Deliverable 6.1 - Demonstration prototype of the EuroMix model toolbox

This document describes in short the new features in a demonstration prototype of the EuroMix toolbox, developed as MCRA 8.2. An important aim of the EuroMix project is to develop and implement a web-based platform (the EuroMix toolbox) including data and models accessible to all key-actors in risk assessment and risk management. In the EuroMix project the development of a mixture selection module based on exposure was prioritised, because the choice of chemicals for the experiments depended on this. A mixture selection module was therefore developed, based on a method called sparse non-negative matrix under-approximation (SNMU). The mixture selection module was then applied to French and Dutch data, leading to a list of suggested chemicals for each adverse outcome pathway in the project

A case study of neurodevelopmental risks from combined exposures to lead, methyl-mercury, inorganic arsenic, polychlorinated biphenyls, polybrominated diphenyl ethers and fluoride

We performed a mixture risk assessment (MRA) case study of dietary exposure to the food contaminants lead, methylmercury, inorganic arsenic (iAs), fluoride, non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs), all substances associated with declines in cognitive abilities measured as IQ loss. Most of these chemicals are frequently measured in human biomonitoring studies. A component-based, personalised modified reference point index (mRPI) approach, in which we expressed the exposures and potencies of our chosen substances as lead equivalent values, was applied to perform a MRA for dietary exposures. We conducted the assessment for four different age groups (toddlers, children, adolescents, and women aged 18–45 years) in nine European countries. Populations in all countries considered exceeded combined tolerable levels at median exposure levels. NDL-PCBs in fish, other seafood and dairy, lead in grains and fruits, methylmercury in fish and other seafoods, and fluoride in water contributed most to the combined exposure. We identified uncertainties for the likelihood of co-exposure, assessment group membership, endpoint-specific reference values (ESRVs) based on epidemiological (lead, methylmercury, iAs, fluoride and NDL-PCBs) and animal data (PBDE), and exposure data. Those uncertainties lead to a complex pattern of under- and overestimations, which would require probabilistic modelling based on expert knowledge elicitation for integration of the identified uncertainties into an overall uncertainty estimate. In addition, the identified uncertainties could be used to refine future MRA for cognitive decline.European Union’s Horizon 2020 research and innovation programme under grant agreement number 874583—the Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project. The author Mousumi Chatterjee is grateful for a Daphne Jackson Trust (UK) fellowship. The authors would like to thank EFSA providing the food consumption databases, data owners for giving permission to use the data, and Gerda van Donkersgoed and Matthijs Sam (RIVM) for organising the food consumption data and chemical concentration data

A plausibility database summarizing the level of evidence regarding the hazards induced by the exposome on children health

Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S143846392300202X#appsec1 .Copyright © 2023 The Authors. Childhood diseases correspond to major public health issues. A large number of studies using different approaches provide evidence regarding effects of environmental exposures, encompassed in the exposome, on children's health. We aimed to summarize the overall level of evidence (LoE) from all streams of evidence regarding exposome effects on child health. For 88 selected chemical and urban factors, we retrieved the conclusions of agency reports or literature reviews published between 2015 and 2021 regarding effects on child health, including cardiovascular, metabolic, neurodevelopmental, respiratory and other health outcomes. Adapted versions of PRISMA flowchart and AMSTAR-2 tool were used to select and assess the quality of the systematic reviews retrieved from PubMed and SCOPUS databases. For each factor-outcome pair, conclusions in three streams of evidence (epidemiological, toxicological and mechanistic, the latter corresponding to in vitro and in silico approaches) were translated into stream-specific LoEs and then combined into an overall LoE ranging from “very unlikely” to “very likely”. The 88 environmental factors were implied in 611 factor-outcome pairs. Forty-four pairs (7%), corresponding to 16 factors, had a very likely overall LoE (≥80%); 127 pairs (21%), corresponding to 49 factors, had a likely or more overall LoE (≥60%). For 81 pairs (13%), no evidence was available in agency reports or published reviews, while for 275 pairs (45%), corresponding to 68 factors, the overall LoE was very unlikely (<20%). Exposure factors with the greatest number of associated health outcomes with a high overall LoE were HCB, PCBs, temperature (8 outcomes), PFOA (7 outcomes), PFOS, cotinine (6 outcomes), arsenic, lead (5 outcomes), bisphenols A and S, PFNA and PM2.5 (4 outcomes), DDT, DDE and DDD, PFHxA, PFDA, green space, UV radiation (3 outcomes). We developed an approach to extract and summarize the existing evidence about effects of environmental factors on health. The plausibility database built for children's health can be used to identify research gaps, conduct quantitative risk assessment studies. It could be expanded to consider a larger fraction of the exposome and other age groups and should be updated on a regular basis.The ATHLETE project was funded by The European Commission, through its Horizon 2020 Framework Program for Research and Innovation (grant agreement 874583). This work was also supported by HERA (Integrating Environment and Health Research: a Vision for the EU) Horizon 2020 project (grant agreement 825417). We acknowledge support from the grant CEX 2018-000806-S funded by MCIN/AEI/10.13039/501100011033, and support from the Generalitat de Catalunya through the CERCA Program

Advancing tools for human early lifecourse exposome research and translation (ATHLETE)

Copyright © 2021 The Authors. 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.European Union’s Horizon 2020 research and innovation programme under grant agreement number 874583—the Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project; Ramón y Cajal fellowship (RYC-2012-10995) awarded by the Spanish Ministry of Economy and Finance; Ramón y Cajal fellowship (RYC-2012-10995) awarded by the Spanish Ministry of Economy and Finance; National Institute of Environmental Health Sciences (R21ES029681, R01ES029944, R01ES030364, R01ES030691, and P30ES007048); National Institutes of Health supported Dr. Conti (P01CA196569, R01CA140561) and Dr. Stratakis (P30DK048522); National Institute for Health Research under its Applied Research Collaboration Yorkshire and Humber; Consolidator Grant from the European Research Council (ERC-2014-CoG-648916); European Union’s Horizon 2020 co-funded programme European Research Area Net on Biomarkers for Nutrition and Health (European Research Area Healthy Diet for a Healthy Life) (Early life programming of childhood health project [number 696295; 2017], ZonMW, The Netherlands [number 529051014; 2017]; Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (EST-18 RF-25)

The PERICLES Research Program: an Original Approach to Characterize the Combined Effects of Pesticides Residues Mixtures Commonly Found in the Diet

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Mirabel: An integrated project for risk and cost/benefit analysis of peanut allergy

Food allergy is a major public health issue. However, no regulatory measures exist when allergens are present at trace levels and the different risk components are poorly described. Thus, knowledge on exposure components such as the allergens present in foods and the consumption behaviour of allergic consumers and models to estimate the related risk need to be enriched. Mirabel proposes for the first time studying each risk component using an integrated approach in order to improve the quality of life of the allergic population. Field surveys were conducted in order to fill in the current gaps in unintentional allergen traces in food, allergic consumers’ food behaviour, threshold doses of allergic reaction, allergy symptoms and severity. The aim is also to propose methodological and operational tools to quantify allergic risk, to test management scenarios and to produce a cost/benefit analysis. Medical data on the peanut allergies of 785 patients were collected in the MIRABEL survey and 443 patients answered the food consumption questionnaire. The population surveyed was mostly paediatric – 86% were children under 16 years of age, with a high percentage of males (60%). This project will generate tangible results on peanut allergen exposure and risk which could be used in future risk assessment work and particularly to provide science-based guidance to set up concentration limits for peanut traces on packages

Cumulative dietary exposure to a selected group of pesticides of the trazole 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

Cumulative dietary exposure to a selected group of pesticides of the trazole 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