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.</p

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

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

Aspectos cognitivos relacionados à noção de intervalos de tempo Cognitive aspects related to time interval notion

OBJETIVO: Procuramos analisar os aspectos cognitivos e metodológicos envolvidos na avaliação da noção de intervalos de tempo, verificando os aspectos cognitivos envolvidos durante a sua execução, e apontar a relevância, aplicabilidade e sensibilidade dessa avaliação no exame neuropsicológico. MÉTODOS: Realizou-se revisão bibliográfica abrangendo artigos e pesquisas das literaturas nacional e internacional no período de 1990 a 2005. RESULTADOS: Encontraram-se 13 diferentes estudos. São controversas as discussões acerca de teorias sobre a noção de tempo. Os estudos podem ser agrupados de acordo com duas perspectivas diferentes: a teoria da contagem atencional, de grande utilização por pesquisadores americanos, e a teoria do relógio interno, muito abordada por estudiosos franceses que se diferem tanto em relação à abordagem teórica quanto à metodológica. CONCLUSÕES: Ambos os grupos de pesquisa, americanos e franceses, retratam a relevância da aplicação dos testes de estimativa, reprodução e produção de tempo no estudo das funções executivas.<br>OBJECTIVE: We tried to analyze the cognitive and methodological aspects involved in the evaluation of time intervals notion, verifying the cognitive aspects involved during your execution, and to point the relevance, applicability and sensibility of this evaluation in the neuropsychologic exam. METHODS: Bibliographical revision was accomplished including articles and researches of the national and international literature in the period of 1990 to 2005. RESULTS: Were found 13 different researches. The discussions concerning theories about the time notion are controversial. These studies can be grouped into two different perspectives: the attentional counter theory, used by American researchers, and the internal clock theory, very boarded by French studious, that are differed in relation to the theoretical and to the methodological approaches. CONCLUSIONS: Both research groups, Americans and French, show the relevance of the application of the time-interval estimation tests, reproduction and production in the study of the executive functions

Cumulative dietary exposure assessment of pesticides that have acute effects on the nervous system using MCRA software

In the context of the second framework partnership agreement between the National Institute for Public Health and the Environment of the Netherlands (RIVM) and the European Food Safety Authority (EFSA)acute cumulative dietary exposure assessments were performed for two cumulative assessment groups (CAGs) of pesticidesthat affect the nervous system: pesticides associated with brain and/or erythrocyte AChE inhibition (CAG-NAN, 47 pesticides) and pesticides associated with functional alterations of the motor division (CAG-NAM, 100 pesticides). The exposure assessments used pesticide monitoring data collected by Member States under their official monitoring programmes in 2014, 2015 and 2016 and individual food consumption data from ten populations of consumers from different countries and from different age groups. Exposure estimates were obtained for each group of pesticides by means of a 2-dimensional Monte Carlo simulation, which was implemented in the Monte Carlo Risk Assessment (MCRA) software.The scope of the assessment and the parameters to be used for cumulative exposure assessment were discussed and agreed by the Standing Committee on Plants, Animals, Food and Feed (SC PAFF). Based on those discussions, a very conservative tier I modelling approach and a refined, but still conservative tier II modelling approach were used. In these assessments, common risk assessment practice was followed and the cumulative exposure was calculated as total margin of exposure (MOET) at the 50th, 90th, 95th, 99th and 99.9th percentiles of the exposure distribution. Five sensitivity analyses aiming to address major uncertainties were performed. The exposure estimates obtained in this report are used in EFSA's scientific report on the cumulative dietary risk characterisation of pesticides that have acute effects on the nervous system

Annexes to the EFSA external scientific report "Proposed prospective scenarios for cumulative risk assessment of pesticide residues"

In the context of prospective cumulative risk assessment of pesticides, different options and scenarios for a tiered approach were investigated by means of 15 case studies for the cumulative assessment group associated with an effect on the motor division of the nervous system (CAG-NAM) and 15 case studies for the cumulative assessment group associated with an effect on hypothyroidism (CAG-TCF) (doi:10.2903/sp.efsa.2021.EN-6811). The results of the prospective exposure calculations are reported in the following annexes: Annex A: Acute exposure calculations - CAG-NAM Annex B: Chronic exposure calculations - CAG-TCF Annex C: Results supporting the discussion on prospective acute scenarios - CAG-NAM Annex D: Results supporting the discussion on prospective chronic scenarios - CAG-TCF The case studies reported above also include fictitious data, which were included for assessing the relevance of the various parameters in these calculations. The results of these case studies do not represent real estimates of exposure or risk, nor do they represent the formal outcome of a risk assessment

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.

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

A retain and refine approach to cumulative risk assessment.

Mixtures of substances to which humans are exposed may lead to cumulative exposure and health effects. To study their effects, it is first necessary to identify a cumulative assessment group (CAG) of substances for risk assessment or hazard testing. Excluding substances from consideration before there is sufficient evidence may underestimate the risk. Conversely, including everything and treating the inevitable uncertainties using conservative assumptions is inefficient and may overestimate the risk, with an unknown level of protection. An efficient, transparent strategy is described to retain a large group, quantifying the uncertainty of group membership and other uncertainties. Iterative refinement of the CAG then focuses on adding information for the substances with high probability of contributing significantly to the risk. Probabilities can be estimated using expert opinion or derived from data on substance properties. An example is presented with 100 pesticides, in which the retain step identified a single substance to target refinement. Using an updated hazard characterisation for this substance reduced the mean exposure estimate from 0.43 to 0.28 μg kg-bw-1 day-1 and reduced the 99.99th percentile exposure from 24.9 to 5.1 μg kg-bw-1 day-1. Other retained substances contributed little to the risk estimates, even after accounting for uncertainty