Gender difference in hepatic toxicity of titanium dioxide nanoparticles after subchronic oral exposure in Sprague‐Dawley rats

Existing literature pointed out that the liver may be the target organ of toxicity induced by titanium dioxide nanoparticles (TiO₂ NPs) via oral exposure. Gender differences in health effects widely exist and relevant toxicological research is important for safety assessment. To explore the gender susceptibility of TiO₂ NP‐induced hepatic toxicity and the underlying mechanism, we examined female and male Sprague‐Dawley rats administrated with TiO₂ NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day for 90 days. The serum biochemical indicators and liver pathological observation were used to assess hepatic toxicity. We found significant hepatic toxicity could be induced by subchronic oral exposure to TiO₂ NPs, which was more obvious and severe in female rats. No accumulation of TiO₂ NPs in the liver was observed, indicating that hepatic toxicity may not be caused through direct pathways. Oxidized glutathione, lipid peroxidation products increased significantly and reduced glutathione decreased significantly in the liver of rats in repeated TiO₂ NP‐exposed groups. Hematological parameters of white blood cells and inflammatory cytokines in serum including interleukin 1α, interleukin 4 and tumor necrosis factor also increased significantly. Indirect pathways through initiating oxidative stress and inflammatory responses were suggested as the possible mechanism of the hepatic toxicity in this experiment. The higher sensitivity to redox homeostasis imbalance and inflammation of female rats may be the main reason for gender differences. Our research suggested that gender should be a susceptible factor for identifying and monitoring long‐term oral toxicity of TiO₂ NPs.     

Dietary exposure to titanium dioxide nanoparticles in rainbow trout, (Oncorhynchus mykiss): no effect on growth, but subtle biochemical disturbances in the brain

Our laboratory recently reported gut pathology following incidental ingestion of titanium dioxide nanoparticles (TiO₂ NPs) during aqueous exposures in trout, but there are almost no data on dietary exposure to TiO₂ NPs in fish. The aim of this experiment was to observe the sub-lethal effects of dietary exposure to TiO₂ NPs in juvenile rainbow trout (Oncorhynchus mykiss). Stock solutions of dispersed TiO₂ NPs were prepared by sonication without the use of solvents and applied to a commercial trout diet. Fish were exposed in triplicate to either, control (no added TiO₂), 10, or 100 mg kg⁻¹ TiO₂ NPs diets for 8 weeks followed by a 2 week recovery period where all fish were fed the control diet. TiO₂ NPs had no impact on growth or nutritional performance, and no major disturbances were observed in red or white blood cell counts, haematocrits, whole blood haemoglobin, or plasma Na⁺. Ti accumulation occurred in the gill, gut, liver, brain and spleen during dietary TiO₂ exposure. Notably, some of these organs, especially the brain, did not clear Ti after exposure. The brain also showed disturbances to Cu and Zn levels (statistically significant at weeks 4 and 6; ANOVA or Kruskal–Wallis, P < 0.05) and a 50% inhibition of Na⁺K⁺-ATPase activity during TiO₂ NP exposure. Na⁺K⁺-ATPase activity was unaffected in the gills and intestine. Total glutathione in the gills, intestine, liver and brain were not affected by dietary TiO₂ NPs, but thiobarbituric acid reactive substances (TBARS) showed up to 50% decreases in the gill and intestine. We conclude that TiO₂ NPs behave like other toxic dietary metals where growth rate and haematology can be protected during sub-lethal exposures, but in the case of TiO₂ NPs this may be at the expense of critical organs such as the brain and the spleen.     

The effect of TiO(2) and Ag nanoparticles on reproduction and development of Drosophila melanogaster and CD-1 mice

In the last two decades, nanoparticles (NPs) have found applications in a wide variety of consumer goods. Titanium dioxide (TiO₂) and silver (Ag) NPs are both found in cosmetics and foods, but their increasing use is of concern due to their ability to be taken up by biological systems. While there are some reports of TiO₂ and Ag NPs affecting complex organisms, their effects on reproduction and development have been largely understudied. Here, the effects of orally administered TiO₂ or Ag NPs on reproduction and development in two different model organisms were investigated. TiO₂ NPs reduced the developmental success of CD-1 mice after a single oral dose of 100 or 1000 mg/kg to dams, resulting in a statistically significant increase in fetal deformities and mortality. Similarly, TiO₂ NP addition to food led to a significant progeny loss in the fruit fly, Drosophila, as shown by a decline in female fecundity. Ag NP administration resulted in an increase in the mortality of fetal mice. Similarly in Drosophila, Ag NP feeding led to a significant decrease in developmental success, but unlike TiO₂ NP treatment, there was no decline in fecundity. The distinct response associated with each type of NP likely reflects differences in NP administration as well as the biology of the particular model. Taken together, however, this study warns that these common NPs could be detrimental to the reproductive and developmental health of both invertebrates and vertebrates.     

The effects of endoplasmic reticulum stress inducer thapsigargin on the toxicity of ZnO or TiO2 nanoparticles to human endothelial cells

It was recently shown that ZnO nanoparticles (NPs) could induce endoplasmic reticulum (ER) stress in human umbilical vein endothelial cells (HUVECs). If ER stress is associated the toxicity of ZnO NPs, the presence of ER stress inducer thapsigargin (TG) should alter the response of HUVECs to ZnO NP exposure. In this study, we addressed this issue by assessing cytotoxicity, oxidative stress and inflammatory responses in ZnO NP exposed HUVECs with or without the presence of TG. Moreover, TiO₂ NPs were used to compare the effects. Exposure to 32?μg/mL ZnO NPs (p?2 NPs (p?>?0.05), significantly induced cytotoxicity as assessed by WST-1 and neutral red uptake assay, as well as intracellular ROS. ZnO NPs dose-dependently increased the accumulation of intracellular Zn ions, and ZnSO₄ induced similar cytotoxic effects as ZnO NPs, which indicated a role of Zn ions. The release of inflammatory proteins tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) or the adhesion of THP-1 monocytes to HUVECs was not significantly affected by ZnO or TiO₂ NP exposure (p?>?0.05). The presence of 250?nM TG significantly induced cytotoxicity, release of IL-6 and THP-1 monocyte adhesion (p?p?>?0.05). ANOVA analysis indicated no interaction between exposure to ZnO NPs and the presence of TG on almost all the endpoints (p?>?0.05) except neutral red uptake assay (p?相似文献   

Acute high-dose titanium dioxide nanoparticle exposure alters gastrointestinal homeostasis in mice

Human exposure to a wide variety of engineered nanoparticles (NPs) is on the rise and use in common food additives increases gastrointestinal (GI) exposure. Host health is intricately linked to the GI microbiome and immune response. Perturbations in the microbiota can affect energy harvest, trigger inflammation and alter the mucosal barrier leading to various disease states such as obesity and inflammatory bowel diseases. We hypothesized that single high-dose titanium dioxide (TiO₂) NP exposure in mice would lead to dysbiosis and stimulate mucus production and local immune populations. Juvenile mice (9-10 weeks) were gavaged with 1 g/kg TiO₂ NPs and examined for changes in mucosa-associated bacteria abundance, inflammatory cytokines, mucin expression and body mass. Our data provide support that TiO₂ NP ingestion alters the GI microbiota and host defenses promoting metabolic disruption and subsequently weight gain in mice.     

Immunotoxic effects of thymus in mice following exposure to nanoparticulate TiO2

Titanium dioxide nanoparticles (TiO₂ NPs) have been extensively used in industry, medicine, and daily life, and have shown potential toxic effects for animals or humans. We noted that the effects of TiO₂ NPs on the immune system and its mechanism of action in animals or humans have not been elucidated. Thus, mice were exposed to the TiO₂ NPs (0, 1.25, 2.5, or 5 mg kg^?1 body weight) for 9 consecutive months. Exposure to TiO₂ NPs was accumulated in the thymus, leading to a decrease in body weight and increases in the weight of the thymus or thymus indices. In the blood, exposure to TiO₂ NPs significantly decreased white blood cell, red blood cell, reticulocyte, haemoglobin, and mean corpuscular haemoglobin concentration; and increased mean corpuscular volume, mean corpuscular haemoglobin, platelets, and mean platelet volume. The reductions of lymphocyte subsets, including CD3+, CD4+, CD8+, B cell, and natural killer cell, were observed in the TiO₂ NP‐treated mouse thymus. Appearance of starry‐sky aspect of the cortex that is given by the body of macrophages, bleeding, severe hemolysis or congestion, fatty degeneration, and cell apoptosis or necrosis were observed in the thymus following TiO₂ NPs exposure. Importantly, TiO₂ NPs increased expression of nucleic factor‐κB(NF‐κB), IκB kinase1/2, interleukin‐1β, interleukin ?4, regulated upon activation normal T‐cell expressed and secreted, cyclooxygenase 2, neutrophil gelatinase‐associated lipocalin, purinergic receptors‐7, interferon‐inducible protein 10, hypoxia inducible factor 1‐α, p‐c‐Jun N‐terminal kinase, p‐p38, and p‐extracellular signal‐regulated kinase 1/2 protein, respectively; whereas suppressed expression of IκB, peroxisome proliferater‐activated receptor‐γ, trefoil factor 1, peroxisome proliferator activated receptor gamma coactivator‐1α, and prostaglandin E2 proteins in the thymus, respectively. Taken together, these results suggest that TiO₂ NPs exerts toxic effects on lymphoid organs and T cell and innate immune cell homeostasis in mice and that these immunotoxic potential effects may result from the activation of NF‐κB‐mediated mitogen‐activated protein kinases (MAPKs) pathway.     

Chronic nasal exposure to nanoparticulate TiO2 causes pulmonary tumorigenesis in male mice

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. Numerous studies have been confirmed that exposure to titanium dioxide nanoparticles (TiO₂ NPs) may result in chronic pulmonary inflammation in both mice and rats. However, very few studies have focused on the pulmonary tumorigenesis. In this study, to examine whether chronic TiO₂ NP exposure induce tumorigenesis in the lung, forty mice (each group) were nasally exposed to 1.25, 2.5, and 5 mg/kg body weight TiO₂ NPs for nine consecutive months, lung pathology was then evaluated, and the biochemical function parameters in bronchoalveolar lavage (BAL) and tumor markers in the serum were investigated using an ELISA method. We observed that nasal exposure to TiO₂ NPs caused infiltration of inflammatory cells, tumorigenesis in the lung, and accompanied by significant increases of lactate dehydrogenase, alkaline phosphatase, and total protein levels in BLAF, significant increases in tumor markers including cytokeratin 19, neuron‐specific enolase, carcinoembryonic antigen, squamous cell carcinoma antigen, and cancer antigen‐125 in the serum. It implies that chronic inhaled TiO₂ NPs may increase possibility of pulmonary tumor formation for human. Therefore, the production and application of TiO₂ NPs should be paid more attention. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1651–1657, 2017.     

Mechanisms of titanium dioxide nanoparticle‐induced oxidative stress and modulation of plasma glucose in mice

Titanium dioxide nanoparticles (TiO₂ NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO₂ NPs but the underlying mechanisms are unclear at present. Data from genome‐wide analyses showed that TiO₂ NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO₂ NP‐induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO₂ NP‐induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO₂ NP‐induced ER stress occurred earlier than ROS generation. Upon treatment with 4‐phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO₂ NP increased ROS production was inhibited. These results suggest that TiO2 NP‐induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO₂ NPs on plasma glucose metabolism.     

Inflammatory response in human alveolar epithelial cells after TiO2 NPs or ZnO NPs exposure: Inhibition of surfactant protein A expression as an indicator for loss of lung function

The increasing use of metal oxide nanoparticles (MONPs) as TiO₂ NPs or ZnO NPs has led to environmental release and human exposure. The respiratory system, effects on lamellar bodies and surfactant protein A (SP-A) of pneumocytes, can be importantly affected. Exposure of human alveolar epithelial cells (A549) induced differential responses; a higher persistence of TiO₂ in cell surface and uptake (measured by Atomic Force Microscopy) and sustained inflammatory response (by means of TNF-α, IL-10, and IL-6 release) and ROS generation were observed, whereas ZnO showed a modest response and low numbers in cell surface. A reduction in SP-A levels at 24 h of exposure to TiO₂ NPs (concentration-dependent) or ZnO NPs (the higher concentration) was also observed, reversed by blocking the inflammatory response (by the inhibition of IL-6). Loss of SP-A represents a relevant target of MONPs-induced inflammatory response that could contribute to cellular damage and loss of lung function.     

Combined effect of titanium dioxide nanoparticles and glucose on the cardiovascular system in young rats after oral administration

Titanium dioxide nanoparticles (TiO₂ NPs) have already been used as food additive in various products and are usually consumed with a considerable amount of sugar. Oral consumption of TiO₂ NPs poses concerning health risks; however, research on the combined effect of ingested TiO₂ NPs and glucose is limited. We examined young Sprague‐Dawley rats administrated TiO₂ NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day with and without 1.8 g/kg body weight glucose for 30 and 90 days. Heart rate, systolic and diastolic blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. The results showed that oral exposure to TiO₂ NPs and high doses of glucose both could induce cardiovascular injuries. The toxic effects were dose‐, time‐ and gender‐dependent. The interaction effects between oral‐exposed TiO₂ NPs and glucose existed and revealed to be antagonism in most of the biological parameters. However, toxic effects of the high‐dose glucose seemed to be more severe than TiO₂ NPs and the interaction of TiO₂ NPs with glucose. These results suggest that it may be more important to control the sugar intake than TiO₂ NPs for protecting the health of TiO₂ NP consumers.     

Nanoparticle size and combined toxicity of TiO2 and DSLS (surfactant) contribute to lysosomal responses in digestive cells of mussels exposed to TiO2 nanoparticles

The aim of this investigation was to understand the bioaccumulation, cell and tissue distribution and biological effects of disodium laureth sulfosuccinate (DSLS)-stabilised TiO₂ nanoparticles (NPs) in marine mussels, Mytilus galloprovincialis. Mussels were exposed in vivo to 0.1, 1 and 10?mg Ti/L either as TiO₂ NPs (60 and 180?nm) or bulk TiO₂, as well as to DSLS alone. A significant Ti accumulation was observed in mussels exposed to TiO₂ NPs, which were localised in endosomes, lysosomes and residual bodies of digestive cells, and in the lumen of digestive tubules, as demonstrated by ultrastructural observations and electron probe X-ray microanalysis. TiO₂ NPs of 60?nm were internalised within digestive cell lysosomes to a higher extent than TiO₂ NPs of 180?nm, as confirmed by the quantification of black silver deposits after autometallography. The latter were localised mainly forming large aggregates in the lumen of the gut. Consequently, lysosomal membrane stability (LMS) was significantly reduced upon exposure to both TiO₂ NPs although more markedly after exposure to TiO₂-60 NPs. Exposure to bulk TiO₂ and to DSLS also affected the stability of the lysosomal membrane. Thus, effects on the lysosomal membrane depended on the nanoparticle size and on the combined biological effects of TiO₂ and DSLS.     

TiO2 nanoparticles induce insulin resistance in liver-derived cells both directly and via macrophage activation

Abstract

Upon exposure, TiO₂ nanoparticles (NPs) have been recovered in internal organs such as the liver, and are proposed to cause cellular/organ dysfunction, particularly in the liver and lungs. We hypothesized that despite being considered “inert” as bulk material, TiO₂ NPs may impair insulin responses in liver-derived cells, either indirectly by inflammatory activation of macrophages, and/or by directly interfering with insulin signaling. Using qRT-PCR and conditioned medium (CM) approaches, we show that exposure to TiO₂ NPs activates macrophages' expression of TNF-α, IL-6, IL-8, IL-1α and IL-1β and the resulting CM induces insulin resistance in Fao cells. Furthermore, direct exposure of Fao cells to TiO₂ results in activation of the stress kinases JNK and p38MAP kinase, and in induction of insulin resistance at the signaling and metabolic levels. Collectively, our findings provide a proof-of-concept for the ability of man-made NPs to induce insulin resistance in liver-derived cells, an endocrine abnormality underlying some of the most common human diseases.     

Effect of titanium dioxide nanoparticles on glucose homeostasis after oral administration

As food additives, titanium dioxide nanoparticles (TiO₂ NPs) have been widely used in various products that are usually simultaneously consumed with a high content of sugar, thus necessitating research on the effect of TiO₂ NPs on glucose homeostasis. We conducted an animal study to explore the effect of orally administrated TiO₂ NPs on glucose absorption and metabolism in rats at 0, 2, 10 and 50 mg kg^–1 body weight day^–1 for 30 and 90 days. The results showed that oral exposure to TiO₂ NPs caused a slight and temporary hypoglycemic effect in rats at 30 days post‐exposure but recovered at 90 days post‐exposure. Decreased levels of intestinal glucose absorption and increased levels of hepatic glucose metabolism may be responsible for the hypoglycemic effect. Remodeling of the villi in the small intestine that decreased the surface area available for glucose absorption and increased levels of hepatic glucose uptake, utilization and storage related to hepatocellular injury are supposed to be the mechanisms. Our results demonstrated that dietary intake of TiO₂ NPs as food additives could affect the absorption and metabolism of glucose.     

Mechanism of TiO2 nanoparticle‐induced neurotoxicity in zebrafish (Danio rerio)

Zebrafish (Danio rerio) has been used historically for evaluating the toxicity of environmental and aqueous toxicants, and there is an emerging literature reporting toxic effects of manufactured nanoparticles (NPs) in zebrafish embryos. Few researches, however, are focused on the neurotoxicity on adult zebrafish after subchronic exposure to TiO₂ NPs. This study was designed to evaluate the morphological changes, alterations of neurochemical contents, and expressions of memory behavior‐related genes in zebrafish brains caused by exposures to 5, 10, 20, and 40 μg/L TiO₂ NPs for 45 consecutive days. Our data indicated that spatial recognition memory and levels of norepinephrine, dopamine, and 5‐hydroxytryptamine were significantly decreased and NO levels were markedly elevated, and over proliferation of glial cells, neuron apoptosis, and TiO₂ NP aggregation were observed after low dose exposures of TiO₂ NPs. Furthermore, the low dose exposures of TiO₂ NPs significantly activated expressions of C‐fos, C‐jun, and BDNF genes, and suppressed expressions of p38, NGF, CREB, NR1, NR2ab, and GluR2 genes. These findings imply that low dose exposures of TiO₂ NPs may result in the brain damages in zebrafish, provide a developmental basis for evaluating the neurotoxicity of subchronic exposure, and raise the caution of aquatic application of TiO₂ NPs. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 163–175, 2016.     

Simultaneous screening of the stability and dosimetry of nanoparticles dispersions for in vitro toxicological studies with static multiple light scattering technique

To evaluate the nanoparticle (NP) toxicity, much efforts have been devoted for developing methods to accurately disperse NPs into aqueous suspensions prior to in vitro toxicological studies. As NP toxicity is strongly dependent on their physicochemical properties, NP characterization is a key step for any in vitro toxicological study. This study demonstrates that the static multiple light scattering (SMLS) technique allows for the simultaneous screening of the NP size, agglomeration state, stability and dosimetry in biological media. Batch dispersions of TiO₂ P25 NPs in water with various bovine serum albumin (BSA) mass fractions (from 0% to 0.5%) and dilutions of these dispersions into cell culture media were characterized with SMLS. In the batch dispersions, TiO₂ NPs are stable and well dispersed for BSA mass fraction lower than 0.2% while agglomeration and rapid settling is observed for higher BSA mass fractions. Paradoxically, when diluted in cell culture media, TiO₂ NPs are well dispersed and stable for BSA mass fractions higher than 0.2%. The TiO₂ NP dosimetry of these dilutions was evaluated experimentally with SMLS and confronted with numerical approaches. The TiO₂ NP bottom concentration evolves far more slowly in the case of the higher BSA mass fraction. Such measurements give valuable insights on the NP fate and transport in biological media to obtain in fine reliable size and dose-cytotoxicity responses.     

Titanium dioxide nanoparticles prime a specific activation state of macrophages

Titanium dioxide nanoparticles (TiO₂ NPs) are widely used in foods, cosmetics, and medicine. Although the inhalation toxicity of TiO₂ NPs has been studied, the potential adverse effects of oral exposure of low-dose TiO₂ NPs are largely unclear. Herein, with macrophage cell lines, primary cells, and mouse models, we show that TiO₂ NPs prime macrophages into a specific activation state characterized by excessive inflammation and suppressed innate immune function. After a month of dietary exposure in mice or exposure in vitro to TiO₂ NPs (10 and 50?nm), the expressions of pro-inflammatory genes in macrophages were increased, and the expressions of anti-inflammatory genes were decreased. In addition, for macrophages exposed to TiO₂ NPs in vitro and in vivo, their chemotactic, phagocytic, and bactericidal activities were lower. This imbalance in the immune system could enhance the susceptibility to infections. In mice, after a month of dietary exposure to low doses of TiO₂ NPs, an aggravated septic shock occurred in response to lipopolysaccharide challenge, leading to elevated levels of inflammatory cytokines in serum and reduced overall survival. Moreover, TLR4-deficient mice and primary macrophages, or TLR4-independent stimuli, showed less response to TiO₂ NPs. These results demonstrate that TiO₂ NPs induce an abnormal state of macrophages characterized by excessive inflammation and suppressed innate immune function in a TLR4-dependent manner, which may suggest a potential health risk, particularly for those with additional complications, such as bacterial infections.     

Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X‐ray fluorescence microscopy after intratracheal administration with a microsprayer in rats

The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose–response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration–response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO₂ NP microdistribution in rats using X‐ray fluorescence microscopy. Ti intensity in lung sections from rats intratracheally administered 10 mg kg^–1 TiO₂ NPs with a microsprayer was measured using X‐ray fluorescence with a 100 µm beam size. Ti reference samples were prepared by dropping different concentrations of Ti solutions on glass slide or lung sections of untreated rat. Ti intensity increased linearly with Ti content in the reference samples on both substrates. The detection limit of TiO₂ was estimated to be 6.3 ng mm^–2. The reproducibility was confirmed for measurements done in the short‐ (2 weeks) and long‐term (6 months). The quantitative results of TiO₂ NP microdistribution suggested that more TiO₂ NPs were distributed in the right caudal and accessory lobes, which are located downstream of the administration direction of the NP suspension, and the lower portion of each lobe. The detection rates of TiO₂ NPs were 16.6–25.0%, 5.19–15.6%, 28.6–39.2%, 21.4–38.7% and 10.6–23.2% for lung sections from the right cranial, middle, caudal, accessory and left lobes, respectively. Copyright © 2015 John Wiley & Sons, Ltd.     

Exposure to metal oxide nanoparticles administered at occupationally relevant doses induces pulmonary effects in mice

In spite of the great promises that the development of nanotechnologies can offer, concerns regarding potential adverse health effects of occupational exposure to nanoparticle (NP) is raised. We recently identified metal oxide NP in lung tissue sections of welders, located inside macrophages infiltrated in fibrous regions. This suggests a role of these NP in the lung alterations observed in welders. We therefore designed a study aimed to investigate the pulmonary effects, in mice, of repeated exposure to NP administered at occupationally relevant doses. We therefore chose four metal oxide NPs representative of those found in the welder’s lungs: Fe₂O₃, Fe₃O₄, MnFe₂O₄ and CrOOH. These NPs were administered weekly for up to 3 months at two different doses: 5?μg, chosen as occupationally relevant to welding activity, and 50?μg, chosen as occupationally relevant to the context of an NP-manufacturing facility. Our results show that 3 month-repeated exposures to 5?μg NP induced limited pulmonary effects, characterized by the development of a mild peribronchiolar fibrosis observed for MnFe₂O₄ and CrOOH NP only. This fibrotic event was further extended in terms of intensity and localization after the repeated administration of 50?μg NP: all but Fe₂O₃ NP induced the development of peribronchiolar, perivascular and alveolar fibrosis, together with an interstitial inflammation. Our data demonstrate for the first time a potential risk for respiratory health posed by repeated exposure to NP at occupationally relevant doses. Given these results, the development of occupational exposure limits (OELs) specifically dedicated to NP exposure might therefore be an important issue to address.     

The effect of airborne Palladium nanoparticles on human lung cells,endothelium and blood – A combinatory approach using three in vitro models

A better understanding of the mechanisms behind adverse health effects caused by airborne fine particles and nanoparticles (NP) is essential to improve risk assessment and identification the most critical particle exposures. While the use of automobile catalytic converters is decreasing the exhausts of harmful gases, concentrations of fine airborne particles and nanoparticles (NPs) from catalytic metals such as Palladium (Pd) are reaching their upper safe level. Here we used a combinatory approach with three in vitro model systems to study the toxicity of Pd particles, to infer their potential effects on human health upon inhalation. The three model systems are 1) a lung system with human lung cells (ALI), 2) an endothelial cell system and 3) a human whole blood loop system. All three model systems were exposed to the exact same type of Pd NPs. The ALI lung cell exposure system showed a clear reduction in cell growth from 24 h onwards and the effect persisted over a longer period of time. In the endothelial cell model, Pd NPs induced apoptosis, but not to the same extent as the most aggressive types of NPs such as TiO₂. Similarly, Pd triggered clear coagulation and contact system activation but not as forcefully as the highly thrombogenic TiO₂ NPs. In summary, we show that our 3-step in vitro model of the human lung and surrounding vessels can be a useful tool for studying pathological events triggered by airborne fine particles and NPs.