This review is concerned with evaluating the toxicity associated with human exposure to silver and gold nanoparticles (NPs), due to the relative abundance of toxicity data available for these ...particles, when compared to other metal particulates. This has allowed knowledge on the current understanding of the field to be gained, and has demonstrated where gaps in knowledge are. It is anticipated that evaluating the hazards associated with silver and gold particles will ultimately enable risk assessments to be completed, by combining this information with knowledge on the level of human exposure. The quantity of available hazard information for metals is greatest for silver particulates, due to its widespread inclusion within a number of diverse products (including clothes and wound dressings), which primarily arises from its antibacterial behaviour. Gold has been used on numerous occasions to assess the biodistribution and cellular uptake of NPs following exposure. Inflammatory, oxidative, genotoxic, and cytotoxic consequences are associated with silver particulate exposure, and are inherently linked. The primary site of gold and silver particulate accumulation has been consistently demonstrated to be the liver, and it is therefore relevant that a number of in vitro investigations have focused on this potential target organ. However, in general there is a lack of in vivo and in vitro toxicity information that allows correlations between the findings to be made. Instead a focus on the tissue distribution of particles following exposure is evident within the available literature, which can be useful in directing appropriate in vitro experimentation by revealing potential target sites of toxicity. The experimental design has the potential to impact on the toxicological observations, and in particular the use of excessively high particle concentrations has been observed. As witnessed for other particle types, gold and silver particle sizes are influential in dictating the observed toxicity, with smaller particles exhibiting a greater response than their larger counterparts, and this is likely to be driven by differences in particle surface area, when administered at an equal-mass dose. A major obstacle, at present, is deciphering whether the responses related to silver nanoparticulate exposure derive from their small size, or particle dissolution contributes to the observed toxicity. Alternatively, a combination of both may be responsible, as the release of ions would be expected to be greater for smaller particles.
The intestine forms the largest interface between the environment and the human organism. Its integrity and functioning are crucial for the uptake of nutrients while preventing access of harmful ...antigens. Inflammatory conditions can significantly change the normal functioning of the intestine. In vitro models that adequately reproduce both healthy and inflamed intestinal tissue could provide a useful tool for studying the mechanisms of intestinal inflammation and investigating new therapeutic drugs.
We established a co-culture of Caco-2 and PMA-differentiated THP-1 cells that mimics the intestine in healthy and controlled inflamed states. In homoeostatic conditions without stimulation, Caco-2 and THP-1 cells were co-cultured for 48h without affecting the barrier integrity and with no increase in the release of cytokines, nitric oxide or lactate dehydrogenase. To simulate the inflamed intestine, the Caco-2 barrier was primed with IFN-γ and THP-1 cells were pre-stimulated with LPS and IFN-γ. In these conditions a significant but temporary reduction in barrier integrity was measured, and large concentrations of pro-inflammatory cytokines and cytotoxicity markers detected.
With its ability to feature numerous hallmarks of intestinal inflammation the presented co-culture model of epithelial cells and macrophages offers a unique possibility to study exposure effects in relation to the health status of the intestine.
•A novel, tunable co-culture model of Caco-2 and THP-1 cells was established.•The THP-1 differentiation protocol is crucial for a stable co-culture with Caco-2.•Synergistic effects of TNF-α and IFN-γ were key to induce inflammation in vitro.•The inflamed co-culture shows barrier disruption, cytokine release and cytotoxicity.•Downregulation of inflammation is prevented by pretreatment of cells with cytokines.
The liver is one of the most important multi-functional organs in the human body. Amongst various crucial functions, it is the main detoxification center and predominantly implicated in the clearance ...of xenobiotics potentially including particulates that reach this organ. It is now well established that a significant quantity of injected, ingested or inhaled nanomaterials (NMs) translocate from primary exposure sites and accumulate in liver. This review aimed to summarize and discuss the progress made in the field of hepatic nanotoxicology, and crucially highlight knowledge gaps that still exist.
Key considerations include
In vivo studies clearly demonstrate that low-solubility NMs predominantly accumulate in the liver macrophages the Kupffer cells (KC), rather than hepatocytes.
KCs lining the liver sinusoids are the first cell type that comes in contact with NMs in vivo. Further, these macrophages govern overall inflammatory responses in a healthy liver. Therefore, interaction with of NM with KCs in vitro appears to be very important.
Many acute in vivo studies demonstrated signs of toxicity induced by a variety of NMs. However, acute studies may not be that meaningful due to liver's unique and unparalleled ability to regenerate. In almost all investigations where a recovery period was included, the healthy liver was able to recover from NM challenge. This organ's ability to regenerate cannot be reproduced in vitro. However, recommendations and evidence is offered for the design of more physiologically relevant in vitro models.
Models of hepatic disease enhance the NM-induced hepatotoxicity.
The review offers a number of important suggestions for the future of hepatic nanotoxicology study design. This is of great significance as its findings are highly relevant due to the development of more advanced in vitro, and in silico models aiming to improve physiologically relevant toxicological testing strategies and bridging the gap between in vitro and in vivo experimentation.
A rich body of literature exists that has demonstrated adverse human health effects following exposure to ambient air particulate matter (PM), and there is strong support for an important role of ...ultrafine (nanosized) particles. At present, relatively few human health or epidemiology data exist for engineered nanomaterials (NMs) despite clear parallels in their physicochemical properties and biological actions in
models.
NMs are available with a range of physicochemical characteristics, which allows a more systematic toxicological analysis. Therefore, the study of ultrafine particles (UFP, <100 nm in diameter) provides an opportunity to identify plausible health effects for NMs, and the study of NMs provides an opportunity to facilitate the understanding of the mechanism of toxicity of UFP.
A workshop of experts systematically analyzed the available information and identified 19 key lessons that can facilitate knowledge exchange between these discipline areas.
Key lessons range from the availability of specific techniques and standard protocols for physicochemical characterization and toxicology assessment to understanding and defining dose and the molecular mechanisms of toxicity. This review identifies a number of key areas in which additional research prioritization would facilitate both research fields simultaneously.
There is now an opportunity to apply knowledge from NM toxicology and use it to better inform PM health risk research and vice versa. https://doi.org/10.1289/EHP424.
The use of nanoparticles in various applications is steadily on the rise, with use in a range of applications, including printer toner, sunscreen, medical imaging, and enhanced drug delivery. While ...research on human effects via, for example, inhalation is relatively well developed, the environmental assessment of nanoparticles is in its infancy. In the present study, we assessed the uptake and quantitative accumulation, as well as the depuration, of a model nanoparticle, a 20-nm fluorescent carboxylated polystyrene bead, in the aquatic invertebrate Daphnia magna and compared it to a larger, 1,000-nm particle. Using confocal microscopy, rapid accumulation in the gastrointestinal tract was observed within an hour of exposure to both particle sizes in both adults and neonates. Fluorescence could also be observed in the oil storage droplets, suggesting that both particle sizes have crossed the gut’s epithelial barrier. Quantification of fluorescence of both sizes of particles showed that although uptake of the 20-nm particles was lower in terms of mass it was equal to or greater than 1,000-nm particle uptake when expressed as surface area or particle number. Depuration was relatively rapid for the 1,000-nm beads, decreasing by more than 90% over 4 h. In contrast, depuration of the 20-nm beads was less extensive, reaching 40% over 4 h. Transmission electron microscopy confirmed uptake of 1,000-nm beads, but uptake of 20-nm beads was inconclusive since similar-sized inclusions could be observed in control treatments.
Summary In this report we review the health effects of three short-lived greenhouse pollutants—black carbon, ozone, and sulphates. We undertook new meta-analyses of existing time-series studies and ...an analysis of a cohort of 352 000 people in 66 US cities during 18 years of follow-up. This cohort study provides estimates of mortality effects from long-term exposure to elemental carbon, an indicator of black carbon mass, and evidence that ozone exerts an independent risk of mortality. Associations among these pollutants make drawing conclusions about their individual health effects difficult at present, but sulphate seems to have the most robust effects in multiple-pollutant models. Generally, the toxicology of the pure compounds and their epidemiology diverge because atmospheric black carbon, ozone, and sulphate are associated and could interact with related toxic species. Although sulphate is a cooling agent, black carbon and ozone could together exert nearly half as much global warming as carbon dioxide. The complexity of these health and climate effects needs to be recognised in mitigation policies.
The portfolio of cytokines is key to the function of macrophages as sentries of the innate immune system as well as being critical for the transition from innate to adaptive immunity. Cytokine bias ...is critical in the fate of macrophages into a continuum of inflammatory to anti-inflammatory macrophages. Due to advances in the field of toxicology, increasingly advanced multi-cellular in vitro safety assessment models are being developed in order to allow for a better predication of potential adverse effects in humans with many of these models include a macrophage population. The selection of the correct macrophage cells in these advanced in vitro models is critical for a physiologically relevant and realistic immune response. In this study we investigated cytokine response profile (IL1-β, IL6, IL10 and TNF-α) of activated and non-activated THP-1 (immortalized monocyte-like cell line), primary human Kupffer cells (liver resident macrophages) and human primary peripheral blood mononuclear cells following exposure of a panel of nanomaterials or ethanol. The data demonstrated that the THP-1 cell line are not great cytokine producers. The PBMC appear to be a good in vitro surrogate for circulating/pro-inflammatory macrophages but are not a suitable replacement for Kupffer cells. The findings from this study highlight the necessity for the selection of appropriate macrophages populations to meet the specific physiological requirements of in vitro experiment.
Different particle types cause excessive lung inflammation that is thought to play a role in the various types of pathology they produce. Recently attention has been focused on nanoparticles due to ...their presence in environmental particulate air pollution, their use and exposure in occupational settings, and their potential use in nanotechnology and novel therapeutics. We have shown previously that the surface area metric drives the overload response. We have instilled a number of low-toxicity dusts of various particle sizes and assessed neutrophil influx into the lung at 18-24 h postinstillation. The extent of inflammation was demonstrated as being a function not of the mass dose instilled but interestingly of the surface area dose instilled. Since low-toxicity nanoparticles present a "special" case of high surface area, they are relatively inflammogenic. We tested whether we could use this approach to model the reactivity of highly toxic dusts. Rats were instilled with either DQ12 quartz or aluminum lactate-treated DQ12 and, as anticipated, the high specific surface toxicity of DQ12 meant that it was much more inflammogenic (63 times more) than the surface area alone would have predicted. By contrast, aluminum lactate-treated DQ12 fell into the line of "low-toxicity" dusts. In addition, as an in vitro testing alternative to that of in vivo testing, interleukin (IL)-8 production in A549 cells exposed to the panel of various particles clearly demonstrated the ability to also identify a relationship between surface area dose and reactivity. These approaches present the possibility of modelling potential toxicity of nanoparticles and nuisance dusts based on the inflammatory response of a given instilled surface area dose.
In vitro three-dimensional (3D) lung cell models have been thoroughly investigated in recent years and provide a reliable tool to assess the hazard associated with nanomaterials (NMs) released into ...the air. In this study, a 3D lung co-culture model was optimized to assess the hazard potential of multiwalled carbon nanotubes (MWCNTs), which is known to provoke inflammation and fibrosis, critical adverse outcomes linked to acute and prolonged NM exposure. The lung co-cultures were exposed to MWCNTs at the air-liquid interface (ALI) using the VITROCELL
Cloud system while considering realistic occupational exposure doses. The co-culture model was composed of three human cell lines: alveolar epithelial cells (A549), fibroblasts (MRC-5), and macrophages (differentiated THP-1). The model was exposed to two types of MWCNTs (Mitsui-7 and Nanocyl) at different concentrations (2-10 μg/cm
) to assess the proinflammatory as well as the profibrotic responses after acute (24 h, one exposure) and prolonged (96 h, repeated exposures) exposure cycles. The results showed that acute or prolonged exposure to different concentrations of the tested MWCNTs did not induce cytotoxicity or apparent profibrotic response; however, suggested the onset of proinflammatory response.
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