There is growing concern that phthalate exposures may have an impact on child neurodevelopment. Prenatal exposure to phthalates has been linked with externalizing behaviors and executive functioning ...defects suggestive of an attention-deficit hyperactivity disorder (ADHD) phenotype.
We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.
Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (
=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (
=553) from the MoBa population was obtained.
In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest OR=2.99 (95% CI: 1.47, 5.49). When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% OR=1.47 (95% CI: 1.09, 1.94). We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.
In this population-based case-control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD. https://doi.org/10.1289/EHP2358.
•Phenols and phthalates were frequently detected in this recent pregnancy cohort.•Weighted Quantile Sum indexes were associated with child behaviour.•Associations tended to be stronger in ...girls.•Bisphenol A, triclosan, MEP were the main mixture contributors for externalizing score.•MEP, MBzP, MnBP were the main mixture contributors for internalizing score.
Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects.
To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements.
We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother–child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5–5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions).
The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: −0.42, 3.81) and 1.17 points (95 %CI: −0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score.
Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.
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 < 0.05). While improved compared to studies that relied on spot samples, Intraclass Correlation Coefficients for the pregnancy were below 0.40 for most metabolites. Spearman correlation coefficients between pooled samples collected in infancy were lower than those observed during pregnancy, and were all below 0.30. Exposure to emerging phthalate substitutes such as DINCH and DPHP seems widespread among pregnant women and infants. Collecting repeated urine samples in pregnant women and infants is feasible. The relatively low correlation across trimesters and between maternal and infant samples highlights the need to collect biospecimens in the assumed sensitive time window.
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•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.
Several single-exposure studies have documented possible effects of environmental factors on lung function, but none has relied on an exposome approach. We aimed to evaluate the association between a ...broad range of prenatal and postnatal lifestyle and environmental exposures and lung function in children.
In this analysis, we used data from 1033 mother–child pairs from the European Human Early-Life Exposome (HELIX) cohort (consisting of six existing longitudinal birth cohorts in France, Greece, Lithuania, Norway, Spain, and the UK of children born between 2003 and 2009) for whom a valid spirometry test was recorded for the child. 85 prenatal and 125 postnatal exposures relating to outdoor, indoor, chemical, and lifestyle factors were assessed, and lung function was measured by spirometry in children at age 6–12 years. Two agnostic linear regression methods, a deletion-substitution-addition (DSA) algorithm considering all exposures simultaneously, and an exposome-wide association study (ExWAS) considering exposures independently, were applied to test the association with forced expiratory volume in 1 s percent predicted values (FEV1%). We tested for two-way interaction between exposures and corrected for confounding by co-exposures.
In the 1033 children (median age 8·1 years, IQR 6·5–9·0), mean FEV1% was 98·8% (SD 13·2). In the ExWAS, prenatal perfluorononanoate (p=0·034) and perfluorooctanoate (p=0·030) exposures were associated with lower FEV1%, and inverse distance to nearest road during pregnancy (p=0·030) was associated with higher FEV1%. Nine postnatal exposures were associated with lower FEV1%: copper (p=0·041), ethyl-paraben (p=0·029), five phthalate metabolites (mono-2-ethyl 5-carboxypentyl phthalate p=0·016, mono-2-ethyl-5-hydroxyhexyl phthalate p=0·023, mono-2-ethyl-5-oxohexyl phthalate p=0·0085, mono-4-methyl-7-oxooctyl phthalate p=0·040, and the sum of di-ethylhexyl phthalate metabolites p=0·014), house crowding (p=0·015), and facility density around schools (p=0·027). However, no exposure passed the significance threshold when corrected for multiple testing in ExWAS, and none was selected with the DSA algorithm, including when testing for exposure interactions.
Our systematic exposome approach identified several environmental exposures, mainly chemicals, that might be associated with lung function. Reducing exposure to these ubiquitous chemicals could help to prevent the development of chronic respiratory disease.
European Community's Seventh Framework Programme (HELIX project).
Chemical and nonchemical environmental exposures are increasingly suspected to influence the development of obesity, especially during early life, but studies mostly consider single exposure groups.
...Our study aimed to systematically assess the association between a wide array of early-life environmental exposures and childhood obesity, using an exposome-wide approach.
The HELIX (Human Early Life Exposome) study measured child body mass index (BMI), waist circumference, skinfold thickness, and body fat mass in 1,301 children from six European birth cohorts age 6-11 y. We estimated 77 prenatal exposures and 96 childhood exposures (cross-sectionally), including indoor and outdoor air pollutants, built environment, green spaces, tobacco smoking, and biomarkers of chemical pollutants (persistent organic pollutants, metals, phthalates, phenols, and pesticides). We used an exposure-wide association study (ExWAS) to screen all exposure-outcome associations independently and used the deletion-substitution-addition (DSA) variable selection algorithm to build a final multiexposure model.
The prevalence of overweight and obesity combined was 28.8%. Maternal smoking was the only prenatal exposure variable associated with higher child BMI (
-score increase of 0.28, 95% confidence interval: 0.09, 0.48, for active vs. no smoking). For childhood exposures, the multiexposure model identified particulate and nitrogen dioxide air pollution inside the home, urine cotinine levels indicative of secondhand smoke exposure, and residence in more densely populated areas and in areas with fewer facilities to be associated with increased child BMI. Child blood levels of copper and cesium were associated with higher BMI, and levels of organochlorine pollutants, cobalt, and molybdenum were associated with lower BMI. Similar results were found for the other adiposity outcomes.
This first comprehensive and systematic analysis of many suspected environmental obesogens strengthens evidence for an association of smoking, air pollution exposure, and characteristics of the built environment with childhood obesity risk. Cross-sectional biomarker results may suffer from reverse causality bias, whereby obesity status influenced the biomarker concentration. https://doi.org/10.1289/EHP5975.
Phthalates and bisphenol A (BPA) are ubiquitous in our environment. These chemicals have been characterized as endocrine disruptors that can cause functional impairment of development and ...reproduction. Processed and packaged foods are among the major sources of human exposure to these chemicals. No previous report showing the levels of these chemicals in food items purchased in Norway is available. The aim of the present study was to determine the concentration of ten different phthalates and BPA in foods and beverages purchased on the Norwegian market and estimate the daily dietary exposure in the Norwegian adult population. Commonly consumed foods and beverages in Norway were purchased in a grocery store and analysed using gas- and liquid chromatography coupled with mass spectrometry. Daily dietary exposures to these chemicals in the Norwegian adult population were estimated using the latest National dietary survey, Norkost 3 (2010–2011). This study showed that phthalates and BPA are found in all foods and beverages that are common to consume in Norway. The detection frequency of phthalates in the food items varied from 11% for dicyclohexyl phthalate (DCHP) to 84% for di-iso-nonyl phthalate (DiNP), one of the substitutes for bis(2-ethylhexyl) phthalate (DEHP). BPA was found in 54% of the food items analysed. Among the different phthalates, the highest concentrations were found for DEHP and DiNP in the food items. Estimated dietary exposures were also equally high and dominated by DEHP and DiNP (400–500ng/kg body weight (bw)/day), followed by di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di-n-octyl phthalate (DnOP) and di-iso-decyl phthalate (DiDP) (30–40ng/kg bw/day). Dimethyl phthalate (DMP), diethylphthalate (DEP) and DCHP had the lowest concentrations and the exposures were around 10–20ng/kg bw/day. Estimated dietary exposure to BPA was 5ng/kg bw/day. In general, levels of phthalates and BPA in foods and beverages from the Norwegian market are comparable to other countries worldwide. Grain and meat products were the major contributors of exposure to these chemicals in the Norwegian adult population. The estimated dietary exposures to these chemicals were considerably lower than their respective tolerable daily intake (TDI) values established by the European Food Safety Authority (EFSA).
•Ten phthalates and bisphenol A were determined in food items bought in Norway.•Concentrations were highest for phthalates DEHP and DiNP.•Grain and meat products were major contributors to these chemicals in Norway.•Estimated dietary exposures were lower than respective tolerable daily intakes.
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•Elevated DPHP and BDCIPP during mid-pregnancy increased ADHD risk in offspring.•Simultaneously decreasing joint exposure to OPEs and phthalates may reduce ADHD risk.•The link between ...prenatal DPHP and ADHD was stronger among girls than boys.•Suggestive modification by maternal paraoxonase1 Q192R genotype was present for DPHP.•DPHP-ADHD association was partly mediated via pregnancy maternal thyroid function.
Organophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD.
To evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa).
We included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals 95% CI using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation.
DPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 95% CI: 0.96, 1.99), which was slightly higher among girls (2.04 1.03, 4.02) and children of mothers with PON1 Q192R genotype QR (1.69 0.89, 3.19) or PON1 Q192R genotype RR (4.59 1.38, 15.29). The relationship between DPHP and ADHD (total risk ratio: 1.34 0.90, 2.02) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 0.87, 1.94; natural indirect effect: 1.04 1.00, 1.10; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 0.98, 2.28). We did not observe notable differences in ADHD by DNBP (0.88 0.62, 1.26) or BBOEP (1.03 0.73, 1.46) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 0.64, 0.72.
Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.
•MiBP and MnBP were positively associated with most second trimester growth parameters.•At second trimester, MiBP was associated with head and abdominal circumferences.•MnBP was associated with all ...fetal measurements at either second or third trimester.•MnBP associations with fetal growth parameters were stronger among males.•Metabolites mixture was positively associated with fetal weight at second trimester.
Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth.
For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models.
Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester.
In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.
Exposome studies are challenged by exposure misclassification for non-persistent chemicals, whose temporal variability contributes to bias in dose-response functions.
We evaluated the variability of ...urinary concentrations of 24 non-persistent chemicals: 10 phthalate metabolites, 7 phenols, 6 organophosphate (OP) pesticide metabolites, and cotinine, between weeks from different pregnancy trimesters in pregnant women, and between days and between seasons in children.
154 pregnant women and 152 children from six European countries were enrolled in 2014–2015. Pregnant women provided three urine samples over a day (morning, midday, and night), for one week in the 2nd and 3rd pregnancy trimesters. Children provided two urines a day (morning and night), over two one-week periods, six months apart. We pooled all samples for a given subject that were collected within a week. In children, we also made four daily pools (combining morning and night voids) during the last four days of the first follow-up week. Pools were analyzed for all 24 metabolites of interest. We calculated intraclass-correlation coefficients (ICC) and estimated the number of pools needed to obtain an ICC above 0.80.
All phthalate metabolites and phenols were detected in >90% of pools whereas certain OP pesticide metabolites and cotinine were detected in <43% of pools. We observed fair (ICC = 0.40–0.59) to good (0.60–0.74) between-day reliability of the pools of two samples in children for all chemicals. Reliability was poor (<0.40) to fair between trimesters in pregnant women and between seasons in children. For most chemicals, three daily pools of two urines each (for weekly exposure windows) and four weekly pools of 15–20 urines each would be necessary to obtain an ICC above 0.80.
This quantification of the variability of biomarker measurements of many non-persistent chemicals during several time windows shows that for many of these compounds a few dozen samples are required to accurately assess exposure over periods encompassing several trimesters or months.
•Urinary measurement variability can bias dose-response functions.•We evaluated the variability of 24 metabolites in pregnant women and children.•An alternative sampling strategy based on pooled urine is proposed.•The pooling strategy does not solve variability for most of these metabolites.
•We investigated the relations between phthalates and thyroid function mid-pregnancy.•We accounted for the urinary phthalate metabolite mixture by factor analyses.•We found relationships between ...phthalate factors and thyroid function, mainly T3.•Dietary iodine intake in pregnancy influenced some of these relationships.
Human populations, including susceptible subpopulations such as pregnant women and their fetuses, are continuously exposed to phthalates. Phthalates may affect the thyroid hormone system, causing concern for pregnancy health, birth outcomes and child development. Few studies have investigated the joint effect of phthalates on thyroid function in pregnant women, although they are present as a mixture with highly inter-correlated compounds. Additionally, no studies have investigated if the key nutrient for thyroid health, iodine, modifies these relationships.
In this study, we examined the cross-sectional relationships between concentrations of 12 urinary phthalate metabolites and 6 plasma thyroid function biomarkers measured mid-pregnancy (~17 week gestation) in pregnant women (N = 1072), that were selected from a population-based prospective birth cohort, The Norwegian Mother, Father and Child Cohort study (MoBa). We investigated if the phthalate metabolite-thyroid function biomarker associations differed by iodine status by using a validated estimate of habitual dietary iodine intake based on a food frequency questionnaire from the 22nd gestation week. We accounted for the phthalate metabolite mixture by factor analyses, ultimately reducing the exposure into two uncorrelated factors. These factors were used as predictors in multivariable adjusted linear regression models with thyroid function biomarkers as the outcomes.
Factor 1, which included high loadings for mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), and monobenzyl phthalate (MBzP), was associated with increased total triiodothyronine (TT3) and free T3 index (fT3i). These associations appeared to be driven primarily by women with low iodine intake (<150 µg/day, ~70% of our sample). Iodine intake significantly modified (p-interaction < 0.05) the association of factor 1 with thyroid stimulating hormone (TSH), total thyroxine (TT4) and free T4 index (fT4i), such that only among women in the high iodine intake category (≥150 µg/day, i.e. sufficient) was this factor associated with increased TSH and decreased TT4 and FT4i, respectively. In contrast, factor 2, which included high loadings for di-2-ethylhexyl phthalate metabolites (∑DEHP) and di-iso-nonyl phthalate metabolites (∑DiNP), was associated with a decrease in TT3 and fT3i, which appeared fairly uniform across iodine intake categories.
We find that phthalate exposure is associated with thyroid function in mid-pregnancy among Norwegian women, and that iodine intake, which is essential for thyroid health, could influence some of these relationships.
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