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Exposure to engineered nanomaterials (ENM) poses a potential health risk to humans throughlong-term, repetitive low-dose exposures. Currently, this is not commonplace within in vitro lungcell cultures. Therefore, the purpose of this study was to consider the optimal exposureapproach toward determining the stability, sensitivity and validity of using in vitro lung cellmono- and co-cultures to determine ENM hazard. A range of exposure scenarios wereconducted with DQ12 (previously established as a positive particle control) (historic and reactivated),TiO2 (JRC NM–105) and BaSO4 (JRC NM–220) on both monocultures of A549 cells aswell as co-cultures of A549 cells anddifferentiated THP-1 cells. Cell cultures were exposed toeither a single, or a repeated exposure over 24, 48- or 72-hours at in vivo extrapolated concentrationsof 0–5.2 mg/cm2, 0-6mg/cm2 and 0-1mg/cm2. The focus of this study was the pro-inflammatory,cytotoxic and genotoxic response elicited by these ENMs. Exposure to DQ12 caused proinflammatoryresponses after 48 hours repeat exposures, as well as increases in micronucleus frequency.Neither TiO2 nor BaSO4 elicited a pro-inflammatory response at this time point.However, there was induction of IL-6 after 24 hours TiO2 exposure. In conclusion, it is importantto consider the appropriateness of the positive control implemented, the cell culture model, thetime of exposure as well as the type of exposure (bolus or fractionated) before establishing if anin vitro model is appropriate to determine the level of response to the specific ENM of interest.

Additional file1. Literature screening methodology, graphical comparisons of in vivo and in vitro responses, and data analysis results. Figure S1. IL-8, IL-6, IL-1β and TNF-α cytokine responses in vitro compared to PMN influx in vivo following exposure to α-quartz. Figure S2. IL-8, IL-6, IL-1β and TNF-α cytokine responses in vitro compared to PMN influx in vivo following exposure to nano-CeO2. Table S1. Data analysis results for in vitro studies. Table S2. Data analysis results for in vivo studies. Table S3. CIs for various BMR applied in BMD analysis. Table S4 Model comparisons for α-quartz using log-log regression analysis. Table S5. Model comparisons for nano-CeO2 using log-log regression analysis.

The aim of this study is to investigate the impact of foreign exchange reserves accumulation on the investment of companies in Vietnam. A detailed data of 332 firms listed on Hochiminh Stock Exchange is collected over the period from the first quarter of 2009 to the first quarter of 2019. Generalized Method of Moments (GMM) is employed to test the proposed hypotheses in this study. Estimation results reveal that great changes in foreign exchange reserves reduce corporate investment. Besides that, according to the growth stage of reserve accumulation, to some extent, foreign exchange reserve accumulation benefits domestic investment. However, when reserves increases tremendously, it may cause negative effect to investment. The study also investigates the impact of foreign exchange reserves on investment of companies in different industries. Empirical findings point out that for firms which are newly listed, young, small, and has low investment in fixed asset and low dividend payout ratio, the investment-cash flow sensitivity is very high. Changing in foreign exchange reserves does not greatly affect firm investment. In contrast, for enterprises which are long-established, large, and has high fixed asset value and high dividend payout ratio, the investment-cash flow sensitivity is lower. However, large change in the accumulation of reserves adversely affects firm investment. The empirical findings imply that government should be more cautious in managing foreign exchange reserves and firms should develop a plan to effectively manage their cash in order to lower borrowing costs as well as to less depend on external financing sources.

The EU H2020 BIORIMA project is one of the first and largest European initiatives that is totally dedicated to the development of innovative and robust methodologies to assess and manage the risks of nano-biomaterials (NBM) that are used in medical devices and advanced medicinal therapy products, along their whole life cycle, and at the same time identify and implement suitable safety-by-design alternatives. The BIORIMA consortium is implementing a comprehensive method testing and validation program to adapt and further develop existing tools for human and environmental exposure and hazard assessment of NBM, beyond clinical studies. All approaches that are tested and developed are integrated into a risk management framework (RMF) to help practitioners and end-users in finding best practical solutions for testing and handling of NBM. The RMF will be implemented by means of a web-based and specially designed Decision Support System (DSS), to comply with existing relevant regulations, such as MDR 2017/745 or REACH. The poster describes the latest findings of the project after 3 years of intensive research on the hazard of NBM and of the underlying mechanisms that are crucial for the effects and exposure we observe in humans and the environment.

ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to evaluate the risks associated with nanomaterial (NM) exposure on human health across pulmonary, cardiovascular, hepatic, renal, and developmental systems. The outputs from this project have formed the basis of this review. A retrospective interpretation of the findings across a wide range of in vitro and in vivo studies was performed to identify the main highlights from the project. In particular, focus was placed on informing what advances were made in the hazard assessment of NM, as well as offering some suggestions on the future of "nanotoxicology research" based on these observations, shortcomings, and lessons learned from the project. A number of issues related to the hazard assessment of NM are discussed in detail and include use of appropriate NM for nanotoxicology investigations; characterization and dispersion of NM; use of appropriate doses for all related investigations; need for the correct choice of experimental models for risk assessment purposes; and full understanding of the test systems and correct interpretation of data generated from in vitro and in vivo systems. It is hoped that this review may assist in providing information in the implementation of guidelines, model systems, validation of assessment methodology, and integrated testing approaches for risk assessment of NM. It is vital to learn from ongoing and/or completed studies to avoid unnecessary duplication and offer suggestions that might improve different aspects of experimental design.

Societies worldwide are investing considerable resources into the safe development and use of nanomaterials. Although each of these protective efforts is crucial for governing the risks of nanomaterials, they are insufficient in isolation. What is missing is a more integrative governance approach that goes beyond legislation. Development of this approach must be evidence based and involve key stakeholders to ensure acceptance by end users. The challenge is to develop a framework that coordinates the variety of actors involved in nanotechnology and civil society to facilitate consideration of the complex issues that occur in this rapidly evolving research and development area. Here, we propose three sets of essential elements required to generate an effective risk governance framework for nanomaterials. (1) Advanced tools to facilitate risk-based decision making, including an assessment of the needs of users regarding risk assessment, mitigation, and transfer. (2) An integrated model of predicted human behavior and decision making concerning nanomaterial risks. (3) Legal and other (nano-specific and general) regulatory requirements to ensure compliance and to stimulate proactive approaches to safety. The implementation of such an approach should facilitate and motivate good practice for the various stakeholders to allow the safe and sustainable future development of nanotechnology.

This file contains the NCBI taxonomy versions used in the experiments, the experimental results to validate the impact of parameters on the classification performance of SeMeta, and the effect of the usage of cluster cores on SeMeta. (PDF 423 kb)

This file contains the details of the simulated datasets used in this study, and the experimental results of SeMeta on a sample of Human Gut Metagenome. (PDF 90 kb)

Nanomaterials (NMs) display many unique and useful physico-chemical properties. However, reliable approaches are needed for risk assessment of NMs. The present study was performed in the FP7-MARINA project, with the objective to identify and evaluate in vitro test methods for toxicity assessment in order to facilitate the development of an intelligent testing strategy (ITS). Six representative oxide NMs provided by the EC-JRC Nanomaterials Repository were tested in nine laboratories. The in vitro toxicity of NMs was evaluated in 12 cellular models representing 6 different target organs/systems (immune system, respiratory system, gastrointestinal system, reproductive organs, kidney and embryonic tissues). The toxicity assessment was conducted using 10 different assays for cytotoxicity, embryotoxicity, epithelial integrity, cytokine secretion and oxidative stress. Thorough physico-chemical characterization was performed for all tested NMs. Commercially relevant NMs with different physico-chemical properties were selected: two TiO2 NMs with different surface chemistry – hydrophilic (NM-103) and hydrophobic (NM-104), two forms of ZnO – uncoated (NM-110) and coated with triethoxycapryl silane (NM-111) and two SiO2 NMs produced by two different manufacturing techniques – precipitated (NM-200) and pyrogenic (NM-203). Cell specific toxicity effects of all NMs were observed; macrophages were the most sensitive cell type after short-term exposures (24-72h) (ZnO>SiO2>TiO2). Longer term exposure (7 to 21 days) significantly affected the cell barrier integrity in the presence of ZnO, but not TiO2 and SiO2, while the embryonic stem cell test (EST) classified the TiO2 NMs as potentially ‘weak-embryotoxic’ and ZnO and SiO2 NMs as ‘non-embryotoxic’. A hazard ranking could be established for the representative NMs tested (ZnO NM-110 > ZnO NM-111 > SiO2 NM-203 > SiO2 NM-200 > TiO2 NM-104 > TiO2 NM-103). This ranking was different in the case of embryonic tissues, for which TiO2 displayed higher toxicity compared with ZnO and SiO2. Importantly, the in vitro methodology applied could identify cell- and NM-specific responses, with a low variability observed between different test assays. Overall, this testing approach, based on a battery of cellular systems and test assays, complemented by an exhaustive physico-chemical characterization of NMs, could be deployed for the development of an ITS suitable for risk assessment of NMs. This study also provides a rich source of data for modeling of NM effects.

Comparative hazard identification of nanomaterials (NMs) can aid in the prioritisation for further toxicity testing. Here, we assessed the acute lung, systemic and liver responses in C57BL/6N mice for three NMs to provide a hazard ranking. A silver (Ag), non-functionalised zinc oxide (ZnO) and a triethoxycaprylylsilane functionalised ZnO NM suspended in water with 2% mouse serum were examined 24 hours following a single intratracheal instillation (I.T.). An acute pulmonary inflammation was noted (marked by a polymorphonuclear neutrophil influx) with cell damage (LDH and total protein) in broncho-alveolar lavage fluid (BALF) after administration of both non-functionalised and functionalised ZnO. The latter also induced systemic inflammation measured as an increase in blood neutrophils and a decrease in blood lymphocytes. Exposure to Ag NM was not accompanied by pulmonary inflammation or cytotoxicity, or by systemic inflammation. A decrease in glutathione levels was demonstrated in the liver following exposure to high doses of all three nanomaterials irrespective of any noticeable inflammatory or cytotoxic effects in the lung. By applying benchmark dose (BMD) modeling statistics to compare potencies of the NMs, we rank functionalised ZnO ranked the highest based on the largest number of affected endpoints, as well as the strongest responses observed after 24 hours. The non-functionalised ZnO NM gave an almost similar response, whereas Ag NM did not cause an acute response at similar doses.

It has been reported that fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat. We set out to replicate and extend these effects using a robust experimental design. Groups of 75 (control vehicle) or 55 (50, 200 or 1000 ng of TCDD kg-1 bodyweight) female Wistar(Han) rats were exposed to TCDD on Gestational Day (GD) 15, then allowed to litter. The high dose group dams showed no sustained weight loss compared to control, but four animals had total litter loss. Pups in the high dose group showed reduced body weight up till day 21, and pups in the medium dose group showed reduced body weight in the first week post partum. Balano-preputial separation (BPS) was significantly delayed in the high dose group male offspring. There were no significant effects of treatment when the offspring were subjected to a functional observational battery, or mated with females to assess reproductive capability. 25 males per group were killed on post natal day (PND) 70, and ~60 animals per group (~30 for the high dose group) on PND120 to assess seminology and other endpoints. At PND120, the two highest dose groups showed a statistically significant elevation of sperm counts, compared to control; however, this effect was small (~30%), within the normal range of sperm counts for this strain of rat, was not reflected in testicular spermatid counts nor PND70 data, and is therefore postulated to have no biological significance. Although there was an increase in the proportion of abnormal sperm at PND70, seminology parameters were otherwise unremarkable. Testis weights in the high dose group were slightly decreased at PND 70 and 120, and at PND120, brain weights were decreased in the high dose group, liver to body weight ratios were increased for all three dose groups, with an increase in inflammatory cell foci in the epididymis in the high dose group. These data show that TCDD is a potent developmental toxin after exposure of the developing fetus, but that acute developmental exposure to TCDD on GD15 caused no decrease in sperm counts.