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[Background] Before introducing proteins from new or alternative dietary sources into the market, a compressive risk assessment including food allergic sensitization should be carried out in order to ensure their safety. We have recently proposed the adverse outcome pathway (AOP) concept to structure the current mechanistic understanding of the molecular and cellular pathways evidenced to drive IgE-mediated food allergies. This AOP framework offers the biological context to collect and structure existing in vitro methods and to identify missing assays to evaluate sensitizing potential of food proteins. [Scope and approach] In this review, we provide a state-of-the-art overview of available in vitro approaches for assessing the sensitizing potential of food proteins, including their strengths and limitations. These approaches are structured by their potential to evaluate the molecular initiating and key events driving food sensitization. [Key findings and conclusions] The application of the AOP framework offers the opportunity to anchor existing testing methods to specific building blocks of the AOP for food sensitization. In general, in vitro methods evaluating mechanisms involved in the innate immune response are easier to address than assays addressing the adaptive immune response due to the low precursor frequency of allergen-specific T and B cells. Novel ex vivo culture strategies may have the potential to become useful tools for investigating the sensitizing potential of food proteins. When applied in the context of an integrated testing strategy, the described approaches may reduce, if not replace, current animal testing approaches., The authors are all part of the COST Action FA1402 entitled: Improving Allergy Risk Assessment Strategy for New Food Proteins (ImpARAS).

The development and introduction of new dietary protein sources has the potential to improve food supply sustainability. Understanding the potential allergenicity of these new or modified proteins is crucial to ensure protection of public health. Exposure to new proteins may result in de novo sensitization, with or without clinical allergy, or clinical reactions through cross-reactivity. In this paper we review the potential of current methodologies (in silico, in vitro degradation, in vitro IgE binding, animal models and clinical studies) to address these outcomes for risk assessment purposes for new proteins, and especially to identify and characterise the risk of sensitization for IgE mediated allergy from oral exposure. Existing tools and tests are capable of assessing potential crossreactivity. However, there are few possibilities to assess the hazard due to de novo sensitization. The only methods available are in vivo models, but many limitations exist to use them for assessing risk. We conclude that there is a need to understand which criteria adequately define allergenicity for risk assessment purposes, and from these criteria develop a more suitable battery of tests to distinguish between proteins of high and low allergenicity, which can then be applied to assess new proteins with unknown risks. © 2017 The Authors Chemicals/CAS: immunoglobulin E, 37341-29-0

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field. © 2017, Springer-Verlag GmbH Germany.

Lifetime testing for carcinogenicity of pharmaceuticals in rodents has been a controversial issue since the start of the International Conference on Harmonisation in 1990. Since 2010 the debate reached a new level following the proposal that a negative outcome of carcinogenicity studies can be predicted based upon the findings of 6 months studies. In addition, the value of pharmacological mode of action (MoA) data for positive prediction has become apparent. Such predictions rest heavily on prior data and first-in-class compounds are difficult to evaluate in this way. Virtual waivers are rarely given to such compounds. We discuss here the utility of in vitro -omics approaches to identify involvement of signalling pathways in the mode of action of human pharmaceuticals that might bear relevance for prediction of carcinogenic properties. It is of particular significance that this approach to mode of action analysis would comprise human relevance, and would not relate solely to the prediction of carcinogenicity outcome in rats. Our ultimate aim is to establish in vitro fluorescent reporters in human cells where individual key events that are functionally relevant in the signalling programs that drive cell proliferation are integrated. This would allow the qualitative and quantitative evaluation of key event activation as a predictive tool for the determination of the intrinsic carcinogenic potential of compounds. In the first instance, this involves the nuclear hormone receptor-mediated tumor promotor activity (e.g. estrogen receptor signalling or peroxisome proliferator PPAR-gamma signalling), which are both current topics of debate. © 2017

Background: Nano-specific inhalation exposure models could potentially be effective tools to assess and control worker exposure to nano-objects, and their aggregates and agglomerates (NOAA). However, due to the lack of reliable and consistent collected NOAA exposure data, the scientific basis for validation of the existing NOAA exposure models is missing or limited. The main objective of this study was to gain more insight into the effect of various determinants underlying the potential on the concentration of airborne NOAA close to the source with the purpose of providing a scientific basis for existing and future exposure inhalation models. Method: Four experimental studies were conducted to investigate the effect of 11 determinants of emission on the concentration airborne NOAA close to the source during dumping of ~100% nanopowders. Determinants under study were: nanomaterial, particle size, dump mass, height, rate, ventilation rate, mixing speed, containment, particle surface coating, moisture content of the powder, and receiving surface. The experiments were conducted in an experimental room (19.5 m3) with well-controlled environmental and ventilation conditions. Particle number concentration and size distribution were measured using real-time measurement devices. Results: Dumping of nanopowders resulted in a higher number concentration and larger particles than dumping their reference microsized powder (P < 0.05). Statistically significant more and larger particles were also found during dumping of SiO2 nanopowder compared to TiO2/Al2O3 nanopowders. Particle surface coating did not affect the number concentration but on average larger particles were found during dumping of coated nanopowders. An increase of the powder's moisture content resulted in less and smaller particles in the air. Furthermore, the results indicate that particle number concentration increases with increasing dump height, rate, and mass and decreases when ventilation is turned on. Discussion: These results give an indication of the direction and magnitude of the effect of the studied determinants on concentrations close to the source and provide a scientific basis for (further) development of existing and future NOAA inhalation exposure models. Chemicals/CAS: silicon dioxide, 10279-57-9, 14464-46-1, 14808-60-7, 15468-32-3, 60676-86-0, 7631-86-9; Air Pollutants, Occupational; Silicon Dioxide

Introduction. Knowledge on the exposure characteristics, including release of nanomaterials, is especially needed in the later stages of nano-enabled products’ life cycles to perform better occupational risk assessments. The objective of this study was to assess the concentrations during sawing and drilling in car bumpers containing multi-walled carbon nanotubes (MWCNTs) and nanosized organic pigment (OP) under variable realistic workplace situations related to the ventilation in the room and machine settings. Methods. Twelve different experiments were performed in triplicate (N = 36) using tools powered by induction engines that allow interference-free particle measurements. A DiSCmini was used to measure particle number concentrations, whereas particle size distributions were measured using Aerodynamic Particle Sizer (TSI), Scanning Mobility Particle Sizer (TSI), and Electrical Low Pressure Impactor (Dekati). In addition, inhalable particles were sampled using IOM samplers on filters for scanning electron microscope/energy-dispersive X-ray spectrometry (SEM/EDX) analyses. Data were analysed to estimate the effects of individual exposure determinants, in a two-stage modelling strategy using Autoregressive Integrated Moving Average models (stage 1) and subsequently combining first stage results in simulations using multiple linear regression models (stage 2). Results. In sawing experiments, partly melted carbon-rich particles (mainly ~2 to ~8 µm) were identified with SEM/EDX, whereas drilling experiments revealed no activity-related particles. In addition, no pristine engineered nanoparticles (MWCNTs and OP) were observed to be liberated from the matrix. Statistical analyses showed significant effects of a higher sawing speed, a reduction in air concentration due to mechanical ventilation, and less exposure during sawing of car bumpers containing MWCNTs compared to bumpers containing OP. Conclusion. The experiments in this study give an indication of the effects of different abrasive activities (sawing, drilling), machine settings (sawing speed, drill size), mechanical ventilation, and material characteristics on the manufactured nano-objects, their agglomerates, and aggregates concentration levels.

The widespread use of engineered nanomaterials (ENMs) in consumer products and the overwhelming uncertainties in their ecological and human health risks have raised concerns regarding their safety among industries and regulators. There has been an ongoing debate over the past few decades on ways to overcome the challenges in assessing and mitigating nano-related risks, which has reached a phase of general consensus that nanotechnology innovation should be accompanied by the application of the precautionary principle and best practice risk management, even if the risk assessment uncertainties are large. We propose a quantitative methodology for selecting the optimal risk control strategy based on information about human health and ecological risks, efficacy of risk mitigation measures, cost and other contextual factors. The risk control (RC) methodology was developed in the European FP7 research project SUN and successfully demonstrated in two case studies involving real industrial nano-enabled products (NEPs): nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) used as antimicrobial and antifungal coatings and impregnations for the preservation of treated wood, and two nanoscale pigments used for colouring plastic automotive parts (i.e. red organic pigment and carbon black). The application of RC for human health risks showed that although nano-related risks could easily be controlled in automotive plastics case study with modifications in production technology or specific type of engineering controls, nano-related risks due to sanding and sawing copper oxide painted wood were non-acceptable in the use lifecycle stage and would need the identification of a more effective risk control strategy. Keywords: Nanomaterials, Risk assessment, Risk management, Life cycle, Nano-copper oxide, Nano-pigments

Introduction. Knowledge on the exposure characteristics, including release of nanomaterials, is especially needed in the later stages of nano-enabled products’ life cycles to perform better occupational risk assessments. The objective of this study was to assess the concentrations during sawing and drilling in car bumpers containing multi-walled carbon nanotubes (MWCNTs) and nanosized organic pigment (OP) under variable realistic workplace situations related to the ventilation in the room and machine settings. Methods. Twelve different experiments were performed in triplicate (N = 36) using tools powered by induction engines that allow interference-free particle measurements. A DiSCmini was used to measure particle number concentrations, whereas particle size distributions were measured using Aerodynamic Particle Sizer (TSI), Scanning Mobility Particle Sizer (TSI), and Electrical Low Pressure Impactor (Dekati). In addition, inhalable particles were sampled using IOM samplers on filters for scanning electron microscope/energy-dispersive X-ray spectrometry (SEM/EDX) analyses. Data were analysed to estimate the effects of individual exposure determinants, in a two-stage modelling strategy using Autoregressive Integrated Moving Average models (stage 1) and subsequently combining first stage results in simulations using multiple linear regression models (stage 2). Results. In sawing experiments, partly melted carbon-rich particles (mainly ~2 to ~8 µm) were identified with SEM/EDX, whereas drilling experiments revealed no activity-related particles. In addition, no pristine engineered nanoparticles (MWCNTs and OP) were observed to be liberated from the matrix. Statistical analyses showed significant effects of a higher sawing speed, a reduction in air concentration due to mechanical ventilation, and less exposure during sawing of car bumpers containing MWCNTs compared to bumpers containing OP. Conclusion. The experiments in this study give an indication of the effects of different abrasive activities (sawing, drilling), machine settings (sawing speed, drill size), mechanical ventilation, and material characteristics on the manufactured nano-objects, their agglomerates, and aggregates concentration levels.

In veel situaties is momenteel onduidelijk wat de blootstelling aan asbest (door inhalatie) werkelijk is, en daarmee wat de bijbehorende gezondheidsrisico’s zijn. Hierdoor is het dus veelal niet mogelijk om vast te stellen wat proportionele veiligheidsmaatregelen zijn.

The increasing use of engineered nanomaterials (ENMs) in nano-enabled products (NEPs) has raised societal concerns about their possible health and ecological implications. To ensure a high level of human and environmental protection it is essential to properly estimate the risks of these new materials and to develop adequate risk management strategies. To this end, we propose a quantitative Human Health Risk Assessment (HHRA) methodology, which was developed in the European Seventh Framework research project SUN (Sustainable Nanotechnologies) and implemented in the web-based SUN Decision Support System (SUNDS). One of the major strengths of this probabilistic approach as compared to its deterministic alternatives is its ability to clearly communicate the uncertainties in the estimated risks in order to support better risk communication for more objective decision making by industries and regulators. To demonstrate this methodology, we applied it in a real case study involving a nanoscale organic red pigment used in the automotive industry. Our analysis clearly showed that the main source of uncertainty was the extrapolation from (sub)acute in vivo toxicity data to long-term risk. This extrapolation was necessary due to a lack of (sub)chronic in vivo studies for the investigated nanomaterial. Despite the high uncertainty in the final results due to the conservative assumptions made in the risks assessment, the estimated risks are acceptable for all investigated exposure scenarios along the product lifecycle.

In veel situaties is momenteel onduidelijk wat de blootstelling aan asbest (door inhalatie) werkelijk is, en daarmee wat de bijbehorende gezondheidsrisico’s zijn. Hierdoor is het dus veelal niet mogelijk om vast te stellen wat proportionele veiligheidsmaatregelen zijn.

A conference design is a rectangular matrix with orthogonal columns, one zero in each column, at most one zero in each row and -1's and +1's elsewhere. A definitive screening design can be constructed by folding over a conference design and adding a row vector of zeroes. We prove that, for a given even number of rows, there is just one isomorphism class for conference designs with two or three columns. Next, we derive all isomorphism classes for conference designs with four columns. Based on our results, we propose a classification criterion for definitive screening designs founded on projections into four factors. We illustrate the potential of the criterion by studying designs with 24 and 82 factors.

The widespread use of engineered nanomaterials (ENMs) in consumer products and the overwhelming uncertainties in their ecological and human health risks have raised concerns regarding their safety among industries and regulators. There has been an ongoing debate over the past few decades on ways to overcome the challenges in assessing and mitigating nano-related risks, which has reached a phase of general consensus that nanotechnology innovation should be accompanied by the application of the precautionary principle and best practice risk management, even if the risk assessment uncertainties are large. We propose a quantitative methodology for selecting the optimal risk control strategy based on information about human health and ecological risks, efficacy of risk mitigation measures, cost and other contextual factors. The risk control (RC) methodology was developed in the European FP7 research project SUN and successfully demonstrated in two case studies involving real industrial nano-enabled products (NEPs): nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) used as antimicrobial and antifungal coatings and impregnations for the preservation of treated wood, and two nanoscale pigments used for colouring plastic automotive parts (i.e. red organic pigment and carbon black). The application of RC for human health risks showed that although nano-related risks could easily be controlled in automotive plastics case study with modifications in production technology or specific type of engineering controls, nano-related risks due to sanding and sawing copper oxide painted wood were non-acceptable in the use lifecycle stage and would need the identification of a more effective risk control strategy.

Many food innovations rely on the introduction and use of new or modified proteins. New or modified food proteins may lead to major health risks due to their inherent potential to cause food allergy. Currently, the pre-market allergenicity assessment for new or modified food proteins and protein sources relies on methods for identifying allergenic hazards based on characteristics of known allergens. However, there is no general consensus on the allergenicity parameters to use and the criteria that should apply for the evaluation and decisions to be made. In this paper, we propose that the strategy for allergenicity risk assessment of new or modified food proteins and the methodologies applied should be governed by the risk management questions to be answered, reflected in the information needed by risk managers to enable their informed decision making. We generated an inventory of health outcome-related assessment parameters and criteria potentially important for risk management decision-making and we discuss the implications of selecting different optional criteria (e.g. cut-off values) for what could be accepted as safe with regards to the health outcomes in the (at risk) population. The impact of these various options on both method development and risk management practices was investigated. A© 2019 Elsevier Ltd

Background: Before introducing proteins from new or alternative dietary sources into the market, a compressive risk assessment including food allergic sensitization should be carried out in order to ensure their safety. We have recently proposed the adverse outcome pathway (AOP) concept to structure the current mechanistic understanding of the molecular and cellular pathways evidenced to drive IgE-mediated food allergies. This AOP framework offers the biological context to collect and structure existing in vitro methods and to identify missing assays to evaluate sensitizing potential of food proteins. Scope and approach: In this review, we provide a state-of-the-art overview of available in vitro approaches for assessing the sensitizing potential of food proteins, including their strengths and limitations. These approaches are structured by their potential to evaluate the molecular initiating and key events driving food sensitization. Key findings and conclusions: The application of the AOP framework offers the opportunity to anchor existing testing methods to specific building blocks of the AOP for food sensitization. In general, in vitro methods evaluating mechanisms involved in the innate immune response are easier to address than assays addressing the adaptive immune response due to the low precursor frequency of allergen-specific T and B cells. Novel ex vivo culture strategies may have the potential to become useful tools for investigating the sensitizing potential of food proteins. When applied in the context of an integrated testing strategy, the described approaches may reduce, if not replace, current animal testing approaches. A© 2019 Elsevier Ltd

Many food innovations rely on the introduction and use of new or modified proteins. New or modified food proteins may lead to major health risks due to their inherent potential to cause food allergy. Currently, the pre-market allergenicity assessment for new or modified food proteins and protein sources relies on methods for identifying allergenic hazards based on characteristics of known allergens. However, there is no general consensus on the allergenicity parameters to use and the criteria that should apply for the evaluation and decisions to be made. In this paper, we propose that the strategy for allergenicity risk assessment of new or modified food proteins and the methodologies applied should be governed by the risk management questions to be answered, reflected in the information needed by risk managers to enable their informed decision making. We generated an inventory of health outcome-related assessment parameters and criteria potentially important for risk management decision-making and we discuss the implications of selecting different optional criteria (e.g. cut-off values) for what could be accepted as safe with regards to the health outcomes in the (at risk) population. The impact of these various options on both method development and risk management practices was investigated. The work presented in this paper as well as the publication of it were part of and made possible by EU COST Action 1402 ImpARAS: Improving Allergy Risk Assessment Strategy for New Food Proteins (http://imparas.eu). Paula Alvito and Ricardo Assunção acknowledge the support from National Institute of Health, Dr. Ricardo Jorge and CESAM through the Fundação para a Ciência e a Tecnologia [UID/AMB/50017/2013], through national funds, and the co-funding by the FEDER [POCI-01- 0145-FEDER-00763], within the PT2020 Partnership info:eu-repo/semantics/publishedVersion

A conference design is a rectangular matrix with orthogonal columns, one zero in each column, at most one zero in each row and -1's and +1's elsewhere. A definitive screening design can be constructed by folding over a conference design and adding a row vector of zeroes. We prove that, for a given even number of rows, there is just one isomorphism class for conference designs with two or three columns. Next, we derive all isomorphism classes for conference designs with four columns. Based on our results, we propose a classification criterion for definitive screening designs founded on projections into four factors. We illustrate the potential of the criterion by studying designs with 24 and 82 factors.

Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration–response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration–response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1690-2) contains supplementary material, which is available to authorized users.

Our health is impacted by the environment we grow up, live, work, sport, sleep and relax in. The combination of exposures during daily activities and over the lifetime constitutes a major risk factor for disease. Many common disorders are closely linked to these exposures ranging from lifestyle factors, to chemical exposures, social interactions and stress. All together such exposures have a huge health impact in society. They contribute to the development and progression of diseases like cancer, respiratory and cardiovascular disease. Many of these combined exposures can potentially be modified to prevent disease. However, the complex interrelations between exposures and effects are still a scientific challenge. We often do not know why one person develops a disease and the other does not.

The development of a dermal exposure model is a challenge because of the complexity of dermal exposure processes on one hand, and the scarcity of good quality and contextually-rich dermal exposure measurements. Dermal exposure modelling is further complicated by the difficulty of measuring dermal exposure due to the lack of standardised methods (CEN/TR 2006). For example, three types of sampling systems are typically used, i.e. interception methods, removal techniques and direct assessment (in situ detection). Despite these challenges, important advancements in dermal exposure modelling have been achieved since the start of the millennium, including the Bayesian Exposure Assessment Tool (BEAT) for biocides, the RISKOFDERM models (Van Hemmen et al. 2003) and structured semi-quantitative method to assess dermal exposure for chemical and biological agents, i.e. DREAM.

Characterization of the exposition to nanoparticles and nano-objects at workplaces is a huge technical challenge. Workplace exposure during short durations is particularly difficult to detect due to the low performances of the samplers. This article proposes a solution allowing for characterizing emissions at workplaces and presents the results obtained from a nanomaterials exposure measurement campaign performed on six different process lines (PLs) distributed all over Europe. By using our Short Time Sampling (STS) approach, the emitted nanomaterials are characterized in terms of their number concentration, size, shape and chemical composition. The background noise without any production activity is first measured for each PL and then it is distinguished from the emitted nanomaterials during production. The PLs yield different nanomaterial emission levels: the PL using the extrusion of polymer composites shows high emission whereas the PL dealing with the electrospinning of polyamide nanofibers shows the least i.e. no significant change in the background noise during the process and no detectable nanofiber emission either. The nanomaterials get emitted in the form of nanoparticles or submicronic fibers, or their agglomerates and aggregates i.e. Nano Objects, Agglomerates and Aggregates (NOAA). By the developed technique, 9 out of 37 of the studied steps have been shown to exhibit exposures to nanoparticles and nano-objects. For nanosafety measures, the energetic processes like spraying, extrusion, transport and cleaning activities of the nanomaterials in the powder form require most attention.

The Advanced REACH Tool (ART) is the most sophisticated tool used for evaluating exposure levels under the European Union's Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) regulations. ART provides estimates at different percentiles of exposure and within different confidence intervals (CIs). However, its performance has only been tested on a limited number of exposure data. The present study compares ART's estimates with exposure measurements collected over many years in Switzerland. Measurements from 584 cases of exposure to vapours, mists, powders, and abrasive dusts (wood/stone and metal) were extracted from a Swiss database. The corresponding exposures at the 50th and 90th percentiles were calculated in ART. To characterize the model's performance, the 90% CI of the estimates was considered. ART's performance at the 50th percentile was only found to be insufficiently conservative with regard to exposure to wood/stone dusts, whereas the 90th percentile showed sufficient conservatism for all the types of exposure processed. However, a trend was observed with the residuals, where ART overestimated lower exposures and underestimated higher ones. The median was more precise, however, and the majority (≥60%) of real-world measurements were within a factor of 10 from ART's estimates. We provide recommendations based on the results and suggest further, more comprehensive, investigations. © The Author 2017.

Characterization of the exposition to nanoparticles and nano-objects at workplaces is a huge technical challenge. Workplace exposure during short durations is particularly difficult to detect due to the low performances of the samplers. This article proposes a solution allowing for characterizing emissions at workplaces and presents the results obtained from a nanomaterials exposure measurement campaign performed on six different process lines (PLs) distributed all over Europe. By using our Short Time Sampling (STS) approach, the emitted nanomaterials are characterized in terms of their number concentration, size, shape and chemical composition. The background noise without any production activity is first measured for each PL and then it is distinguished from the emitted nanomaterials during production. The PLs yield different nanomaterial emission levels: the PL using the extrusion of polymer composites shows high emission whereas the PL dealing with the electrospinning of polyamide nanofibers shows the least i.e. no significant change in the background noise during the process and no detectable nanofiber emission either. The nanomaterials get emitted in the form of nanoparticles or submicronic fibers, or their agglomerates and aggregates i.e. Nano Objects, Agglomerates and Aggregates (NOAA). By the developed technique, 9 out of 37 of the studied steps have been shown to exhibit exposures to nanoparticles and nano-objects. For nanosafety measures, the energetic processes like spraying, extrusion, transport and cleaning activities of the nanomaterials in the powder form require most attention.

The development of a dermal exposure model is a challenge because of the complexity of dermal exposure processes on one hand, and the scarcity of good quality and contextually-rich dermal exposure measurements. Dermal exposure modelling is further complicated by the difficulty of measuring dermal exposure due to the lack of standardised methods (CEN/TR 2006). For example, three types of sampling systems are typically used, i.e. interception methods, removal techniques and direct assessment (in situ detection). Despite these challenges, important advancements in dermal exposure modelling have been achieved since the start of the millennium, including the Bayesian Exposure Assessment Tool (BEAT) for biocides, the RISKOFDERM models (Van Hemmen et al. 2003) and structured semi-quantitative method to assess dermal exposure for chemical and biological agents, i.e. DREAM.

Fume hoods are one of the most common types of equipment applied to reduce the potential of particle exposure in laboratory environments. A number of previous studies have shown particle release during work with nanomaterials under fume hoods. Here, we assessed laboratory workers’ inhalation exposure during synthesis and handling of CuO, TiO2 and ZnO in a fume hood. In addition, we tested the capacity of a fume hood to prevent particle release to laboratory air during simulated spillage of different powders (silica fume, zirconia TZ-3Y and TiO2). Airborne particle concentrations were measured in near field, far field, and in the breathing zone of the worker. Handling CuO nanoparticles increased the concentration of small particles (< 58 nm) inside the fume hood (up to 1 × 105 cm−3). Synthesis, handling and packaging of ZnO and TiO2 nanoparticles did not result in detectable particle release to the laboratory air. Simulated powder spills showed a systematic increase in the particle concentrations inside the fume hood with increasing amount of material and drop height. Despite powder spills were sometimes observed to eject into the laboratory room, the spill events were rarely associated with notable release of particles from the fume hood. Overall, this study shows that a fume hood generally offers sufficient exposure control during synthesis and handling of nanomaterials. An appropriate fume hood with adequate sash height and face velocity prevents 98.3% of particles release into the surrounding environment. Care should still be made to consider spills and high cleanliness to prevent exposure via resuspension and inadvertent exposure by secondary routes. © 2018, The Author(s). Chemicals/CAS: silicon dioxide, 10279-57-9, 14464-46-1, 14808-60-7, 15468-32-3, 60676-86-0, 7631-86-9; titanium dioxide, 1317-70-0, 1317-80-2, 13463-67-7, 51745-87-0; zirconium oxide, 1314-23-4, 53801-45-9

The development and introduction of new dietary protein sources has the potential to improve food supply sustainability. Understanding the potential allergenicity of these new or modified proteins is crucial to ensure protection of public health. Exposure to new proteins may result in de novo sensitization, with or without clinical allergy, or clinical reactions through cross-reactivity. In this paper we review the potential of current methodologies (in silico, in vitro degradation, in vitro IgE binding, animal models and clinical studies) to address these outcomes for risk assessment purposes for new proteins, and especially to identify and characterise the risk of sensitization for IgE mediated allergy from oral exposure. Existing tools and tests are capable of assessing potential crossreactivity. However, there are few possibilities to assess the hazard due to de novo sensitization. The only methods available are in vivo models, but many limitations exist to use them for assessing risk. We conclude that there is a need to understand which criteria adequately define allergenicity for risk assessment purposes, and from these criteria develop a more suitable battery of tests to distinguish between proteins of high and low allergenicity, which can then be applied to assess new proteins with unknown risks. © 2017 The Authors Chemicals/CAS: immunoglobulin E, 37341-29-0

Food allergies are recognized as a global health concern. In order to protect allergic consumers from severe symptoms, allergenic risk assessment for well-known foods and foods containing genetically modified ingredients is installed. However, population is steadily growing and there is a rising need to provide adequate protein-based foods, including novel sources, not yet used for human consumption. In this context safety issues such as a potential increased allergenic risk need to be assessed before marketing novel food sources. Therefore, the established allergenic risk assessment for genetically modified organisms needs to be re-evaluated for its applicability for risk assessment of novel food proteins. Two different scenarios of allergic sensitization have to be assessed. The first scenario is the presence of already known allergenic structures in novel foods. For this, a comparative assessment can be performed and the range of cross-reactivity can be explored, while in the second scenario allergic reactions are observed toward so far novel allergenic structures and no reference material is available. This review summarizes the current analytical methods for allergenic risk assessment, highlighting the strengths and limitations of each method and discussing the gaps in this assessment that need to be addressed in the near future. © 2017 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Fume hoods are one of the most common types of equipment applied to reduce the potential of particle exposure in laboratory environments. A number of previous studies have shown particle release during work with nanomaterials under fume hoods. Here, we assessed laboratory workers’ inhalation exposure during synthesis and handling of CuO, TiO2 and ZnO in a fume hood. In addition, we tested the capacity of a fume hood to prevent particle release to laboratory air during simulated spillage of different powders (silica fume, zirconia TZ-3Y and TiO2). Airborne particle concentrations were measured in near field, far field, and in the breathing zone of the worker. Handling CuO nanoparticles increased the concentration of small particles (< 58 nm) inside the fume hood (up to 1 × 105 cm−3). Synthesis, handling and packaging of ZnO and TiO2 nanoparticles did not result in detectable particle release to the laboratory air. Simulated powder spills showed a systematic increase in the particle concentrations inside the fume hood with increasing amount of material and drop height. Despite powder spills were sometimes observed to eject into the laboratory room, the spill events were rarely associated with notable release of particles from the fume hood. Overall, this study shows that a fume hood generally offers sufficient exposure control during synthesis and handling of nanomaterials. An appropriate fume hood with adequate sash height and face velocity prevents 98.3% of particles release into the surrounding environment. Care should still be made to consider spills and high cleanliness to prevent exposure via resuspension and inadvertent exposure by secondary routes. © 2018, The Author(s). Chemicals/CAS: silicon dioxide, 10279-57-9, 14464-46-1, 14808-60-7, 15468-32-3, 60676-86-0, 7631-86-9; titanium dioxide, 1317-70-0, 1317-80-2, 13463-67-7, 51745-87-0; zirconium oxide, 1314-23-4, 53801-45-9

The use of nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) in both ionic and micronized wood preservatives has raised concerns about the potential of these substances to cause adverse humans health effects. To address these concerns, we performed quantitative (probabilistic) human health risk assessment (HHRA) along the lifecycles of these formulations used in antibacterial and antifungal wood coatings and impregnations by means of the EU FP7 SUN project's Decision Support System (SUNDS, www.sunds.gd). The results from the risk analysis revealed inhalation risks from CuO in exposure scenarios involving workers handling dry powders and performing sanding operations as well as potential ingestion risks for children exposed to nano Cu2(OH)2CO3 in a scenario involving hand-to-mouth transfer of the substance released from impregnated wood. There are, however, substantial uncertainties in these results, so some of the identified risks may stem from the safety margin of extrapolation to fill data gaps and might be resolved by additional testing. Our stochastic approach successfully communicated the contribution of different sources of uncertainty in the risk assessment. The main source of uncertainty was the extrapolation from short to long-term exposure, which was necessary due to the lack of (sub)chronic in vivo studies with CuO and Cu2(OH)2CO3. Considerable uncertainties also stemmed from the use of default inter- and intra-species extrapolation factors.

The use of nano-scale copper oxide (CuO) and basic copper carbonate (Cu2(OH)2CO3) in both ionic and micronized wood preservatives has raised concerns about the potential of these substances to cause adverse humans health effects. To address these concerns, we performed quantitative (probabilistic) human health risk assessment (HHRA) along the lifecycles of these formulations used in antibacterial and antifungal wood coatings and impregnations by means of the EU FP7 SUN project’s Decision Support System (SUNDS, www.sunds.gd). The results from the risk analysis revealed inhalation risks from CuO in exposure scenarios involving workers handling dry powders and performing sanding operations as well as potential ingestion risks for children exposed to nano Cu2(OH)2CO3 in a scenario involving hand-to-mouth transfer of the substance released from impregnated wood. There are, however, substantial uncertainties in these results, so some of the identified risks may stem from the safety margin of extrapolation to fill data gaps and might be resolved by additional testing. Our stochastic approach successfully communicated the contribution of different sources of uncertainty in the risk assessment. The main source of uncertainty was the extrapolation from short to long-term exposure, which was necessary due to the lack of (sub)chronic in vivo studies with CuO and Cu2(OH)2CO3. Considerable uncertainties also stemmed from the use of default inter- and intra-species extrapolation factors.

The Advanced REACH Tool (ART) is the most sophisticated tool used for evaluating exposure levels under the European Union's Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) regulations. ART provides estimates at different percentiles of exposure and within different confidence intervals (CIs). However, its performance has only been tested on a limited number of exposure data. The present study compares ART's estimates with exposure measurements collected over many years in Switzerland. Measurements from 584 cases of exposure to vapours, mists, powders, and abrasive dusts (wood/stone and metal) were extracted from a Swiss database. The corresponding exposures at the 50th and 90th percentiles were calculated in ART. To characterize the model's performance, the 90% CI of the estimates was considered. ART's performance at the 50th percentile was only found to be insufficiently conservative with regard to exposure to wood/stone dusts, whereas the 90th percentile showed sufficient conservatism for all the types of exposure processed. However, a trend was observed with the residuals, where ART overestimated lower exposures and underestimated higher ones. The median was more precise, however, and the majority (≥60%) of real-world measurements were within a factor of 10 from ART's estimates. We provide recommendations based on the results and suggest further, more comprehensive, investigations. © The Author 2017.

Nanoscale TiO2 (nTiO2) is manufactured in high volumes and is of potential concern in occupational health. Here, we measured workers exposure levels while ceramic honeycombs were dip coated with liquid photoactive nanoparticle suspension and dried with an air blade. The measured nTiO2 concentration levels were used to assess process specific emission rates using a convolution theorem and to calculate inhalation dose rates of deposited nTiO2 particles. Dip coating did not result in detectable release of particles but air blade drying released fine-sized TiO2 and nTiO2 particles. nTiO2 was found in pure nTiO2 agglomerates and as individual particles deposited onto background particles. Total particle emission rates were 420 × 109 min−1, 1.33 × 109 μm2 min−1, and 3.5 mg min−1 respirable mass. During a continued repeated process, the average exposure level was 2.5 × 104 cm−3, 30.3 μm2 cm−3,−3 for particulate matter. The TiO2 average exposure level was 4.2 μg m−3, which is well below the maximum recommended exposure limit of 300 μg m−3 for nTiO2 proposed by the US National Institute for Occupational Safety and Health. During an 8-hour exposure, the observed concentrations would result in a lung deposited surface area of 4.3 × 10−3 cm2 g−1 of lung tissue and 13 μg of TiO2 to the trachea-bronchi, and alveolar regions. The dose levels were well below the one hundredth of the no observed effect level (NOEL1/100) of 0.11 cm2 g−1 for granular biodurable particles and a daily no significant risk dose level of 44 μg day−1. These emission rates can be used in a mass flow model to predict the impact of process emissions on personal and environmental exposure levels.

Transcriptomics in combination with in vitro cell systems is a powerful approach to unravel modes of action of toxicants. An important question is to which extent the modes of action as revealed by transcriptomics depend on cell type, species and study type (in vitro or in vivo). To acquire more insight into this, we assessed the transcriptomic effects of the immunosuppressive drug cyclosporine A (CsA) upon 6 h of exposure of the mouse cytotoxic T cell line CTLL-2, the thymoma EL-4 and primary splenocytes and compared these to the effects in spleens of mice orally treated with CsA for 7 days. EL-4 and CTLL-2 cells showed the highest similarities in response. CsA affected many genes in primary splenocytes that were not affected in EL-4 or CTLL-2. Pathway analysis demonstrated that CsA upregulated the unfolded protein response, endoplasmic reticulum stress and NRF2 activation in EL-4 cells, CTLL-2 cells and primary mouse splenocytes but not in mouse spleen in vivo. As expected, CsA downregulated cell cycle and immune response in splenocytes in vitro, spleens in vivo as well as CTLL-2 in vitro. Genes up- and downregulated in human Jurkat, HepG2 and renal proximal tubular cells were similarly affected in CTLL-2, EL-4 and primary splenocytes in vitro. In conclusion, of the models tested in this study, the known mechanism of immunotoxicity of CsA is best represented in the mouse cytotoxic T cell line CTLL-2. This is likely due to the fact that this cell line is cultured in the presence of a T cell activation stimulant (IL-2) making it more suitable to detect inhibitory effects on T cell activation. © 2014, Springer-Verlag Berlin Heidelberg. Chemicals/CAS: cyclosporin A, 59865-13-3, 63798-73-2; interleukin 2, 85898-30-2 Manufacturers: Sigma, Netherlands

Each oil reservoir could be characterized by a set of parameters such as temperature, pressure, oil composition, and brine salinity, etc. In the context of the chemical enhanced oil recovery (EOR), the selection of high performance surfactants is a challenging and time-consuming task since this strongly depends on the reservoir's conditions. The situation becomes even more complicated if the surfactant formulation is a blend of two or more surfactants. In the present work, we report quantitative structure-property relationships (QSPR) correlating surfactants'structures and their composition in a mixture with optimal salinity (Sopt), corresponding to minimal interfacial tension in the reference brine/surfactants/n-dodecane system, at T = 313 K and P = 0.1 MPa. Particular attention was paid to selected families of surfactants: α-olefin sulfonate (AOS), internal olefin sulfonate (IOS), alkyl ether sulfate (AES), and alkyl glyceryl ether sulfonate (AGES). The models were built and validated on the database containing Sopt values for 75 surfactants' formulations. Molecular structures of amphiphilic molecules were encoded by functional group count descriptors (FGCD), ISIDA substructural molecular fragment (SMF) descriptors, and CODESSA molecular descriptors (CMD). For mixtures, descriptors were calculated as linear combinations of descriptors of individual compounds weighted by their mass fractions in mixtures. Different machine-learning methods-support vector machine (SVM), partial least-squares (PLS) regression, and random subspace (RS)-have been used for the modeling. Both global (on the entire database) and local (on individual families) models have been built. Models display reasonable accuracy (about 0.2 log Sopt units) which is comparable with the experimental error of measured Sopt. Our results show that the suggested approach can be successfully used to build predictive models for relatively small data sets of mixtures of chemical compounds. © 2015 American Chemical Society.

Nanomaterials are expected to find applications in numerous consumer products, posing the challenge to guarantee their safety and environmental sustainability before they can be transferred from research labs to end-consumer products. One emerging solution, called safe design, relies on the implementation, throughout the R&D phase, of key aspects related to the safety and sustainability of nanomaterials, in this way anticipating potential negative health effects. This article proposes a computational screening approach to design safer nanomaterials. The work is based on the calculation of key physicochemical properties of nanomaterials that are related to their safety, functionality and synthetic feasibility. These properties are then used to select a pool of promising structures for further experimental testing and development. The concept is demonstrated on a set of core@shell metal oxide nanoparticles for transparent UV-protecting coating applications. This journal is © The Royal Society of Chemistry.

With our recently developed in vitro physiologically based kinetic (PBK) modelling approach, we could extrapolate in vitro toxicity data to human toxicity values applying PBK-based reverse dosimetry. Ideally information on kinetic differences among human individuals within a population should be considered. In the present study, we demonstrated a modelling approach that integrated in vitro toxicity data, PBK modelling and Monte Carlo simulations to obtain insight in interindividual human kinetic variation and derive chemical specific adjustment factors (CSAFs) for phenol-induced developmental toxicity. The present study revealed that UGT1A6 is the primary enzyme responsible for the glucuronidation of phenol in humans followed by UGT1A9. Monte Carlo simulations were performed taking into account interindividual variation in glucuronidation by these specific UGTs and in the oral absorption coefficient. Linking Monte Carlo simulations with PBK modelling, population variability in the maximum plasma concentration of phenol for the human population could be predicted. This approach provided a CSAF for interindividual variation of 2.0 which covers the 99th percentile of the population, which is lower than the default safety factor of 3.16 for interindividual human kinetic differences. Dividing the dose-response curve data obtained with in vitro PBK-based reverse dosimetry, with the CSAF provided a dose-response curve that reflects the consequences of the interindividual variability in phenol kinetics for the developmental toxicity of phenol. The strength of the presented approach is that it provides insight in the effect of interindividual variation in kinetics for phenol-induced developmental toxicity, based on only in vitro and in silico testing. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.

Background Multi Wall Carbon nanotubes (MWCNTs) are manufactured nanomaterials to which workers and the general population will be increasingly exposed in coming years. Little is known about potential human health effects of exposure to MWCNTs, but effects on the lung and the immune system have been reported in animal and mechanistic studies. Objectives We conducted a cross-sectional study to assess the association between occupational exposure to MWCNTs and effects on lung health and the immune system. Methods We assessed fifty-one immune markers and three pneumoproteins in serum, complete blood cell counts (CBC), fractional exhaled nitric oxide (FENO), and lung function among twenty-two workers of a MWCNT producing facility and thirty-nine age- and gender-matched, unexposed controls. Measurements were repeated four months later among 16 workers also included in the first phase of the study. Regression analyses were adjusted for potentially confounding parameters age, body mass index, smoking, and sex and we explored potential confounding by other factors in sensitivity analyses. Results We observed significant upward trends for immune markers C-C motif ligand 20 (p = 0.005), basic fibroblast growth factor (p = 0.05), and soluble IL-1 receptor II (p = 0.0004) with increasing exposure to MWCNT. These effects were replicated in the second phase of the study and were robust to sensitivity analyses. We also observed differences in FENO and several CBC parameters between exposed and non-exposed, but no difference in lung function or the pneumoproteins. Conclusions We observed indications of early effects of occupational exposure to MWCNTs on lung health and the immune system. peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=inan20 ispartof: Nanotoxicology vol:11 issue:3 pages:395-404 ispartof: location:England status: published