Combined chronic dietary exposure to four nephrotoxic metals exceeds tolerable intake levels in the adult population of 10 European countries.

A mixture risk assessment (MRA) for four metals relevant to chronic kidney disease (CKD) was performed. Dietary exposure to cadmium or lead alone exceeded the respective reference values in the majority of the 10 European countries included in our study. When the dietary exposure to those metals and inorganic mercury and inorganic arsenic was combined following a classical or personalised modified reference point index (mRPI) approach, not only high exposure (95th percentile) estimates but also the mean exceeded the tolerable intake of the mixture in all countries studied. Cadmium and lead contributed most to the combined exposure, followed by inorganic arsenic and inorganic mercury. The use of conversion factors for inorganic arsenic and inorganic mercury from total arsenic and total mercury concentration data was a source of uncertainty. Other uncertainties were related to the use of different principles to derive reference points. Yet, MRA at the target organ level, as performed in our study, could be used as a way to efficiently prioritise assessment groups for higher-tier MRA. Since the combined exposure to the four metals exceeded the tolerable intake, we recommend a refined MRA based on a common, specific nephrotoxic effect and relative potency factors (RPFs) based on a similar effect size.

Dose Addition in the Induction of Craniofacial Malformations in Zebrafish Embryos Exposed to a Complex Mixture of Food-Relevant Chemicals with Dissimilar Modes of Action.

BACKGROUND: Humans are exposed to combinations of chemicals. In cumulative risk assessment (CRA), regulatory bodies such as the European Food Safety Authority consider dose addition as a default and sufficiently conservative approach. The principle of dose addition was confirmed previously for inducing craniofacial malformations in zebrafish embryos in binary mixtures of chemicals with either similar or dissimilar modes of action (MOAs). OBJECTIVES: In this study, we explored a workflow to select and experimentally test multiple compounds as a complex mixture with each of the compounds at or below its no observed adverse effect level (NOAEL), in the same zebrafish embryo model. METHODS: Selection of candidate compounds that potentially induce craniofacial malformations was done using in silico methods-structural similarity, molecular docking, and quantitative structure-activity relationships-applied to a database of chemicals relevant for oral exposure in humans via food (EuroMix inventory, n=1,598). A final subselection was made manually to represent different regulatory fields (e.g., food additives, industrial chemicals, plant protection products), different chemical families, and different MOAs. RESULTS: A final selection of eight compounds was examined in the zebrafish embryo model, and craniofacial malformations were observed in embryos exposed to each of the compounds, thus confirming the developmental toxicity as predicted by the in silico methods. When exposed to a mixture of the eight compounds, each at its NOAEL, substantial craniofacial malformations were observed; according to a dose-response analysis, even embryos exposed to a 7-fold dilution of this mixture still exhibited a slight abnormal phenotype. The cumulative effect of the compounds in the mixture was in accordance with dose addition (added doses of the individual compounds after adjustment for relative potencies), despite different MOAs of the compounds involved. DISCUSSION: This case study of a complex mixture inducing craniofacial malformations in zebrafish embryos shows that dose addition can adequately predicted the cumulative effect of a mixture of multiple substances at low doses, irrespective of the (expected) MOA. The applied workflow may be useful as an approach for CRA in general. https://doi.org/10.1289/EHP9888.

Advancing tools for human early lifecourse exposome research and translation (ATHLETE): Project overview.

Early life stages are vulnerable to environmental hazards and present important windows of opportunity for lifelong disease prevention. This makes early life a relevant starting point for exposome studies. The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project aims to develop a toolbox of exposome tools and a Europe-wide exposome cohort that will be used to systematically quantify the effects of a wide range of community- and individual-level environmental risk factors on mental, cardiometabolic, and respiratory health outcomes and associated biological pathways, longitudinally from early pregnancy through to adolescence. Exposome tool and data development include as follows: (1) a findable, accessible, interoperable, reusable (FAIR) data infrastructure for early life exposome cohort data, including 16 prospective birth cohorts in 11 European countries; (2) targeted and nontargeted approaches to measure a wide range of environmental exposures (urban, chemical, physical, behavioral, social); (3) advanced statistical and toxicological strategies to analyze complex multidimensional exposome data; (4) estimation of associations between the exposome and early organ development, health trajectories, and biological (metagenomic, metabolomic, epigenetic, aging, and stress) pathways; (5) intervention strategies to improve early life urban and chemical exposomes, co-produced with local communities; and (6) child health impacts and associated costs related to the exposome. Data, tools, and results will be assembled in an openly accessible toolbox, which will provide great opportunities for researchers, policymakers, and other stakeholders, beyond the duration of the project. ATHLETE's results will help to better understand and prevent health damage from environmental exposures and their mixtures from the earliest parts of the life course onward.

The MCRA toolbox of models and data to support chemical mixture risk assessment.

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.

A European model and case studies for aggregate exposure assessment of pesticides.

Exposures to plant protection products (PPPs) are assessed using risk analysis methods to protect public health. Traditionally, single sources, such as food or individual occupational sources, have been addressed. In reality, individuals can be exposed simultaneously to multiple sources. Improved regulation therefore requires the development of new tools for estimating the population distribution of exposures aggregated within an individual. A new aggregate model is described, which allows individual users to include as much, or as little, information as is available or relevant for their particular scenario. Depending on the inputs provided by the user, the outputs can range from simple deterministic values through to probabilistic analyses including characterisations of variability and uncertainty. Exposures can be calculated for multiple compounds, routes and sources of exposure. The aggregate model links to the cumulative dietary exposure model developed in parallel and is implemented in the web-based software tool MCRA. Case studies are presented to illustrate the potential of this model, with inputs drawn from existing European data sources and models. These cover exposures to UK arable spray operators, Italian vineyard spray operators, Netherlands users of a consumer spray and UK bystanders/residents. The model could also be adapted to handle non-PPP compounds.

Cumulative dietary exposure to a selected group of pesticides of the triazole group in different European countries according to the EFSA guidance on probabilistic modelling.

The practicality was examined of performing a cumulative dietary exposure assessment according to the requirements of the EFSA guidance on probabilistic modelling. For this the acute and chronic cumulative exposure to triazole pesticides was estimated using national food consumption and monitoring data of eight European countries. Both the acute and chronic cumulative dietary exposures were calculated according to two model runs (optimistic and pessimistic) as recommended in the EFSA guidance. The exposures obtained with these model runs differed substantially for all countries, with the highest exposures obtained with the pessimistic model run. In this model run, animal commodities including cattle milk and different meat types, entered in the exposure calculations at the level of the maximum residue limit (MRL), contributed most to the exposure. We conclude that application of the optimistic model run on a routine basis for cumulative assessments is feasible. The pessimistic model run is laborious and the exposure results could be too far from reality. More experience with this approach is needed to stimulate the discussion of the feasibility of all the requirements, especially the inclusion of MRLs of animal commodities which seem to result in unrealistic conclusions regarding their contribution to the dietary exposure.

Stakeholder attitudes towards cumulative and aggregate exposure assessment of pesticides.

This study evaluates the attitudes and perspectives of different stakeholder groups (agricultural producers, pesticide manufacturers, trading companies, retailers, regulators, food safety authorities, scientists and NGOs) towards the concepts of cumulative and aggregate exposure assessment of pesticides by means of qualitative in-depth interviews (n = 15) and a quantitative stakeholder survey (n = 65). The stakeholders involved generally agreed that the use of chemical pesticides is needed, primarily for meeting the need of feeding the growing world population, while clearly acknowledging the problematic nature of human exposure to pesticide residues. Current monitoring was generally perceived to be adequate, but the timeliness and consistency of monitoring practices across countries were questioned. The concept of cumulative exposure assessment was better understood by stakeholders than the concept of aggregate exposure assessment. Identified pitfalls were data availability, data limitations, sources and ways of dealing with uncertainties, as well as information and training needs. Regulators and food safety authorities were perceived as the stakeholder groups for whom cumulative and aggregate pesticide exposure assessment methods and tools would be most useful and acceptable. Insights obtained from this exploratory study have been integrated in the development of targeted and stakeholder-tailored dissemination and training programmes that were implemented within the EU-FP7 project ACROPOLIS.

The MCRA model for probabilistic single-compound and cumulative risk assessment of pesticides.

Pesticide risk assessment is hampered by worst-case assumptions leading to overly pessimistic assessments. On the other hand, cumulative health effects of similar pesticides are often not taken into account. This paper describes models and a web-based software system developed in the European research project ACROPOLIS. The models are appropriate for both acute and chronic exposure assessments of single compounds and of multiple compounds in cumulative assessment groups. The software system MCRA (Monte Carlo Risk Assessment) is available for stakeholders in pesticide risk assessment at mcra.rivm.nl. We describe the MCRA implementation of the methods as advised in the 2012 EFSA Guidance on probabilistic modelling, as well as more refined methods developed in the ACROPOLIS project. The emphasis is on cumulative assessments. Two approaches, sample-based and compound-based, are contrasted. It is shown that additional data on agricultural use of pesticides may give more realistic risk assessments. Examples are given of model and software validation of acute and chronic assessments, using both simulated data and comparisons against the previous release of MCRA and against the standard software DEEM-FCID used by the Environmental Protection Agency in the USA. It is shown that the EFSA Guidance pessimistic model may not always give an appropriate modelling of exposure.

Testing a cumulative and aggregate exposure model using biomonitoring studies and dietary records for Italian vineyard spray operators.

The need for improved tools to estimate the cumulative and aggregate exposure to compounds such as plant protection products (PPPs) is recognised in the EU Regulation 1107/2009. A new model has been developed to estimate the exposure within a population to single compounds or compounds within a Cumulative Action Group, considering dietary and non-dietary sources and multiple exposure routes. To test the model a field study was carried out in Italy with operators applying tebuconazole fungicides, with measurements of dermal exposure collected. Whole urine samples were collected and analysed to provide values for the absorbed dose of tebuconazole, with duplicate diet samples collected and analysed as a measure of dietary exposures. The model provided predicted values of exposure for combined dietary and non-dietary routes of exposures which were compared to the measured absorbed dose values based on urinary analysis. The model outputs provided mean daily exposure values of 1.77 (± 1.96) µg a.s./kg BW which are comparable to measured mean values from the biomonitoring field study of 1.73 (± 1.31) µg a.s./kg BW. To supplement the limited measurement data available, comparisons against other models were also made and found to be comparable.

Computational tool for usual intake modelling workable at the European level.

In this paper two models present in the computational tool Monte Carlo Risk Assessment (MCRA) were compared for assessing the usual intake of lead in five countries. For this, we used national food consumption data organised according to the format of the European Food Safety Authority (EFSA) Comprehensive database and a single lead concentration database in which analysed commodities were organised according to EFSA's Standard Sampling Description (SSD) system. This meant that both input data were coded according to the hierarchical FoodEx1 classification system. We demonstrate that the naïve Observed Individual Means model resulted in more conservative estimates of the exposure in the right tail of the exposure distribution compared to a refined usual intake model, the LogisticNormal­Normal model. With MCRA, the usual intake could be estimated with both models using food consumption and concentration data that were coded according to the hierarchical FoodEx1 classification system demonstrating that this tool can be used in EFSA's data environment. Additionally, the computational tool has functionalities 1) to check the input data quality by presenting detailed information about these data around a specified percentile of exposure and 2) to decide whether the use of a more refined usual intake model is appropriate.

Comparison of different exposure assessment methods to estimate the long-term dietary exposure to dioxins and ochratoxin A.

Long-term exposures to dioxins (PCCD/F and dioxin-like PCBs) and ochratoxin A were calculated using food consumption data of the European concise database combined with concentration data of the Netherlands (NL) using a deterministic approach. To refine these assessments, exposures were also calculated using three long-term exposure models, observed individual means (OIM), Iowa State University Foods (ISUF), and betabinomial-normal (BBN) models, combined with individual food consumption data of NL. BBN and ISUF correct the variation in long-term exposure for the within-person variation, whereas OIM calculates the mean exposure over the days in the food consumption survey. Exposures obtained with the concise database were highest, and those obtained with OIM higher than with BBN and ISUF. Contribution of the major sources of exposure differed between the concise database and the three models. Given the constraints of the concise database, exposures obtained with this database should be interpreted as a first tier assessment. Preferably, refined assessments using models that correct the variation in long-term exposure for the within-person variation combined with individual food consumption data and national concentration data should be used to assess the long-term exposure. We recommend the use of BBN since it can model exposure distributions that depend on covariates.

Dietary exposure assessments for children in europe (the EXPOCHI project): rationale, methods and design.

BACKGROUND/PURPOSE: The number of dietary exposure assessment studies focussing on children is very limited. Children are however a vulnerable group due to their higher food consumption level per kg body weight. Therefore, the EXPOCHI project aims 1 to create a relational network of individual food consumption databases in children, covering different geographical areas within Europe, and 2 to use these data to assess the usual intake of lead, chromium, selenium and food colours. METHODS: EXPOCHI includes 14 food consumption databases focussed on children (1-14 y old). The data are considered representative at national/regional level: 14 regions covering 13 countries. Since the aim of the study is to perform long-term exposure assessments, only data derived from 24 hr dietary recalls and dietary records recorded on at least two non-consecutive days per individual were included in the dietary exposure assessments. To link consumption data and concentration data of lead, chromium and selenium in a standardised way, categorisation of the food consumption data was based on the food categorisation system described within the SCOOP Task report 3.2.11. For food colours, the food categorisation system specified in the Council Directive 94/36/EC was used. CONCLUSION: The EXPOCHI project includes a pan-European long-term exposure assessment of lead, chromium, selenium and food colours among children living in 13 different EU countries. However, the different study methods and designs used to collect the data in the different countries necessitate an in-depth description of these different methods and a discussion about the resulting limitations.

Probabilistic risk assessment of dietary exposure to single and multiple pesticide residues or contaminants: summary of the work performed within the SAFE FOODS project.

This introduction to the journal's supplement on probabilistic risk assessment of single and multiple exposure to pesticide residues or contaminants summarizes the objectives and results of the work performed in work package 3 of the EU-funded project SAFE FOODS. Within this work package, we developed an electronic platform of food consumption and chemical concentration databases harmonised at raw agricultural commodity level. In this platform the databases are connected to probabilistic software to allow probabilistic modelling of dietary exposure in a standardised way. The usefulness of this platform is demonstrated in two papers, which describe the exposure to pesticides and glycoalkaloids in several European countries. Furthermore, an integrated probabilistic risk assessment (IPRA) model was developed: a new tool to integrate exposure and effect modelling, including uncertainty analyses. The use of this model was shown in a paper on the cumulative exposure to anti-androgen pesticides. Combined with a health impact prioritization system, developed within this work package to compare heath risks between chemicals, the IPRA tool can also be used to compare health risks between multiple chemicals in complex risk assessment situation such as risk-benefit and risk trade-off analyses. Both the electronic platform of databases as the IPRA model may proof to be powerful tools to tackle the challenges risk managers are or will be faced with in the future.

Harmonisation of food consumption data format for dietary exposure assessments of chemicals analysed in raw agricultural commodities.

In this paper, we present an approach to format national food consumption data at raw agricultural commodity (RAC) level. In this way, the data is both formatted in a harmonised way given the comparability of RACs between countries, and suitable to assess the dietary exposure to chemicals analysed in RACs at a European level. In this approach, consumption data needs to be converted to edible part of RAC (e-RAC) level using a RAC conversion database. To subsequently use this data in exposure assessments, both e-RACs and RACs analysed in chemical control programmes should be classified via a uniform system. Furthermore, chemical concentrations in RACs may need to be converted to e-RAC level using processing factors. To illustrate the use of this approach, we describe how the Dutch RAC conversion database was used to convert consumption data of four national consumption surveys to e-RAC level, and the use of the FAO/WHO Codex Classification system of Foods and Animal Feeds to harmonise the classification. We demonstrate that this approach works well for pesticides and glycoalkaloids, and is an essential step forward in the harmonisation of risk assessment procedures within Europe when addressing chemicals analysed in RACs by all national food control systems.

Probabilistic acute dietary exposure assessments to captan and tolylfluanid using several European food consumption and pesticide concentration databases.

Probabilistic dietary acute exposure assessments of captan and tolylfluanid were performed for the populations of the Czech Republic, Denmark, Italy, the Netherlands and Sweden. The basis for these assessments was national databases for food consumption and pesticide concentration data harmonised at the level of raw agricultural commodity. Data were obtained from national food consumption surveys and national monitoring programmes and organised in an electronic platform of databases connected to probabilistic software. The exposure assessments were conducted by linking national food consumption data either (1) to national pesticide concentration data or (2) to a pooled database containing all national pesticide concentration data. We show that with this tool national exposure assessments can be performed in a harmonised way and that pesticide concentrations of other countries can be linked to national food consumption surveys. In this way it is possible to exchange or merge concentration data between countries in situations of data scarcity. This electronic platform in connection with probabilistic software can be seen as a prototype of a data warehouse, including a harmonised approach for dietary exposure modelling.

Comparison of human health risks resulting from exposure to fungicides and mycotoxins via food.

The interest in holistic considerations in the area of food safety is increasing. Risk managers may face the problem that reducing the risk of one compound may increase the risk of another compound. An example is the potential increase in mycotoxin levels due to a reduced use of fungicides in crop production. The Integrated Probabilistic Risk Assessment (IPRA) model was used to compare the estimated health impacts on humans caused by crops contaminated with the fungicides spiroxamine (SPI) and tebuconazole (TEB) or with the mycotoxins deoxynivalenol (DON) and zearalenone (ZEA). The IPRA model integrates a distribution characterising the exposure of individuals with a distribution characterising the susceptibility of individuals towards toxic effects. Its outcome, a distribution of Individual Margins of Exposure (IMoE), served as basis to perform comparisons of compounds, effects, countries, and population groups. Based on the available data and the assumptions made, none of the four compounds was found to have impact on human health in the addressed scenarios. The IMoE distributions were located as follows: DON

Dietary intake and risk evaluation of polybrominated diphenyl ethers in The Netherlands.

The current study aims at estimating the dietary intake of PBDEs in the Netherlands and evaluating the resultant risk. Dietary intake was estimated using results of PBDE analyses in Dutch food products from 2003/2004 and consumption data of the third Dutch National Food Consumption Survey (1997/1998). Assuming that non-detects represent levels of half the detection limit, the median long-term intake of the Dutch population of the sum of five major PBDEs (namely PBDEs 47, 99, 100, 153+154) is 0.79 ng/kg body weight bw/day (P97.5: 1.62 ng/kg bw/day). When non-detects are considered as zeros the values are 0.53 (median) and 1.34 (P97.5) ng/kg bw/day. Environmental concentrations of PBDEs in Europe are expected to decline in the near future because of the ban on penta- and octaBDE technical products. However, it will take at least a decade before this will result in lower PBDE concentrations in food products. Hence, a regular monitoring program for PBDEs is recommended. A risk evaluation at the most sensitive endpoints of BDE 99 carried out in this paper indicates that, although the long-term exposure to BDE 99 is well below the human exposure threshold level for neurodevelopmental toxicity, it may be close to that for reproductive toxicity.

A probabilistic model for simultaneous exposure to multiple compounds from food and its use for risk-benefit assessment.

A model is presented which allows to quantify the simultaneous distribution of the exposure to two compounds, for example a health-risk and a health promoting compound. The model considers the total dietary intake, and can be used as a first step to study the effects on the balance between risks and benefits following changes in the consumption pattern. The exposure is modelled separately for intake probabilities using a betabinomial model, and for intake amounts using a lognormal model, and these parts are afterwards integrated by Monte Carlo simulation. The model is illustrated using the risk-benefit case of dioxins and the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). High concentrations of both the health adverse compounds and the health promoting compounds are simultaneously present in fatty fish. Calculated exposures were compared with intake limits: the adequate intake for EPA+DHA and the tolerable daily intake (TDI) for dioxins. We estimate the probability that dioxin exposure is below TDI, the probability that EPA+DHA exposure is above the adequate intake, and the probability that both conditions occur simultaneously. We also model the dependence of these probabilities on age. In the studied population the exposure to both compounds is almost completely below the limits. A scenario study in which meat consumption was replaced by fatty fish consumption shows an increase in the fraction of the population with the recommended intake of EPA+DHA, however also the fraction of the population exceeding the TDI for dioxins is increased. For the example scenario the optimal amount of fatty fish consumption is derived.

Effect of increased vegetable and fruit consumption on plasma folate and homocysteine concentrations.

OBJECTIVE: We assessed the effects of an intervention aimed at increasing the consumption of fruits and vegetables on plasma folate and homocysteine concentrations. METHODS: Seventy-one healthy non-smoking women (mean +/- SD 41 +/- 4 y of age) were randomized to an intervention or a control group. Participants in the intervention group (n = 36) received weekly packets containing fruits and vegetables free of charge and were asked to consume a daily amount of >or=200 g of vegetables and two pieces of fruit (the Dutch recommended intake level) over a period of 1 mo. Control subjects did not receive any intervention. RESULTS: Compared with the control group, reported fruit and vegetable intakes in the intervention group increased by 133 g/d (95% confidence interval [CI] 87-179, P < 0.001) for fruits and juice and 64 g/d (95% CI 37-91, P < 0.001) for vegetables and estimated folate intake from fruits and vegetables increased by 40 microg/d (95% CI 22-58, P < 0.001). However, no effect was observed on plasma folate concentrations (intervention effect 0.3 nmol/L, 95% CI -1.8 to 2.8, P = 0.77) or homocysteine concentrations (intervention effect 0.26 micromol/L, 95% CI -0.34 to 0.87, P = 0.39). CONCLUSION: The results suggest that 4 wk of increased fruit and vegetable consumption to the recommended amounts may be insufficient to change plasma folate and homocysteine concentrations.