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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.

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

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.

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.

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

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

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.

The EU Food Supplements Directive (2002/46/EC) mandates the determination of both maximum and minimum permitted levels (MPLs) for micronutrients. In order to determine MPLs which are feasible for particular population groups, a scientific approach should be used in which risk of high intake, risk of inadequacy and benefits are assessed in an integrated way taking all available data and severity and incidence of effect into account. In 2004, Renwick et al. (ILSI Europe) published a scientifically valid, flexible and pragmatic basis for a risk–benefit approach, which has been further developed here to make it a practical and quantifiable approach to be used by risk managers. The applicability of the approach is demonstrated using demo cases on iron and folate. The proposed approach has the capacity to utilize all relevant data available, including data from human studies, bioavailability data showing variability between specific forms of micronutrients and, in the case of animal studies, data on species comparability. The approach is therefore both practical and flexible, making it well suited to risk managers tasked with determining safe intake levels for micronutrients in different forms and for particular population groups. © 2017 The Author(s). Published by Taylor & Francis Group, LLC © 2017, © Lisette Krul, Bas H. A. Kremer, Niels B. Lucas Luijckx, and Winfried R. Leeman.

The EU Food Supplements Directive (2002/46/EC) mandates the determination of both maximum and minimum permitted levels (MPLs) for micronutrients. In order to determine MPLs which are feasible for particular population groups, a scientific approach should be used in which risk of high intake, risk of inadequacy and benefits are assessed in an integrated way taking all available data and severity and incidence of effect into account. In 2004, Renwick et al. (ILSI Europe) published a scientifically valid, flexible and pragmatic basis for a risk–benefit approach, which has been further developed here to make it a practical and quantifiable approach to be used by risk managers. The applicability of the approach is demonstrated using demo cases on iron and folate. The proposed approach has the capacity to utilize all relevant data available, including data from human studies, bioavailability data showing variability between specific forms of micronutrients and, in the case of animal studies, data on species comparability. The approach is therefore both practical and flexible, making it well suited to risk managers tasked with determining safe intake levels for micronutrients in different forms and for particular population groups. © 2017 The Author(s). Published by Taylor & Francis Group, LLC © 2017, © Lisette Krul, Bas H. A. Kremer, Niels B. Lucas Luijckx, and Winfried R. Leeman.

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.

Grouping of substances and utilizing read-across of data within those groups represents an important data gap filling technique for chemical safety assessments. Categories/analogue groups are typically developed based on structural similarity and, increasingly often, also on mechanistic (biological) similarity. While read-across can play a key role in complying with legislation such as the European REACH regulation, the lack of consensus regarding the extent and type of evidence necessary to support it often hampers its successful application and acceptance by regulatory authorities. Despite a potentially broad user community, expertise is still concentrated across a handful of organizations and individuals. In order to facilitate the effective use of read-across, this document presents the state of the art, summarizes insights learned from reviewing ECHA published decisions regarding the relative successes/pitfalls surrounding read-across under REACH, and compiles the relevant activities and guidance documents. Special emphasis is given to the available existing tools and approaches, an analysis of ECHA's published final decisions associated with all levels of compliance checks and testing proposals, the consideration and expression of uncertainty, the use of biological support data, and the impact of the ECHA Read-Across Assessment Framework (RAAF) published in 2015. Funding Details: T32 ES007141, NIEHS, National Institute of Environmental Health Sciences

We present a conceptual framework that can be used to assign risk bands to inhaled low aspect ratio nanoparticles starting from exposure bands assigned to a specific exposure situation. The framework mimics a basic physiological scheme that captures the essential mechanisms of fate and toxicity of inhaled nanoparticles and is composed of several models and rules that estimate

Recently, the European Food Safety Authority (EFSA) stated that the Threshold of Toxicological Concern (TTC) thresholds should not be used for substances that are known or predicted to accumulate. Bioaccumulation of substances is usually considered unfavourable but so far a relation with toxicity at low dose exposure is insufficiently investigated to draw conclusions on the relevance of bioaccumulation at low dose exposure. In this manuscript it is investigated which physical chemical properties are related to bioaccumulation in order to predict accumulating properties of a substance, and is evaluated if the toxicity of known bioaccumulating substances is higher than for non-accumulating substances. Based on the evaluation it is concluded that the current TTC thresholds are derived with a dataset in which bioaccumulating substances are present, whereas the toxicity of the bioaccumulating substances is already taken into account in the TTC thresholds. The authors demonstrated that there is no need to exclude potential bioaccumulating substances from the TTC concept.

We present a conceptual framework that can be used to assign risk bands to inhaled low aspect ratio nanoparticles starting from exposure bands assigned to a specific exposure situation. The framework mimics a basic physiological scheme that captures the essential mechanisms of fate and toxicity of inhaled nanoparticles and is composed of several models and rules that estimate

Absorption of toxic substances via the skin is an important phenomenon in the assessment of the risk of exposure to these substances. People are exposed to a variety of substances and products via the skin, either directly or indirectly, while at work, at home or in public space. Pesticides, organic solvents and metalworking fluids are seen to be important contributors to adverse health effects due to occupational exposure via the skin. In daily life, cosmetics, clothing and household products are the most relevant commodities with respect to exposure via the skin. Given the importance of skin exposure in the assessment of the risk of toxic substances, the objective of this thesis was to further develop, evaluate and improve methods for including skin absorption data this assessment. In this thesis, four factors influencing dermal absorption, namely dermal loading (chapters 3 and 6), irritative/corrosive potential (chapters 3 and 4), frequency of exposure (chapters 3, 4 and 5) and the vehicle used (chapter 5), were investigated in more detail. Furthermore, a model to extrapolate infinite dose absorption data to finite dose conditions, baptized Dermal Absorption Model for Extrapolation (DAME), was developed and tested. I n chapter 2 of this thesis, the relationship between relative dermal absorption and dermal loading was investigated. Hundred-and-thirty-eight dermal publicly available absorption experiments with 98 substances were evaluated. The results obtained revealed that dermal loading ranged mostly between 0.001 and 10 mg/cm2. In 87 experiments (63%), an inverse relationship was observed between relative dermal absorption and dermal loading. On average, relative absorption at high dermal loading was 33 times lower than at low dermal loading. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption. It was concluded that when using relative dermal absorption in regulatory risk assessment, its value should be determined at or extrapolated to dermal loadings relevant for the exposure conditions being evaluated. I n chapter 3 of this thesis, a literature search was presented with the aim to investigate whether neglecting the effects of repeated exposure may lead to an incorrect estimate of dermal absorption. The results demonstrated that the effect of repeated versus single exposure does not demonstrate a unique trend. Nevertheless, an increase in daily absorption was frequently observed upon repeated daily exposure. The little information available mostly concerned pharmaceuticals. However, consumers and workers may be repeatedly exposed to other types of chemicals, like disinfectants and cleaning products, which often contain biocidal active substances that may decrease the barrier function of the skin, especially after repeated exposure. These biocidal products, therefore, may present a safety risk that is not covered by the current risk assessment practice since absorption data are usually obtained by single exposure experiments. Consequently, it was decided to investigate the importance of this issue for biocide safety evaluation. As the literature search revealed that hardly any data on absorption upon repeated dermal exposure to biocides are available, it was concluded that data need to be generated by testing. To cover the entire range of biocidal products in such testing, a representative series of biocidal substances should be tested, making in vitro testing of dermal absorption the preferred choice over in vivo testing. Based on an inventory made, it appeared that the 16 product types represented among the biocidal products authorised in the Netherlands could be clustered into 6 more or less homogeneous categories based on similarity in active substances. This result could facilitate experimental testing by providing a basis for selection of a limited number of representative compounds to be evaluated. I n chapter 4 of this thesis, the importance of the effect of repeated dermal exposure on skin permeability for biocide safety evaluation was investigated, using a selection of nine representative biocides from the inventory made in chapter 3. The in vitro dermal penetration of tritiated water and [14C]propoxur was chosen as a measure of the permeability and integrity of human abdominal skin after single and repeated exposure. The results indicated that single and repeated exposure to specific biocidal products (e.g. the quaternary ammonium chlorides DDAC and ADBAC) may significantly increase skin permeability, especially when the compounds are applied at high concentrations, while a substance like formaldehyde may reduce skin permeability under specific conditions. I n chapter 5 of this thesis, the in vitro dermal absorption kinetics of the quaternary ammonium compound didecyldimethylammonium chloride (DDAC) during single and repeated exposure was studied in more detail. In addition, the influence of biocidal formulations on the absorption of DDAC was investigated, because it was expected that formulation characteristics may be another factor influencing its dermal absorption. The analysis of biocidal products on the Dutch market, reported in chapter 3, indicated that DDAC is often used in combination with other active ingredients. DDAC was most frequently combined with formaldehyde, glutaraldehyde and/or alkyldimethylbenzyl­ammo­nium chloride (ADBAC). Consequently, commercial formulations containing one or more of these additional active ingredients were selected, in addition to one formulation containing only DDAC as an active ingredient. The selected commercial formulations tended to reduce skin penetration of DDAC. This was most pronounced with the formulation containing the highest concentration of formaldehyde (196 mg/mL) and glutaraldehyde (106 mg/mL), which reduced the flux of DDAC across the skin by 95%. The reduction caused by the only tested formulation containing no other active ingredients than DDAC, and thus incorporating no aldehydes, was smallest, and did not reach statistical significance. I n chapter 6 of this thesis, a simple in silico model to predict finite dose dermal absorption from infinite dose data (kp and lag time) and the stratum corneum/water partition coefficient (KSC,W) was developed. This model was tentatively called Dermal Absorption Model for Extrapolation (DAME). As dermal exposure may occur under a large variety of conditions leading to quite different rates of absorption, such a predictive model using simple experimental or physicochemical inputs provides a cost-effective means to estimate dermal absorption under different conditions. To evaluate the DAME, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using a variety of different substances. The kp’s and lag times determined in the infinite dose experiments were entered into DAME to predict relative dermal absorption value under finite dose conditions. For six substances, the predicted relative dermal absorption under finite dose conditions was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by DAME, but most of the overpredicted values were still lower than 100%, the European default absorption value for the tested compounds. In conclusion, our finite dose prediction model (DAME) provides a useful and cost-effective estimate of in vitro dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations. I n chapter 7 of this thesis, the results of the research reported in chapters 2 to 6 were put into perspective, the pitfalls and promises emanating from them discussed and general conclusions drawn. The possible influence of vehicles on absorption and the possible impact of irritative or corrosive vehicles or chemicals on the skin barrier have been demonstrated in this thesis. An in silico predictive model tentatively called DAME was developed, which enables the user to evaluate a variety of dermal exposure scenarios with limited experimental data (kp and lag time) and easy to obtain physicochemical properties (MW and log KOW). The predictions of our experiments reported in chapter 6 were compared to those of the Finite Dose Skin Permeation (FDSP) model published on the internet by the US Centers for Disease Control and Prevention (CDC). DAME outperformed FDSP (R2 of the correlation predicted/measured potential absorption 0.64 and 0.12, respectively). At present, the applicability domain of DAME is limited to non-volatile substances dissolved in aqueous solvents. However, in future the model will be adapted to include volatile substances as well. Altogether, it is concluded that dermal exposure can be an important factor in risks posed by chemicals and should be taken into account in risk assessment. The methods to actually do this are still open for further improvement to better account for the various factors influencing skin penetration and to develop adequate combinations of in vitro and in silico models that can accurately predict human dermal absorption.

Recently, the European Food Safety Authority (EFSA) stated that the Threshold of Toxicological Concern

The aim of this work was to identify the key mechanisms governing transport of organic chemical substances from consumer articles to cotton wipes. The results were used to establish a mechanistic model to improve assessment of dermal contact exposure. Four types of PVC flooring, 10 types of textiles and one type of inkjet printed paper were used to establish the mechanisms and model. Kinetic extraction studies in methanol demonstrated existence of matrix diffusion and indicated the presence of a substance surface layer on some articles. Consequently, the proposed substance transfer model considers mechanical transport from a surface film and matrix diffusion in an article with a known initial total substance concentration. The estimated chemical substance transfer values to cotton wipes were comparable to the literature data (relative transfer ∼2%), whereas relative transfer efficiencies from spiked substrates were high (∼50%). For consumer articles, high correlation (r 2 =0.92) was observed between predicted and measured transfer efficiencies, but concentrations were overpredicted by a factor of 10. Adjusting the relative transfer from about 50% used in the model to about 2.5% removed overprediction. Further studies are required to confirm the model for generic use. © 2016 Nature America, Inc. All rights reserved.

The fast penetration of nanoproducts on the market under conditions of significant uncertainty of their environmental properties and risks to humans creates a need for companies to assess sustainability of their products. Evaluation of the potential benefits and risks to build a coherent story for communication with clients, authorities, consumers, and other stakeholders is getting to be increasingly important, but SMEs often lack the knowledge and expertise to assess risks and communicate them appropriately. This paper introduces LICARA nanoSCAN, a modular web based tool that supports SMEs in assessing benefits and risks associated with new

Background: Control banding can be used as a first-tier assessment to control worker exposure to nano-objects and their aggregates and agglomerates (NOAA). In a second tier, more advanced modelling approaches are needed to produce quantitative exposure estimates. As currently no general quantitative nano-specific exposure models are available, this study evaluated the validity and applicability of using a generic exposure assessment model (the Advanced REACH Tool - ART) for occupational exposure to NOAA. Method: The predictive capability of ART for occupational exposure to NOAA was tested by calculating the relative bias and correlations (Pearson) between the model estimates and measured concentrations using a dataset of 102 NOAA exposure measurements collected during experimental and workplace exposure studies. Results: Moderate to (very) strong correlations between the ART estimates and measured concentrations were found. Estimates correlated better to measured concentration levels of dust (r = 0.76, P < 0.01) than liquid aerosols (r = 0.51, P = 0.19). However, ART overestimated the measured NOAA concentrations for both the experimental and field measurements (factor 2-127). Overestimation was highest at low concentrations and decreased with increasing concentration. Correlations seemed to be better when looking at the nanomaterials individually compared to combined scenarios, indicating that nanomaterial-specific characteristics are not well captured within the mechanistic model of the ART. Discussion: Although ART in its current state is not capable to estimate occupational exposure to NOAA, the strong correlations for the individual nanomaterials indicate that the ART (and potentially other generic exposure models) have the potential to be extended or adapted for exposure to NOAA. In the future, studies investigating the potential to estimate exposure to NOAA should incorporate more explicitly nanomaterial-specific characteristics in their models. © The Author 2016. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study. © 2016 The Author(s)

The fast penetration of nanoproducts on the market under conditions of significant uncertainty of their environmental properties and risks to humans creates a need for companies to assess sustainability of their products. Evaluation of the potential benefits and risks to build a coherent story for communication with clients, authorities, consumers, and other stakeholders is getting to be increasingly important, but SMEs often lack the knowledge and expertise to assess risks and communicate them appropriately. This paper introduces LICARA nanoSCAN, a modular web based tool that supports SMEs in assessing benefits and risks associated with new or existing nanoproducts. This tool is unique because it is scanning both the benefits and risks over the nanoproducts life cycle in comparison to a reference product with a similar functionality in order to enable the development of sustainable and competitive nanoproducts. SMEs can use data and expert judgment to answer mainly qualitative and semi-quantitative questions as a part of tool application. Risks to public, workers and consumers are assessed, while the benefits are evaluated for economic, environmental and societal opportunities associated with the product use. The tool provides an easy way to visualize results as well as to identify gaps, missing data and associated uncertainties. The LICARA nanoSCAN has been positively evaluated by several companies and was tested in a number of case studies. The tool helps to develop a consistent and comprehensive argument on the weaknesses and strengths of a nanoproduct that may be valuable for the communication with authorities, clients and among stakeholders in the value chain. LICARA nanoSCAN identifies areas for more detailed assessments, product design improvement or application of risk mitigation measures. Keywords: Risk assessment, Benefit assessment, Nanoproducts, Decision-making tool, Sustainable nanotechnology, Life Cycle Assessment

To derive an acute TTC threshold, the correlation between Allowable Daily Intakes (ADIs, chronic values) and Acute Reference Doses (ARfDs) of pesticides evaluated in the EU was investigated and their distributions were compared. The correlation between ARfDs and ADIs was significant (p = 0.01), but weak (r(2) = 0.051). Consequently, using this approach to derive acute TTC values does not seem valid. Therefore, the distributions of ARfDs and ADIs were compared directly, in order to extrapolate from chronic to acute TTC values. This comparison made for the combined Cramer structural class II and III pesticides showed a ratio ARfD/ADI of approximately 3 at the fifth percentile of the distributions. Based on these results, it is justified to propose a TTC for acute effects for Cramer III substances by multiplying the Cramer class III TTC threshold of 90 μg/person/day with a factor 3. This leads to an acute TTC threshold based on the Munro dataset for Cramer class III substances of 270 μg/person/day.

International audience; Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counterproductive for consumers with food allergies. This review aims to summarize the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimization goals. The lack of agreed reference doses has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach and its limitations. Consumers with food allergy then need to be educated to undertake individualized risk assessments in relation to any PAL present.

In spite of recent advances in describing the health outcomes of exposure to nanoparticles (NPs), it still remains unclear how exactly NPs interact with their cellular targets. Size, surface, mass, geometry, and composition may all play a beneficial role as well as causing toxicity. Concerns of scientists, politicians and the public about potential health hazards associated with NPs need to be answered. With the variety of exposure routes available, there is potential for NPs to reach every organ in the body but we know little about the impact this might have. The main objective of the FP7 NanoTEST project (www.nanotest-fp7.eu) was a better understanding of mechanisms of interactions of NPs employed in nanomedicine with cells, tissues and organs and to address critical issues relating to toxicity testing especially with respect to alternative tests to animals. Here we describe an approach towards alternative testing strategies for hazard and risk assessment of nanomaterials, highlighting the adaptation of standard methods demanded by the special physicochemical features of nanomaterials and bioavailability studies. The work has assessed a broad range of toxicity tests, cell models and NP types and concentrations taking into account the inherent impact of NP properties and the effects of changes in experimental conditions using well-characterized NPs. The results of the studies have been used to generate recommendations for a suitable and robust testing strategy which can be applied to new medical NPs as they are developed., JRC.I.5-Systems Toxicology

Consumer health risk assessment for feed additives is based on the estimated human exposure to the additive that may occur in livestock edible tissues compared to its hazard.We present an approach using alternative methods for consumer health risk assessment. The aim was to use the fewest possible number of animals to estimate its hazard and human exposure without jeopardizing the safety upon use. As an example we selected the feed flavoring substance piperine and applied in silico modeling for residue estimation, results from literature surveys, and Read-Across to assess metabolism in different species. Results were compared to experimental in vitro metabolism data in rat and chicken, and to quantitative analysis of residues' levels from the in vivo situation in livestock. In silico residue modeling showed to be a worst case: the modeled residual levels were considerably higher than the measured residual levels. The in vitro evaluation of livestock versus rodent metabolism revealed no major differences in metabolism between the species.We successfully performed a consumer health risk assessment without performing additional animal experiments. As shown, the use and combination of different alternative methods supports animal welfare consideration and provides future perspective to reducing the number of animals.

The likelihood of oral exposure to nanoparticles (NPs) is increasing, and it is necessary to evaluate the oral bioavailability of NPs. In vitro approaches could help reducing animal studies, but validation against in vivo studies is essential. Previously, we assessed the translocation of 50 nm polystyrene NPs of different charges (neutral, positive and negative) using a Caco-2/HT29-MTX in vitro intestinal translocation model. The NPs translocated in a surface charge-dependent manner. The present study aimed to validate this in vitro intestinal model by an in vivo study. For this, rats were orally exposed to a single dose of these polystyrene NPs and the uptake in organs was determined. A negatively charged NP was taken up more than other NPs, with the highest amounts in kidney (37.4 µg/g tissue), heart (52.8 µg/g tissue), stomach wall (98.3 µg/g tissue) and small intestinal wall (94.4 µg/g tissue). This partly confirms our in vitro findings, where the same NPs translocated to the highest extent. The estimated bioavailability of different types of NPs ranged from 0.2 to 1.7 % in vivo, which was much lower than in vitro (1.6–12.3 %). Therefore, the integrated in vitro model cannot be used for a direct prediction of the bioavailability of orally administered NPs. However, the model can be used for prioritizing NPs before further in vivo testing for risk assessment. © 2015, The Author(s).

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed.

Background Allergens in food may pose a risk to allergic consumers. While there is EU regulation for allergens present as an ingredient, this is not the case for unintended allergen presence (UAP). Food companies use precautionary allergen labels to inform allergic individuals of a potential risk from UAPs. This study investigates the risk of an allergic reaction within the milk-, wheat-, hazelnut- and peanut-allergic populations when ingesting UK foods across multiple product categories with and without precautionary allergen labelling. Methods Allergen risk assessment using probabilistic techniques enables the estimation of the residual risk after the consumption of a product that unintentionally contains an allergen. Results Within this selection of UK products, the majority that tested positive for an allergen contained a concentration of allergen predicted to cause a reaction in >1% of the allergic population. The concentrations of allergens measured were greater than the VITAL® 2.0 action levels and would trigger precautionary allergen labelling. This was found for products both with and without precautionary allergen labelling. Conclusions The results highlight the need for the food industry and regulators to adopt a transparent, risk-based approach for the communication of the risk associated with potential cross-contact that could occur in the processing facility or production chain. © 2015 John Wiley & Sons A/S.

Precautionary allergen labelling (PAL) was introduced by the food industry to help manage and communicate the possibility of reaction from the unintended presence of allergens in foods. However, in its current form, PAL is counter-productive for consumers with food allergies. This review aims to summarise the perspectives of all the key stakeholders (including clinicians, patients, food industry and regulators), with the aim of defining common health protection and risk minimisation goals. The lack of agreed reference doses, has resulted in inconsistent application of PAL by the food industry and in levels of contamination that prompt withdrawal action by enforcement officers. So there is a poor relationship between the presence or absence of PAL and actual reaction risk. This has led to a loss of trust in PAL, reducing the ability of consumers with food allergies to make informed choices. The result has been reduced avoidance, reduced quality of life and increased risk-taking by consumers who often ignore PAL. All contributing stakeholders agree that PAL must reflect actual risk. PAL should be transparent and consistent with rules underpinning decision-making process being communicated clearly to all stakeholders. The use of PAL should indicate the possible, unintended presence of an allergen in a consumed portion of a food product at or above any proposed action level. This will require combined work by all stakeholders to ensure everyone understands the approach, and its limitations. Consumers with food allergy then need to be educated to undertake individualised risk assessments in relation to any PAL present.

Background Allergens in food may pose a risk to allergic consumers. While there is EU regulation for allergens present as an ingredient, this is not the case for unintended allergen presence (UAP). Food companies use precautionary allergen labels to inform allergic individuals of a potential risk from UAPs. This study investigates the risk of an allergic reaction within the milk-, wheat-, hazelnut- and peanut-allergic populations when ingesting UK foods across multiple product categories with and without precautionary allergen labelling. Methods Allergen risk assessment using probabilistic techniques enables the estimation of the residual risk after the consumption of a product that unintentionally contains an allergen. Results Within this selection of UK products, the majority that tested positive for an allergen contained a concentration of allergen predicted to cause a reaction in >1% of the allergic population. The concentrations of allergens measured were greater than the VITAL® 2.0 action levels and would trigger precautionary allergen labelling. This was found for products both with and without precautionary allergen labelling. Conclusions The results highlight the need for the food industry and regulators to adopt a transparent, risk-based approach for the communication of the risk associated with potential cross-contact that could occur in the processing facility or production chain. © 2015 John Wiley & Sons A/S.

Consumer health risk assessment for feed additives is based on the estimated human exposure to the additive that may occur in livestock edible tissues compared to its hazard.We present an approach using alternative methods for consumer health risk assessment. The aim was to use the fewest possible number of animals to estimate its hazard and human exposure without jeopardizing the safety upon use. As an example we selected the feed flavoring substance piperine and applied in silico modeling for residue estimation, results from literature surveys, and Read-Across to assess metabolism in different species. Results were compared to experimental in vitro metabolism data in rat and chicken, and to quantitative analysis of residues' levels from the in vivo situation in livestock. In silico residue modeling showed to be a worst case: the modeled residual levels were considerably higher than the measured residual levels. The in vitro evaluation of livestock versus rodent metabolism revealed no major differences in metabolism between the species.We successfully performed a consumer health risk assessment without performing additional animal experiments. As shown, the use and combination of different alternative methods supports animal welfare consideration and provides future perspective to reducing the number of animals.

Background: To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary. Objective: To establish EDs for objective and subjective symptoms and analyse the effect of sensitization levels and other patient characteristics on threshold distribution curves (TDCs). Methods: Threshold data from 100 adults and 262 children with a positive food challenge were analysed with interval-censoring survival analysis (ICSA) and fitted to a TDC from which EDs could be extracted. Possible influencing factors were analysed as covariates by ICSA. A hazard ratio (HR) was calculated in case of a significant effect. Results: TDCs for both objective and subjective symptoms were significantly different between adults and children (P < 0.001). Objective ED05 values, however, were comparable (2.86 mg peanut protein in adults and 6.38 mg in children). Higher levels of sIgE to Ara h 2 and peanut extract were associated with a larger proportion of patient groups reacting to a dose increase with objective symptoms (adults and children) or subjective symptoms (adults, in children a trend). Age had a similar effect in children (HR 1.05 for objective symptoms and 1.09 for subjective symptoms). Gender had no effect on TDCs. Conclusion and Clinical Relevance: Subjective and objective TDCs were different between adults and children, but objective ED05 values were comparable, meaning that threshold data from children and adults can be combined for elaboration of reference doses for risk assessment. Higher sIgE levels to Ara h 2 and peanut extract were associated with a larger proportion of both patient groups to react to a certain dose increase. © 2015 John Wiley & Sons Ltd.

There is a great need for rapid testing strategies for reproductive toxicity testing, avoiding animal use. The EU Framework program 7 project ChemScreen aimed to fill this gap in a pragmatic manner preferably using validated existing tools and place them in an innovative alternative testing strategy. In our approach we combined knowledge on critical processes affected by reproductive toxicants with knowledge on the mechanistic basis of such effects. We used in silico methods for prescreening chemicals for relevant toxic effects aiming at reduced testing needs. For those chemicals that need testing we have set up an in vitro screening panel that includes mechanistic high throughput methods and lower throughput assays that measure more integrative endpoints. In silico pharmacokinetic modules were developed for rapid exposure predictions via diverse exposure routes. These modules to match in vitro and in vivo exposure levels greatly improved predictivity of the in vitro tests. As a further step, we have generated examples how to predict reproductive toxicity of chemicals using available data. We have executed formal validations of panel constituents and also used more innovative manners to validate the test panel using mechanistic approaches. We are actively engaged in promoting regulatory acceptance of the tools developed as an essential step towards practical application, including case studies for read-across purposes. With this approach, a significant saving in animal use and associated costs seems very feasible.

In spite of recent advances in describing the health outcomes of exposure to nanoparticles (NPs), it still remains unclear how exactly NPs interact with their cellular targets. Size, surface, mass, geometry, and composition may all play a beneficial role as well as causing toxicity. Concerns of scientists, politicians and the public about potential health hazards associated with NPs need to be answered. With the variety of exposure routes available, there is potential for NPs to reach every organ in the body but we know little about the impact this might have. The main objective of the FP7 NanoTEST project (www.nanotest-fp7.eu) was a better understanding of mechanisms of interactions of NPs employed in nanomedicine with cells, tissues and organs and to address critical issues relating to toxicity testing especially with respect to alternatives to tests on animals. Here we describe an approach towards alternative testing strategies for hazard and risk assessment of nanomaterials, highlighting the adaptation of standard methods demanded by the special physicochemical features of nanomaterials and bioavailability studies. The work has assessed a broad range of toxicity tests, cell models and NP types and concentrations taking into account the inherent impact of NP properties and the effects of changes in experimental conditions using well-characterized NPs. The results of the studies have been used to generate recommendations for a suitable and robust testing strategy which can be applied to new medical NPs as they are developed. © 2015 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.

Carbon capture and storage (CCS) technologies are considered vital and economic elements for achieving global CO2 reduction targets, and is currently introduced worldwide (for more information on CCS, consult for example the websites of the International Energy Agency (http://www.iea.org/topics/ccs/) and the Global CCS Institute (http://www.globalccsinstitute.com/)). One prominent CCS technology, the amine-based post-combustion process, may generate nitrosamines and their related nitramines as by-products, the former well known for their potential mutagenic and carcinogenic properties. In order to efficiently assess the carcinogenic potency of any of these by-products this paper reviews and discusses novel prediction approaches consuming less time, money and animals than the traditionally applied 2-year rodent assay. For this, available animal carcinogenicity studies with N-nitroso compounds and nitramines have been used to derive carcinogenic potency values, that were subsequently used to assess the predictive performance of alternative prediction approaches for these chemicals. Promising cancer prediction models are the QSARs developed by the Helguera group, in vitro transformation assays, and the in vivo initiation-promotion, and transgenic animal assays. All these models, however, have not been adequately explored for this purpose, as the number of N-nitroso compounds investigated is yet too limited, and therefore further testing with relevant N-nitroso compounds is needed.

Background: Food legislation in the European Union and elsewhere includes both hazard- and risk-based approaches for ensuring safety. In hazard-based approaches, simply the presence of a potentially harmful agent at a detectable level in food is used as a basis for legislation and/or risk management action. Risk-based approaches allow consideration of exposure in assessing whether there may be unacceptable risks to health. Scope and approach: The advantages and disadvantages of hazard- and risk-based approaches for ensuring the safety of food chemicals, allergens, ingredients and microorganisms were explored at an ILSI Europe workshop. Key findings and conclusions: It was concluded that both types of approach have their place, depending on the context. However, problems can arise when both types of approach are used in regulation by separate agencies that address different aspects of the same agent/substance present in food. This separation of decision-making can result in hazard-based restrictions on marketing and use, whereas risk-based assessments for those exposed show there is reasonable certainty no harm will result. This in turn can lead to contradictory, confusing and ultimately unnecessary actions. Use of hazard-based approaches for foods also means that comparisons with benefits for nutrition and food security cannot be undertaken. This has the potential to lead to bias in the overall conclusions of regulators and risk managers, who may not have been presented with the benefits of particular foods. The value of risk-based approaches is becoming increasingly recognised. © 2015 ILSI Europe A.I.S.B.L.

In 2009, the European Union adopted the Directive on Sustainable Use of pesticides (SUD, Directive 2009/128/EC) establishing a framework for achieving a sustainable use of Plant Protection Products (PPPs) through reducing the risks and impacts of PPP use on human health and the environment, promoting integrated pest management and stimulating effective non-chemical alternatives. The core idea of the SUD is that it is necessary to monitor the use of PPPs through the implementation of an appropriate set of risk indicators to monitor progress and trends in risk reduction within the Member States. To contribute to this direction, following a comprehensive analysis of the risk (including procedures of risk assessment and risk management) and involving stakeholders in the decision process, specific toolboxes of practical indirect risk indicators of exposure of Operators, Workers, Bystanders and Residents were developed and are now available to be used by Member States (MSs) based on their specific context. © 2015, Springer-Verlag Berlin Heidelberg.

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., The authors are all part of the COST Action FA1402 entitled: ImpARAS. This work was in part funded by the Austrian Science Fund (FWF SFB F4603) to KHS; The Ministry of Education, Science and Technological Development of the Republic of Serbia Grant Number OI172024 to TCV; MINECO, Spain, through the project AGL2014‐59771‐R to EM; Project 31‐03‐05‐FEP‐0060 – Aquavalor, cofinanced by PROMAR: Projetos Pilotos e a Transformação de Embarcações de Pesca to PR.

In the EU collaborative project ChemScreen an alternative, in vitro assay-based test strategy was developed to screen compounds for reproductive toxicity. A toxicokinetic modeling approach was used to allow quantitative comparison between effective concentrations in the in vitro test battery and observations of developmental toxicity in vivo. This modeling strategy is based on (1) the definition of relevant observations of toxicity in vivo, (2) simulation of the corresponding systemic concentrations in vivo by toxicokinetic modeling, and (3) correction for differences in protein binding and lipid partitioning between plasma and in vitro test media. The test results of a feasibility study with a number of known reproductive toxicants has been described previously (Piersma et al. [15]). In the present paper, we take a more detailed look at the toxicokinetics of these compounds, and add the analysis of some compounds from subsequent studies. We discuss how the consideration of toxicokinetics allowed comparison between test systems with differing test medium composition, has helped to interpret the in vitro findings in light of in vivo observations, and to gain confidence in the predictive value of the test battery outcomes. The same toxicokinetic modeling strategy, in reverse order, can now be used for risk assessment purposes to predict toxic doses in vivo from effective concentrations in vitro. © 2014 Elsevier Inc..

Regulatory thresholds for allergenic foods have not yet been developed. This means that public and industrial risk managers do not have regulatory thresholds to decide if a content or level of contamination is acceptable or not. For a long time, data have been inadequate to define safe thresholds for food allergens. More and more challenge data from food allergic patients are now available, and this opens the possibility to perform more advanced food allergy safety and risk assessments. These can be used to inform risk management decisions and ultimately to form the basis for regulatory thresholds. In the chapter we describe three different approaches for safety/risk assessment based on no/low observed adverse effect level, benchmark dose, or probabilistic modeling. These methods are illustrated by examples from real life and the possibilities and limitations are discussed. © 2014 Elsevier Inc. All rights reserved.

Background: To improve food labelling strategies, information regarding eliciting doses (EDs) and the effect of patient characteristics on these EDs is necessary. Objective: To establish EDs for objective and subjective symptoms and analyse the effect of sensitization levels and other patient characteristics on threshold distribution curves (TDCs). Methods: Threshold data from 100 adults and 262 children with a positive food challenge were analysed with interval-censoring survival analysis (ICSA) and fitted to a TDC from which EDs could be extracted. Possible influencing factors were analysed as covariates by ICSA. A hazard ratio (HR) was calculated in case of a significant effect. Results: TDCs for both objective and subjective symptoms were significantly different between adults and children (P < 0.001). Objective ED05 values, however, were comparable (2.86 mg peanut protein in adults and 6.38 mg in children). Higher levels of sIgE to Ara h 2 and peanut extract were associated with a larger proportion of patient groups reacting to a dose increase with objective symptoms (adults and children) or subjective symptoms (adults, in children a trend). Age had a similar effect in children (HR 1.05 for objective symptoms and 1.09 for subjective symptoms). Gender had no effect on TDCs. Conclusion and Clinical Relevance: Subjective and objective TDCs were different between adults and children, but objective ED05 values were comparable, meaning that threshold data from children and adults can be combined for elaboration of reference doses for risk assessment. Higher sIgE levels to Ara h 2 and peanut extract were associated with a larger proportion of both patient groups to react to a certain dose increase. © 2015 John Wiley & Sons Ltd.

Background: Food legislation in the European Union and elsewhere includes both hazard- and risk-based approaches for ensuring safety. In hazard-based approaches, simply the presence of a potentially harmful agent at a detectable level in food is used as a basis for legislation and/or risk management action. Risk-based approaches allow consideration of exposure in assessing whether there may be unacceptable risks to health. Scope and approach: The advantages and disadvantages of hazard- and risk-based approaches for ensuring the safety of food chemicals, allergens, ingredients and microorganisms were explored at an ILSI Europe workshop. Key findings and conclusions: It was concluded that both types of approach have their place, depending on the context. However, problems can arise when both types of approach are used in regulation by separate agencies that address different aspects of the same agent/substance present in food. This separation of decision-making can result in hazard-based restrictions on marketing and use, whereas risk-based assessments for those exposed show there is reasonable certainty no harm will result. This in turn can lead to contradictory, confusing and ultimately unnecessary actions. Use of hazard-based approaches for foods also means that comparisons with benefits for nutrition and food security cannot be undertaken. This has the potential to lead to bias in the overall conclusions of regulators and risk managers, who may not have been presented with the benefits of particular foods. The value of risk-based approaches is becoming increasingly recognised. © 2015 ILSI Europe A.I.S.B.L.