‘Long’ commercial MWCNTs (2.1 ”m, SD = 1.2) caused compression resistance at the same mass loadings. ‘Very long’ MWCNTs (35 ”m, SD = 19) sequestered DPPC and were squeezed out of the film. Positive and neutral functionalised hydrophilic MWCNTs also caused significant monolayer expansion. In a complementary imaging study, ordered DPPC coronas were found to form on the MWCNT surface. MWCNT aspect ratio and charge can therefore both influence the compression resistance and maximum pressure of PS lipids, each believed to influence PS function. Secondly, 6 popular commercial MWCNT types were characterised, and their toxicity to alveolar macrophage cells (AMs) investigated. The MWCNTs shared some similar characteristics: all MWCNTs contained only iron and carbon, diameters were 10-25 nm, the D/G ratios were ~1, and the measured agglomerate sizes in cell culture medium were 0.26-0.39 ”m^2. However, the samples displayed different cytotoxicities, with 4 samples causing significant reductions in AM viability. Imaging of critical point dried cells, using field ion beam scanning electron microscopy, showed that the AMs tended to surround and engulf MWCNT agglomerates. The more toxic MWCNTs were associated with lower cell numbers and signs of an inability of the AMs to phagocytose the MWCNT agglomerates. Certain classes of commercial MWCNTs therefore pose a threat to lung health if inhaled. Further investigations are needed to understand which of their characteristics cause increased toxicity.Open Acces

    Global Eradication of Infectious Diseases: Can 'Not Very Much' undermine the goal of 'None at All'?

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    Despite the well-publicised success of global smallpox eradication, 'zero' remains an elusive goal for the majority of vaccine-preventable diseases, making reduced pathogen circulation, or direct protection of the vulnerable more achievable strategies. We will consider potential deleterious consequences of reduced infection transmission, in the context of diseases such as influenza and pertussis, where immunity following natural exposure may be superior to that following immunisation. Implications for vaccine design and implementation will be discussed.

    Translocation of Functionalized Multi-Walled Carbon Nanotubes across Human Pulmonary Alveolar Epithelium: Dominant Role of Epithelial Type 1 Cells

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    Uptake and translocation of short functionalized multi-walled carbon nanotubes (short-fMWCNTs) through the pulmonary respiratory epithelial barrier depend on physicochemical property and cell type. Two monoculture models, immortalized human alveolar epithelial type 1 (TT1) cells and primary human alveolar epithelial type 2 cells (AT2), which constitute the alveolar epithelial barrier, were employed to investigate the uptake and transport of 300 and 700 nm in length, poly­(4-vinylpyridine)-functionalized, multi-walled carbon nanotubes (p­(4VP)-MWCNTs) using quantitative imaging and spectroscopy techniques. The p­(4VP)-MWCNT exhibited no toxicity on TT1 and AT2 cells, but significantly decreased barrier integrity (*<i>p</i> < 0.01). Uptake of p­(4VP)-MWCNTs was observed in 70% of TT1 cells, correlating with compromised barrier integrity and basolateral p­(4VP)-MWCNT translocation. There was a small but significantly greater uptake of 300 nm p­(4VP)-MWCNTs than 700 nm p­(4VP)-MWCNTs by TT1 cells. Up to 3% of both the 300 and 700 nm p­(4VP)-MWCNTs reach the basal chamber; this relatively low amount arose because the supporting transwell membrane minimized the amount of p­(4VP)-MWCNT translocating to the basal chamber, seen trapped between the basolateral cell membrane and the membrane. Only 8% of AT2 cells internalized p­(4VP)-MWCNT, accounting for 17% of applied p­(4VP)-MWCNT), with transient effects on barrier function, which initially fell then returned to normal; there was no MWCNT basolateral translocation. The transport rate was MWCNT length modulated. The comparatively lower p­(4VP)-MWCNT uptake by AT2 cells is proposed to reflect a primary barrier effect of type 2 cell secretions and the functional differences between the type 1 and type 2 alveolar epithelial cells

    Getting to Zero: Michaelmas Term Seminar Series 2009

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    Achieving an end-state of "zero" has emerged as an important policy goal for a number of 21st Century challenges. The most prominent example is the "Global Zero" campaign to eliminate nuclear weapons. Yet, in a century of globalization, when the life of every individual is directly affected by a vast network of forces beyond their control, this concept has the power to inspire action on some of the most intractable problems of our time.

    Pathway-Based Predictive Approaches for Non-Animal Assessment of Acute Inhalation toxicity

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    New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.JRC.F.3-Chemicals Safety and Alternative Method

    Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity

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