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Data de publicació electrònica: 29-03-2023 A scoping review was conducted to identify interventions that successfully alter biomarker concentrations of phenols, glycol ethers, and phthalates resulting from dietary intake and personal care product (PCPs) use. Twenty-six interventions in populations ranging from children to older adults were identified; 11 actively removed or replaced products, 9 provided products containing the chemicals being studied, and 6 were education-only based interventions. Twelve interventions manipulated only dietary intake with a focus on bisphenol A (BPA) and phthalates, 8 studies intervened only on PCPs use and focused on a wider range of chemicals including BPA, phthalates, triclosan, parabens, and ultraviolet absorbers, while 6 studies intervened on both diet and PCPs and focused on phthalates, parabens, and BPA and its alternatives. No studies assessed glycol ethers. All but five studies reported results in the expected direction, with interventions removing potential sources of exposures lowering EDC concentrations and interventions providing exposures increasing EDC concentrations. Short interventions lasting a few days were successful. Barriers to intervention success included participant compliance and unintentional contamination of products. The identified interventions were generally successful but illustrated the influence of participant motivation, compliance, ease of intervention adherence, and the difficulty of fully removing exposures due their ubiquity and the difficulties of identifying “safer” replacement products. Policy which reduces or removes EDC in manufacturing and processing across multiple sectors, rather than individual behavior change, may have the greatest impact on population exposure. This project has received funding from the 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 and LIFECYCLE, grant agreement number 733206. This publication reflects only the authors’ view and the European Commission is not responsible for any use that may be made of the information it contains. Drs. McEachan and Yang receive funding from the National Institute for Health Research under its Applied Research Collaboration Yorkshire and Humber [NIHR200166]. ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000,806-S), and support from the Generalitat de Catalunya through the CERCA Program. Maribel Casas holds a Miguel Servet fellowship (CP16/00128) funded by Instituto de Salud Carlos III and co-funded by European Social Fund “Investing in your future “.

Studies characterizing associations between phenols, phthalates and thyroid hormones during pregnancy produce inconsistent results. This divergence may be partly attributable to false positives due to multiple comparison testing of large numbers of chemicals, and measurement error as studies rely on small numbers of biospecimens despite high intra-individual variability in urinary chemical metabolite concentrations.This study employsA two-tiered approach was implemented:The ToxCast/Tox21 screening reduced the chemical set from 16 to 13 and the associated number of statistical comparisons by 19%. Parabens were negatively associated with free triiodothyronine (T3) and the T3/T4 (total thyroxine) ratio. Monobenzyl phthalate was positively associated with total T4 and negatively with the T3/T4 ratio. Effect modification by iodine status was detected for several compounds (among themFor these chemicals, screening for compounds with an increased likelihood for thyroid-related effects and relying on repeated urine samples to assess exposures improved the overall performance of multichemical analyses of thyroid disruption. This approach may improve future evaluations of human data for the thyroid pathway with implication for fetal health and may serve as a model for evaluating other toxicity outcomes. https://doi.org/10.1289/EHP10239.

International audience; Background and objectives: Studies focusing on the neurodevelopmental effects of phthalates seldom consider exposure during infancy, a critical period for brain development. Most rely on parent-completed questionnaires to assess child neurodevelopment, which may be subject to reporting error. We studied the associations between prenatal and infancy exposure to phthalates and objective measures of neurodevelopment at the age of two. Methods: We relied on 151 mother-child pairs from the SEPAGES mother-child cohort. Women were asked to collect three spot urine samples per day over seven consecutive days during the second (median: 18.0 gestational weeks) and third (median: 34.2 gestational weeks) trimesters of pregnancy. They then collected one urine sample per day over seven consecutive days from their infants around the age of 12 months. Metabolites of phthalates and non-phthalate plasticizers were measured in within-subject and within-period pools of repeated urine samples. Eye tracking tasks were performed at two years allowing to compute four indicators linked with cognitive development and visual behavior: mean fixation duration, novelty preference, percent time spent looking at the eyes and mean reaction time. Results: Pre-natal exposure to monobenzyl phthalate at the second and third trimesters was associated with shorter fixation durations. In models allowing for interaction with child sex, these associations were only observed among girls. Exposure to di(2-ethylhexyl) phthalate at the third but not the second trimester was associated with increased time spent looking at a novel face and eyes. We observed faster reaction times and decreased time spent looking at the eyes in a face recognition task, with increased post-natal exposure to monoethyl, mono-iso-butyl and mono-n-butyl phthalates. Discussion: Relying on improved exposure assessment, we highlighted associations of pre-and post-natal exposure to phthalates with indicators derived from eye tracking tasks, mainly in girls. Some of these indicators have been affected in individuals with neurodevelopmental disorders.

Introduction Parents reported degraded sleep outcomes up to several years after child birth. Most published studies were cross-sectional, in early post-partum and focusing on maternal-child dyads. We aimed at identifying sleep multi-trajectories (SMT) including night (NSD) and daytime (DSD) sleep duration and subjective sleep loss (SSL) between 3 and 36 months postpartum in couples from the SEPAGES cohort. Methods From 484 mothers and 410 fathers included in the SEPAGES cohort, sleep information was collected by self-reports at 3, 18, 24 and 36 months postpartum. Couple SMT were modelled using Group-Based Trajectory Modelling method. Each couple was assigned to the group of SMT with the highest probability of belonging to. Multinomial logistic regression assessed sociodemographic, parental and child covariates associated SMT Results Three groups SMT were identified in couple who reported sleep data at least 2 times across the 4 time-points (N=188). In G1 (29.3%), couples had 8-9hr of mean NSD and a stable and relatively short mean maternal and paternal DSD (≈10min and ≈5min, respectively) while SSL was decreasing for mother (58% to 31%) but stable for father (≈30%) between 3 and 36 months postpartum. In G2 (27.7%), they had a stable but relatively short mean NSD (7-8hr), a maternal DSD decreasing by 20min between 3 and 18 months then being stable at 23min, a stable paternal DSD (≈10min) and high but decreasing SSL from 90% to 86% for mothers and 76% to 61% for fathers. In G3 (43.0%), couples had a stable mean NSD (8-9hr), a relatively long mean DSD, decreasing from 54 to 41min for mothers but increasing from 28 to 39min for fathers, and a stable but relatively high SSL (≈70% for mothers and ≈55% for fathers). From logistic regression, belated paternal chronotype increased odds for belonging to G2 while having a first child and born in autumn decreased odds to belong to G2 compared to G1. Conclusion We identified 3 different SMT between 3 and 36 months postpartum for the first time. We found several factors associated with each SMT. Studies are still warranted to investigate further interrelation with the child sleep patterns. Support (if any)

[EN]Background: The urban environment may influence neurodevelopment from conception onwards, but there is no evaluation of the impact of multiple groups of exposures simultaneously. We investigated the association between early-life urban environment and cognitive and motor function in children. Methods: We used data from 5403 mother-child pairs from four population-based birth-cohorts (UK, France, Spain, and Greece). We estimated thirteen urban home exposures during pregnancy and childhood, including: built environment, natural spaces, and air pollution. Verbal, non-verbal, gross motor, and fine motor functions were assessed using validated tests at five years old. We ran adjusted multi-exposure models using the Deletion-Substitution-Addition algorithm. Results: Higher greenness exposure within 300 m during pregnancy was associated with higher verbal abilities (1.5 points (95% confidence interval 0.4, 2.7) per 0.20 unit increase in greenness). Higher connectivity density within 100 m and land use diversity during pregnancy were related to lower verbal abilities. Childhood exposure to PM2.5 mediated 74% of the association between greenness during childhood and verbal abilities. Higher exposure to PM2.5 during pregnancy was related to lower fine motor function (-1.2 points (-2.1, -0.4) per 3.2 mu g/m3 increase in PM2.5). No associations were found with non-verbal abilities and gross motor function. Discussion: This study suggests that built environment, greenness, and air pollution may impact child cognitive and motor function at five years old. This study adds evidence that well-designed urban planning may benefit children's cognitive and motor development. Acknowledgements We are grateful to all the participating children, parents, practi-tioners and researchers in the four countries who took part in this study. This work was supported by funding from the European Community's Seventh Framework Programme [FP7/2007-206 n 308333; the HELIX project] . This INMA cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds, FIS PI06/0867, FIS-PI09/00090, FIS and FIS-PI18/01142 incl. FEDER funds, FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI16/00118 and PI17/00663; FIS-FSE: 17/00260; Miguel Servet-FEDER CP11/00178, CP15/00025, CPII16/00051, and CPII18/00018) , from UE (FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1, and H2020 n 824989) , Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundacio La marato de TV3 (090430) , Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249) , Alicia Koplowitz Foundation 2017, CIBERESP, Department of Health of the Basque Government (2013111089, 2009111069, 2013111089, 2015111065 and 2018111086) , Provincial Government of Gipuzkoa (DFG06/002, DFG08/001, DFG15/221 and DFG 89/17) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu , Legazpi, Azkoitia y Azpeitia y Beasain) . We acknowledge support from the Spanish Ministry of Science and Inno-vation and the State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S) , and support from the Generalitat de Catalunya through the CERCA Program. The work was also supported by MICINN [MTM2015-68140-R] and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII (Spain) . The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011-2014; "Rhea Plus": Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15) . This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber (UK) . The EDEN study was supported by Foundation for medical research (FRM) , National Agency for Research (ANR) , National Institute for Research inPublic health (IRESP: TGIR cohorte sante 2008 program) , French Min-istry of Health (DGS) , French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) , and Human Nutrition Na-tional Research Programs, Paris-Sud University, Nestle, French National Institute for Population Health Surveillance (InVS) , French National Institute for Health Education (INPES) , the European Union FP7 pro-grams (ESCAPE, ENRIECO, Medall projects) , Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD) ) , French Agency for Environmental Health Safety and French National Agency for Food Security (now ANSES) , Mutuelle Generale de l'Education Nationale a complementary health insurance (MGEN) , French-speaking association for the study of diabetes and metabolism (ALFEDIAM) . Core support for Born in Bradford is also provided by the Wellcome Trust (WT101597MA, UK) . Born in Bradford (BiB) is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools and researchers who have made BiB happen. BiB receives funding from the ESRC/MRC, the Wellcome Trust (WT101597MA) and the National Institute for Health Research York-shire and Humber ARC (reference: NIHR20016) . M. Mon-Williams was supported by a Fellowship from the Alan Turing Institute. Additional funding from the National Institute of Environmental Health Science supported Dr Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, and P30ES007048) . The views expressed are those of the authors, and not necessarily those of the NHS or the NIHR. None of the funders were involved in designing the study, collecting the data, analyzing or interpreting the data, deciding to submit the article for publication, or the writing of the report. Data sharing statement The HELIX data warehouse has been established as an accessible resource for collaborative research involving researchers external to the project. Access to HELIX data is based on approval by the HELIX Project Executive Committee and by the individual cohorts. Further details on the content of the data warehouse (data catalogue) and procedures for external access are described on the project website (http:// www.proj-ecthelix.eu/index.php/es/data-inventory) .

International audience; Background: Some synthetic phenols alter pathways involved in fetal development. Despite their high within-subject temporal variability, earlier studies relied on spot urine samples to assess pregnancy exposure. In this study, we examined associations between prenatal phenol exposure and fetal growth. Methods: We measured concentrations of two bisphenols, four parabens, benzophenone-3, and triclosan in 478 pregnant women in two weekly pools of 21 samples each, collected at 18 and 34 gestational weeks. We used adjusted linear regressions to study associations between phenol concentrations and growth outcomes assessed twice during pregnancy and at birth. Results: Benzophenone-3 was positively associated with all ultrasound growth parameters in at least one time point, in males but not females. In females, butylparaben was negatively associated with third-trimester abdominal circumference and weight at birth. We observed isolated associations for triclosan (negative) and for methylparaben and bisphenol S (positive) and late pregnancy fetal growth. Conclusions: Our results suggest associations between prenatal exposure to phenols and fetal growth. Benzophenone-3 was the exposure most consistently (positively) associated across all growth parameters.

Importance: Prenatal exposures to endocrine-disrupting chemicals (EDCs) may increase the risk for liver injury in children; however, human evidence is scarce, and previous studies have not considered potential EDC-mixture effects. Furthermore, the association between prenatal EDC exposure and hepatocellular apoptosis in children has not been studied previously. Objective: To investigate associations of prenatal exposure to EDC mixtures with liver injury risk and hepatocellular apoptosis in childhood. Design, setting, and participants: This prospective cohort study used data collected from April 1, 2003, to February 26, 2016, from mother-child pairs from the Human Early-Life Exposome project, a collaborative network of 6 ongoing, population-based prospective birth cohort studies from 6 European countries (France, Greece, Lithuania, Norway, Spain, and the UK). Data were analyzed from April 1, 2021, to January 31, 2022. Exposures: Three organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 3 phenols, 4 parabens, 10 phthalates, 4 organophosphate pesticides, 5 perfluoroalkyl substances, and 9 metals. Main outcomes and measures: Child serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and CK-18 were measured at 6 to 11 years of age. Risk for liver injury was defined as having ALT, AST, and/or GGT levels above the 90th percentile. Associations of liver injury or cytokeratin 18 (CK-18) levels with each chemical group among the 45 EDCs measured in maternal blood or urine samples collected in pregnancy were estimated using 2 complimentary exposure-mixture methods: bayesian weighted quantile sum (BWQS) and bayesian kernel machine regression. Results: The study included 1108 mothers (mean [SD] age at birth, 31.0 [4.7] years) and their singleton children (mean [SD] age at liver assessment, 8.2 [1.6] years; 598 [54.0%] boys). Results of the BWQS method indicated increased odds of liver injury per exposure-mixture quartile increase for organochlorine pesticides (odds ratio [OR], 1.44 [95% credible interval (CrI), 1.21-1.71]), PBDEs (OR, 1.57 [95% CrI, 1.34-1.84]), perfluoroalkyl substances (OR, 1.73 [95% CrI, 1.45-2.09]), and metals (OR, 2.21 [95% CrI, 1.65-3.02]). Decreased odds of liver injury were associated with high-molecular-weight phthalates (OR, 0.74 [95% CrI, 0.60-0.91]) and phenols (OR, 0.66 [95% CrI, 0.54-0.78]). Higher CK-18 levels were associated with a 1-quartile increase in polychlorinated biphenyls (β, 5.84 [95% CrI, 1.69-10.08] IU/L) and PBDEs (β, 6.46 [95% CrI, 3.09-9.92] IU/L). Bayesian kernel machine regression showed associations in a similar direction as BWQS for all EDCs and a nonlinear association between phenols and CK-18 levels. Conclusions and relevance: With a combination of 2 state-of-the-art exposure-mixture approaches, consistent evidence suggests that prenatal exposures to EDCs are associated with higher risk for liver injury and CK-18 levels and constitute a potential risk factor for pediatric nonalcoholic fatty liver disease. This study was supported by grants R21ES029681, R01ES029944 (Dr Chatzi), R01ES030364 (Dr Chatzi), R21ES028903 (Dr Chatzi), R21ES029681 (Dr Chatzi), P30ES007048 (Dr Chatzi), R21ES029328 (Dr Valvi), R01ES029944 (Dr Valvi), R01ES028903 (Dr Valvi), P30ES023515 (Dr Valvi), and P30ES023515 (Dr Midya) from the NIEHS. The HELIX project was supported by FP7/2007-2013 under grant agreement 308333–the HELIX project from the European Community’s Seventh Framework Programme.

For non-persistent chemicals such as phthalates, a single spot urine sample only reflects exposure in the past few hours. Collecting repeated urine samples for each participant over windows of sensitivity is expected to improve exposure characterization but has rarely been done. We aimed to rely on within-subject pools of repeated urine samples to assess phthalate exposure during pregnancy and infancy. Women of the French SEPAGES mother-child cohort were asked to collect three urine samples per day over seven consecutive days, twice during their pregnancy (approximatively second (T2) and third (T3) trimesters). For their infants they also collected one sample per day during a week at two (M2) and twelve months (M12). Samples were pooled (within-subject, within-period) prior to phthalate and DINCH metabolite concentrations assessment. Number of pooled samples assayed was 477, 456, 152 and 100 for T2, T3, M2 and M12, respectively. All metabolites were detected in more than 95% of the pooled samples except for the two DINCH metabolites (oh- and oxo-MINCH), MMCHP and oh-MPHP at M2 for which detection frequencies ranged between 64% and 88%. Maternal concentrations of MiBP, MBzP, DEHP metabolites and oxo-MiNP decreased between 2014 and 2017, whereas concentrations of oh-MiNP and the two DINCH metabolites increased (Mann-Kendall p-values, Graphical abstract Image 1, Highlights • Repeated urine samples were collected and pooled within-subject, within period. • Metabolites of phthalates and DINCH were measured in pooled samples. • Frequencies of detection were overall high. • Pregnancy concentrations of MiBP, MBzP, DEHP and oxo-MINP decreased with time. • Pregnancy concentrations of oh-MiNP and DINCH metabolites increased with time., Relying on a recent cohort (2014–2017) with repeated urine samples collected during pregnancy and infancy, we showed that exposure to phthalates and DINCH is still widespread in the general population.

Epidemiological studies mostly focus on single environmental exposures. This study aims to systematically assess associations between a wide range of prenatal and childhood environmental exposures and cognition. The study sample included data of 1298 mother-child pairs, children were 6–11 years-old, from six European birth cohorts. We measured 87 exposures during pregnancy and 122 cross-sectionally during childhood, including air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals and life styles. The measured cognitive domains were fluid intelligence (Raven's Coloured Progressive Matrices test, CPM), attention (Attention Network Test, ANT) and working memory (N-Back task). We used two statistical approaches to assess associations between exposure and child cognition: the exposome-wide association study (ExWAS) considering each exposure independently, and the deletion-substitution-addition algorithm (DSA) considering all exposures simultaneously to build a final multiexposure model. Based on this multiexposure model that included the exposure variables selected by ExWAS and DSA models, child organic food intake was associated with higher fluid intelligence (CPM) scores (beta = 1.18; 95% CI = 0.50, 1.87) and higher working memory (N-Back) scores (0.23; 0.05, 0.41), and child fast food intake (−1.25; −2.10, −0.40), house crowding (−0.39; −0.62, −0.16), and child environmental tobacco smoke (ETS) (−0.89; −1.42, −0.35), were all associated with lower CPM scores. Indoor PM2.5 exposure was associated with lower N-Back scores (−0.09; −0.16, −0.02). Additional associations in the unexpected direction were found: Higher prenatal mercury levels, maternal alcohol consumption and child higher perfluorooctane sulfonic acid (PFOS) levels were associated with better cognitive performance; and higher green exposure during pregnancy with lower cognitive performance. This first comprehensive and systematic study of many prenatal and childhood environmental risk factors suggests that unfavourable child nutrition, family crowdedness and child indoor air pollution and ETS exposures adversely and cross-sectionally associate with cognitive function. Unexpected associations were also observed and maybe due to confounding and reverse causality., Graphical abstract Prenatal and childhood exposome-wide associations with child fluid intelligence (CPM). The exposures selected by Deletion-substitution-addition algorithm are represented by a triangle. Child fluid intelligence is mainly associated with childhood exposome, fast-food (negative association, left sided) and organic food consumption (positive, right sided), house crowding (negative, left sided), and child environmental tobacco smoke (ETS, negative, left sided). Image 1, Highlights • Previous evidence for environmental risk factor associations with neurodevelopment is based on analyses of single exposures. • We systematically analysed multiple environmental exposures in relation to child neurodevelopment. • The findings describe a list of outcome-related exposures: Diet, house crowding, indoor air pollution and tobacco smoke. • The findings show methodological complexities of analysing multiple exposures and their associations with neurodevelopment.

International audience; Background: Within-subject biospecimens pooling can theoretically reduce bias in dose-response functions from biomarker-based studies when exposure assessment suffers from classical-type error. However, collecting many urine voids each day is cumbersome. We evaluated the empirical validity of a within-subject pooling approach and compared several options to avoid sampling each void.Methods: In 16 pregnant women who collected a spot of each urine void over several nonconsecutive weeks, we compared concentrations of 10 phenols in daily, weekly, and pregnancy within-subject pools. We pooled either three or all daily samples. In a simulation study using these data, we quantified bias in dose-response functions when using one to 20 urine samples per subject to assess methylparaben (a compound with moderate within-subject variability) and bisphenol A (high variability) exposures.Results: Correlations between exposure estimates from pools of all and of only three voids per day were above 0.80 for all time windows and compounds, except for benzophenone-3 and triclosan in the daily time window (correlations, 0.57-0.68). With one spot sample to assess pregnancy exposure, correlations were all below 0.74. Using only one biospecimen led to attenuation bias in the dose-response functions of 29% (methylparaben) and 69% (bisphenol A); four samples for methylparaben and 18 for bisphenol A decreased bias to 10%.Conclusions: For nonpersistent chemicals, collecting and pooling three samples per day instead of all daily samples efficiently estimates exposures over a week or more. Collecting around 20 biospecimens can strongly limit attenuation bias for nonpersistent chemicals such as bisphenol A.

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. ISGlobal acknowledges support from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the Centres de Recerca de Catalunya Program. We acknowledge collaboration with European projects, specifically: Human Early Life Exposome (HELIX) (FP7 grant agreement number 308333), LifeCycle (H2020 grant agreement number 733206), and Connecting Europe and Canada in personalized health (EUCAN-Connect) (H2020 Grant Agreement number 824989). The Born in Bradford (BiB) cohort is only possible because of the enthusiasm and commitment of the Children and Parents in BiB. We are grateful to all the participants, health professionals, and researchers who have made BiB happen. The BiB cohort is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools, and researchers who have made BiB happen. BiB has received funding from the Wellcome Trust (101597), a joint grant from the UK Medical Research Council and UK Economic and Social Science Research Council (MR/N024391/1), a British Heart Foundation Clinical Study grant (CS/16/4/32482). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation, and other minor grants. The Danish National Birth Cohort Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06-066023, O602-01042B, 0602-02738B); the Lundbeck Foundation (195/04, R100-A9193); The Innovation Fund Denmark 0603-00294B (09-067124); the Nordea Foundation (02-2013-2014); Aarhus Ideas (AU R9-A959-13-S804); University of Copenhagen Strategic Grant (IFSV 2012); and the Danish Council for Independent Research (DFF—4183-00594 and DFF—4183-00152). The general design of the Generation R Study is made possible by financial support from the Erasmus MC, University Medical Center, Rotterdam, Erasmus University Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), Netherlands Organisation for Scientific Research (NWO), Ministry of Health, Welfare and Sport, and Ministry of Youth and Families. This project received funding from the European Union’s Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement number 733206, 2016; EUCAN-Connect grant agreement number 824989; ATHLETE, grant agreement number 874583). We gratefully acknowledge the contribution of participants, research collaborators, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The INfancia y Medio Ambiente cohort (INMA) Sababell study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. Fondo Europeo de Desarollo Regional (FEDER) funds; PI12/01890 incl. FEDER funds; CP13/00054 incl. FEDER funds; PI15/00118 incl. FEDER funds; CP16/00128 incl. FEDER funds; PI16/00118 incl. FEDER funds; PI16/00261 incl. FEDER funds; PI17/01340 incl. FEDER funds, PI18/00547 incl. FEDER funds, PI20/01695 incl. FEDER funds), Centro de Investigación Biomédica en Red - Epidemiología y Salud Pública (CIBERESP), Generalitat de Catalunya-Comissió Interdepartamental de Recerca i Innovació Tecnològia 1999SGR 00241, Generalitat de Catalunya-Agencia de Gestión de Ayudas Universitarias y de Investigación (2009 SGR 501, 2014 SGR 822), Fundació La Marató de TV3 (090430), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010; EST-2016 RF-21, EST-19 RF-04), and the European Commission (261357, 308333, 603794 and 634453). The INMA Valencia study was supported by grants from Instituto de Salud Carlos III (FIS-FEDER: 13/2032, 13/1944, 14/00891, 16/1288, 17/00663, and 19/1338; Miguel Servet-FSE: CP15/0025 and MSII16/00051, 00051, and MSII20/0006), Alicia Koplowitz Foundation 2017, Generalitat Valenciana (AICO/2020/285), and Spanish Association Against Cancer (AECC) “Seed Ideas” 2019 (IDEAS19098LOPE). INMA Gipuzkoa was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090, FIS-PI13/02187, and FIS-PI18/01142 incl. FEDER funds), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089, and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001, and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). The Sepages cohort would like to thank the Grenoble University Hospital (CHU-GA) biobank (bb-0033-00069). We thank the Sepages Study group (E. Eyriey, P. Hoffmann, E. Hullo, J. Lepeule, C. Llerena, S. Lyon-Caen, X. Morin, A. Morlot, C. Philippat, I. Pin, J. Quentin, V. Siroux, R. Slama) and the participants of the Suivi de l’Exposition à la Pollution Atmosphérique durant la Grossesse et Effets sur la Santé (SEPAGES) study. We acknowledge support from Auvergne-Rhône-Alpes Région, Soutien aux coopérations universitaires et scientifiques internationales fund to support collaborations between Catalunya and Auvergne-Rhône-Alpes. SEPAGES cohort was supported by the European Research Council (consolidator grant N 311765-E-DOHaD, Principal Investigator [PI], R. Slama), by French National Research Agency (ANR), the ANR (Pregnancy, Air Pollution, Epigenetics and Respiratory health project ANR-12-PDOC-0029-01, PI, J. Lepeule; A Longitudinal Analysis of Effects of Early Life Exposure to Phenols on Health in Humans project, 14-CE21-0007-01, PI, R. Slama; Gut Microbiota in early childhood and Maternal Environmental exposures project, PI, R. Slama; Prenatal Exposure to Tobacco smoking and Air Pollution and Effects on offspring respiratory and neurodevelopmental outcomes ANR 18-CE36-005, PI, J. Lepeule). The Central European Longitudinal Study of Pregnacy and Childhood: The Next Generation (TNG) cohort is supported by the RECETOX research infrastructure (the Ministry of Education, Youth and Sports of the Czech Republic: LM2018121) and the CETOCOEN EXCELLENCE Teaming 2 project of European Union (EU) Horizon 2020 (857560) and the MEYS of the Czech Republic (02.1.01/0.0/0.0/18_ 046/0015975). The Barcelona Life Study Cohort has received funding from European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement number (785994) (Prenatal exposure to urban air pollution and pre and post-natal brain development project) and from the Health Effects Institute (HEI) under Agreement number 4959-RFPA15-1/18-1 (FRONTIER project). Genotyping in the HELIX study was supported by project PI17/01225 (Instituto de Salud Carlos III, co-funded by European Union [European Regional Development Fund], “A way to make Europe”) and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII). The Nascita e Infanzia: gli Effetti dell’Ambiente cohort was partially funded by the Compagnia SanPaolo Foundation and the Piedmont Region. The Piccolipiù project was funded by the Italian National Center for Disease Prevention and Control (National Centre for Disease Prevention and Control grants years 2010 and 2014) and by the Italian Ministry of Health (art 12 and 12 bis D.lgs 502/92). The Perturbateurs Endocriniens: Étude Longitudinale sur les Anomalies de la Grossesse, l’Infertilité et l’Enfance study is supported by National Institute of Health and Medical Research and has received multiple funds from the ANR, the French Agency for Food, Environmental and Occupational Health and Safety (ANSES), the Fondation de France, the National Institute for Public Health Surveillance (InVS), the French, Ministry of Labor, the French Ministry of Health, and the French Ministry of Ecology. DataSHIELD is funded under a group of projects that underpin a program of development and application of secure methods for co-analysis, data sharing, and visualization in the Population Health Sciences Institute at Newcastle University (United Kingdom). These include: the “Connected Health Cities project” (North East and North Cumbria) funded by the UK Department of Health (RES/0150/7943/202); the “EUCanConnect project” (European Commission H2020 Flagship Collaboration with Canada); the “58FORWARDS project” (Fostering new Opportunities for Researchers via Wider Access to Research Data and Samples) funded jointly by the Wellcome Trust and the Medical Research Council (108439/Z/15/Z); and the “METADAC project” (Managing Ethico-social, Technical and Administrative issues in Data ACcess) funded jointly by the Medical Research Council, the Wellcome Trust, and the Economic and Social Research Council (MR/N01104X/1 and MR/N01104X/2). We acknowledge the Molecular Genetics Information System team, including Fleur Kelpin, Tommy de Boer, Mariska Slofstra, Connor Stroomberg, Jelmer Veen, Jeroen van Veen, Fernanda de Andrade, Marije van der Geest, Dieuwke Roelofs-Prins, Dennis Hendriksen, Bart Charbon, Joeri van der Velde, Max Postema, Erik Schaberg, Christiaan Hilbrands, Alexander Kellmann, and Luuk Dijkhuis.

Background: Recent studies have suggested the involvement of several endocrine disruptors, including synthetic phenols and phthalates, in the development of infant behavioural disorders. These stud...

International audience; Since reports published in 2015 and 2016 identified 15 probable exposure-outcome associations, there has been an increase in studies in humans of exposure to endocrine-disrupting chemicals (EDCs) and a deepened understanding of their effects on human health. In this Series paper, we have reviewed subsequent additions to the literature and identified new exposure-outcome associations with substantial human evidence. Evidence is particularly strong for relations between perfluoroalkyl substances and child and adult obesity, impaired glucose tolerance, gestational diabetes, reduced birthweight, reduced semen quality, polycystic ovarian syndrome, endometriosis, and breast cancer. Evidence also exists for relations between bisphenols and adult diabetes, reduced semen quality, and polycystic ovarian syndrome; phthalates and prematurity, reduced anogenital distance in boys, childhood obesity, and impaired glucose tolerance; organophosphate pesticides and reduced semen quality; and occupational exposure to pesticides and prostate cancer. Greater evidence has accumulated than was previously identified for cognitive deficits and attention-deficit disorder in children following prenatal exposure to bisphenol A, organophosphate pesticides, and polybrominated flame retardants. Although systematic evaluation is needed of the probability and strength of these exposure-outcome relations, the growing evidence supports urgent action to reduce exposure to EDCs.

Background We assessed the relationships between prenatal pyrethroid pesticide exposure and autism spectrum disorders (ASD) or non-typical development (non-TD) at 3 years. Methods Participants were mother-child pairs (n = 201) in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) cohort. Because familial recurrence risk is high, MARBLES enrolls pregnant women with a family history of ASD. Children from these pregnancies were clinically assessed at 3 years of age and classified into 3 outcome categories: ASD, typically developing (TD), or non-TD (neither TD or ASD). Repeated maternal second and third trimester urine samples were analyzed for pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). Multinomial logistic regression was used to obtain relative risk ratios (RRR) linking 3-PBA concentrations averaged across each trimester and over pregnancy with child's outcome: ASD or non-TD vs. TD. Models were adjusted for specific gravity, maternal pre-pregnancy BMI, prenatal vitamin use, birth year, home-ownership, and pregnancy concentrations of TCPy (3,5,6-trichloro-2-pyridinol, a metabolite of chlorpyrifos). Results The median specific gravity corrected 3-PBA concentration of all samples was 1.46 ng/mL. Greater second trimester 3-PBA concentrations were associated with a relative risk ratio (RRR) for ASD of (RRR: 1.50 (95% CI 0.89 to 2.51), p = 0.12). There were no differences between non-TD and TD. Conclusions This study found no evidence for differences in 3-PBA comparing non-TD with TD. A modestly elevated RRR was found comparing second trimester urinary 3-PBA concentrations for ASD versus TD; however, the confidence interval was wide and hence, these findings cannot be considered definitive.

BACKGROUND: Exposure to certain synthetic phenols is of growing concern, in particular among pregnant women, because of their endocrine disrupting nature. Many phenols are still authorized in personal care products (PCP). We aimed to assess if use of PCPs, by pregnant women could influence their urinary concentrations of synthetic phenols. METHODS: We used a panel design with intense urine sample collection. Eight women completed a diary with exact time and use of PCP in three weeks. We measured the concentrations of phenols (four parabens, bisphenol A and S, two dichlorophenols, triclosan, and benzophenone-3) in 178 urine samples, collected during 7 consecutive days at 3 time points during pregnancy. We characterized PCP use as the total number of PCP applications or as a single PCP use (yes / no) in three time windows (0 to 6, 6 to 12 and 12 to 24 before each urine sample collection). We used adjusted linear and Tobit regressions to assess associations between PCP use and phenol urinary concentrations. RESULTS: The total number of PCP applications was positively associated with ethylparaben, propylparaben and butylparaben concentrations. We observed a peak in urinary concentration of ethylparaben, butylparaben and propylparaben at 2.86, 2.55 and 2.67 hours since last PCP use, respectively and twelve different types of PCPs were positively associated with at least one of these parabens. The bisphenol S concentration increased by 12.4% (95%CI: confidence interval: 5.9; 19.3) for each additional PCP application in the 12 to 24 time window and use of specific PCPs such as anti-stretchmarks cream, facial cleanser and shower gel. Associations varied by time window. CONCLUSION: Our study showed that PCP use was associated with a short-term increase in the urinary concentration of ethylparaben, butylparaben and propylparaben, but not methylparaben. This study also reported a positive association between the use of PCPs and the bisphenol S concentration, a finding that warrants further investigation in cohorts with repeated collection of urine samples and detailed information on PCP use.

In humans, studies based on Developmental Origins of Health and Disease (DOHaD) concept and targeting short half-lived chemicals, including many endocrine disruptors, generally assessed exposures from spot biospecimens. Effects of early-life exposure to atmospheric pollutants were reported, based on outdoor air pollution levels. For both exposure families, exposure misclassification is expected from these designs: for non-persistent chemicals, because a spot biospecimen is unlikely to capture exposure over windows longer than a few days; for air pollutants, because indoor levels are ignored. We developed a couple-child cohort relying on deep phenotyping and extended personal exposure assessment aiming to better characterize the effects of components of the exposome, including air pollutants and non-persistent endocrine disruptors, on child health and development. Pregnant women were included in SEPAGES couple-child cohort (Grenoble area) from 2014 to 2017. Maternal and children exposure to air pollutants was repeatedly assessed by personal monitors. DNA, RNA, serum, plasma, placenta, cord blood, meconium, child and mother stools, living cells, milk, hair and repeated urine samples were collected. A total of 484 pregnant women were recruited, with excellent compliance to the repeated urine sampling protocol (median, 43 urine samples per woman during pregnancy). The main health outcomes are child respiratory health using early objective measures, growth and neurodevelopment. Compared to former studies, the accuracy of assessment of non-persistent exposures is expected to be strongly improved in this new type of birth cohort tailored for the exposome concept, with deep phenotyping and extended exposure characterization. By targeting weaknesses in exposure assessment of the current approaches of cohorts on effects of early life environmental exposures with strong temporal variations, and relying on a rich biobank to provide insight on the underlying biological pathways whereby exposures affect health, this design is expected to provide deeper understanding of the interplay between the Exposome and child development and health.

Background: The placenta performs crucial physiological functions to ensure normal fetal development. Few epidemiological studies investigated placental weight sensitivity to phthalates and phenols. Objective: Our goal was to explore whether maternal exposure to select phthalates and phenols is associated with changes in placental weight at birth and in placental–to–birth weight ratio (PFR). Methods: Placental weight and birth weight were available for 473 mother–son pairs in the EDEN (Etude des Déterminants pré et postnatals du développement et de la santé de l’Enfant) cohort for whom 9 phenols (4 parabens, 2 dichlorophenols, triclosan, benzophenone-3, bisphenol A) and 11 phthalate metabolites were measured in spot urine samples collected between weeks 23 and 29 of gestation. We used adjusted Elastic Net penalized regression models (ENET) to select biomarkers associated with placental weight, birth weight and PFR. Unpenalized effect estimates were then obtained by fitting linear regression models simultaneously adjusted for the ENET-selected biomarkers and a priori chosen confounders. Results: The multipollutant ENET model for placental weight retained four biomarkers: triclosan and monocarboxy-isononyl phthalate (MCNP), which were negatively associated with placental weight, and benzophenone-3 and the sum of parabens, which were positively associated with this outcome. The ENET model for PFR retained two phthalate metabolites [MCNP and monocarboxy-isooctyl phthalate (MCOP)], which were negatively associated with this outcome. Discussion: The positive association between the sum of parabens and placental weight was consistent with results of a previous study among 49 male births. Our results provide preliminary evidence of possible associations between other compounds such as triclosan, benzophenone-3, MCNP, and MCOP and both placental weight and PFR. These associations were not reported in previous studies and should be seen as hypothesis generating. Studies relying on repeated assessments of exposure in prospective mother–child cohorts are needed to substantiate the plausibility of the hypotheses generated by our results. https://doi.org/10.1289/EHP3523

Background In biomarker-based studies, collecting repeated biospecimens per participant can decrease measurement error, particularly for biomarkers displaying high within-subject variability. Guidelines to combine such repeated biospecimens do not exist. Aims To compare the efficiency of several designs relying on repeated biospecimens to estimate exposure over 7 days. Methods We quantified triclosan and bisphenol A (BPA) in all urine voids (N = 427) collected over seven days from eight individuals. We estimated the volume-weighted concentrations for all urine samples collected during a week and compared these gold standards with the concentrations obtained for equal-volume pools (standardized or not for urine dilution), unequal-volume pools (based on sample volume or creatinine concentration), and for the mean of the creatinine-standardized concentrations measured in each spot sample. Results For both chemicals, correlations with gold standards were similar for equal- and unequal-volume pooling designs. Only for BPA, correlation coefficients were markedly lower after standardization for specific gravity or creatinine of concentrations estimated in equal-volume pools. Averaging BPA creatinine-standardized concentrations measured in each spot sample led also to lower correlations with gold standards compared to those obtained for unstandardized pooling designs. Conclusion For BPA and triclosan, considering individual urine sample volume or creatinine concentrations when pooling is unnecessary because equal-volume pool adequately estimates concentrations in gold standards. Standardization for specific gravity or creatinine of the concentrations assessed in equal-volume pool as well as averaging creatinine-standardized concentrations measured in each individual spot sample are not suitable for BPA. These results provide a practical framework on how to combine repeated biospecimens in epidemiological studies.

Supplemental Digital Content is available in the text., Background: For chemicals with high within-subject temporal variability, assessing exposure biomarkers in a spot biospecimen poorly estimates average levels over long periods. The objective is to characterize the ability of within-subject pooling of biospecimens to reduce bias due to exposure misclassification when within-subject variability in biomarker concentrations is high. Methods: We considered chemicals with intraclass correlation coefficients of 0.6 and 0.2. In a simulation study, we hypothesized that the chemical urinary concentrations averaged over a given time period were associated with a health outcome and estimated the bias of studies assessing exposure that collected 1 to 50 random biospecimens per subject. We assumed a classical type error. We studied associations using a within-subject pooling approach and two measurement error models (simulation extrapolation and regression calibration), the latter requiring the assay of more than one biospecimen per subject. Results: For both continuous and binary outcomes, using one sample led to attenuation bias of 40% and 80% for compounds with intraclass correlation coefficients of 0.6 and 0.2, respectively. For a compound with an intraclass correlation coefficient of 0.6, the numbers of biospecimens required to limit bias to less than 10% were 6, 2, and 2 biospecimens with the pooling, simulation extrapolation, and regression calibration methods (these values were, respectively, 35, 8, and 2 for a compound with an intraclass correlation coefficient of 0.2). Compared with pooling, these methods did not improve power. Conclusion: Within-subject pooling limits attenuation bias without increasing assay costs. Simulation extrapolation and regression calibration further limit bias, compared with the pooling approach, but increase assay costs.

Objectif Explorer les relations entre l’exposition fœtale a certains phenols et phtalates et le sommeil de l’enfant a 2 ans. Methodes Au total, 4456 dyades mere–fils d’une cohorte de naissance avec des dosages de metabolites urinaires maternels de 9 phenols et 11 phtalates et des donnees sur le sommeil de 2 ans (duree de sommeil, reveils nocturnes frequents [> 1 nuit sur 2]) ont ete incluses. Les relations entre les expositions considerees en tertiles et les caracteristiques du sommeil a 2 ans ont ete etudiees par des modeles de regression lineaire ou logistique ajustes sur les facteurs de confusion. Resultats Les concentrations urinaires etaient parmi les plus elevees pour le triclosan (TCS, biocide, cosmetiques), le methylparaben (MP, conservateur, cosmetiques), le mono-n-butyle phthalte (MBP, parfum, cosmetiques), et parmi les plus faibles pour bisphenol A (BPA, plastifiant, contenants) et le monocarboxyisononyl phthalate (MCNP, plastifiant, contenants). Le TCS etait associe a une moindre frequence des reveils nocturnes a 2 ans tandis que le MP etait associe avec une duree de sommeil plus longue. Le MBP etait associe a une moindre frequence des reveils nocturnes tandis que le MCNP etait associe a une moindre duree de sommeil a 2 ans. Aucune association n’etait observee avec les autres metabolites dont le BPA. Conclusion Nous montrons l’existence d’associations entre exposition prenatale a certains perturbateurs endocriniens et sommeil. La confirmation de ces resultats est necessaire par des etudes toxicologiques chez l’animal et des etudes epidemiologiques dans des populations plus larges.

National audience

There is increase concerns over child behavioral problems due to changing environments. Children are typically exposed to a long list of industrial chemicals that are neurotoxic but also to benefic...

Context: Benzene is a recognized reprotoxicant but its effects on fetal growth in humans at levels encountered in the general population are poorly known. A study reported decreases in head circumf...