Prenatal exposure to glycol ethers and response inhibition in 6-year-old children: The PELAGIE cohort study.

BACKGROUND: Exposure to glycol ethers (GEs) is suspected of impairing neurodevelopment in children, but the specific impact on their inhibitory capacity, a central deficit of ADHD, has never been studied. We aimed to assess the impact of prenatal exposure to GEs on the response inhibition of children aged six years. METHODS: In total, 169 mother-child pairs from the French cohort PELAGIE (2002-2006) were studied. Maternal urinary concentrations of six GE metabolites (alkoxycarboxylic acids) were measured during pregnancy. Multiple imputation by quantile regression was used to handle non-detected values and the data were then classified into quartiles. Inhibition of children was evaluated by the Rhythmic Continuous Performance Test 90 (R-CPT90). The inhibition score (percentage of correct responses to non-target stimuli) was corrected for compliance with the instructions (percentage of correct responses to target stimuli). The analysis used a multiple linear regression model, adjusting for confounding factors for each metabolite. RESULTS: Median concentrations of metabolites ranged from 0.02 mg/L (Ethoxyacetic acid, EAA) to 0.39 mg/L (Phenoxyacetic acid, PhAA). The median corrected inhibition score was 37.9% [first quartile: 29.8 - third quartile: 47.9]. We found a negative and statistically significant association between the inhibition score and prenatal urinary EAA concentration (p-trend = 0.03), with a significant ß coefficient for the third quartile (ß = -0.064; 95% confidence interval: -0.121, -0.007). There were no statistically significant associations for the other five metabolites. CONCLUSION: These results are consistent with the hypothesis of possible impact of prenatal environmental exposure on inhibitory capacity among children. Data about the GEs metabolized to EAA (history of exposure sources and toxicokinetics) should be gathered to further interpret these results and guide precautionary measures.

Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case-control study.

OBJECTIVES: Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure. METHODS: We conducted a case-control study nested in two joint mother-child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth's penalisation. RESULTS: Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism. CONCLUSIONS: In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA.

Exposure of the general French population to herbicides, pyrethroids, organophosphates, organochlorines, and carbamate pesticides in 2014-2016: Results from the Esteban study.

Esteban is a nationwide cross-sectional study conducted in France in 2014-2016, including 2503 adults aged 18-74 years old and 1104 children aged 6-17 years old, as part of the French Human Biomonitoring programme. The present paper describes the biological levels of five families of pesticides analysed on random sub-samples of 900 adults and 500 children for urine concentrations, and 759 adults and 255 children for serum concentrations, and the determinants of exposure. Organophosphates, carbamates and herbicides were measured in urine by UPLC-MS/MS; chlorophenols and pyrethroids were measured in urine by GC-MS/MS; specific organochlorines were measured in serum by GC-HRMS. Multivariate analyses were performed to identify the determinants of exposure using a generalized linear model. Pyrethroid metabolites were quantified in 99% of adults and children, with the exeption of F-PBA, which was quantified in 31% of adults and 27% of children, respectively. Carbamates and some specific organophosphates were barely or not quantified. DMTP was quantified in 82% of adults and 93% of children, and γ-HCH (lindane) was quantified in almost 50% of adults and children. Concentration levels of pesticide biomarkers were consistent with comparable international studies, except for ß-HCH, DMTP, and the deltamethrin metabolite Br2CA, whose levels were sometimes higher in France. Household insecticide use and smoking were also associated with higher levels of pyrethroids. All pyrethroids concentration levels were below existing health-based HBM guidance values, HBM-GVsGenPop, except for 3-PBA, for which approximately 1% and 10% of children were above the lower and upper urine threshold values of 22 µg/L and 6.4 µg/L, respectively. Esteban provides a French nationwide description of 70 pesticide biomarkers for the first time in children. It also describes some pesticide biomarkers for the first time in adults, including glyphosate and AMPA. For the latter, urine concentration levels were overall higher in children than in adults. Our results highlight a possible beneficial impact of existing regulations on adult exposure to organochlorine and organophosphate pesticides between 2006 and 2016, as concentration levels decreased over this period.

Prenatal exposure to glycol ethers and visual contrast sensitivity in 6-year-old children in the PELAGIE mother-child cohort.

BACKGROUND: Maternal occupational exposure to organic solvents during pregnancy has been associated with decreased visual function in offspring. Glycol ethers (GEs) belong to oxygenated solvents and are widely used both in occupational and domestic contexts. OBJECTIVES: We aimed to assess associations between prenatal GEs exposure and contrast sensitivity in children. METHODS: Six GE alkoxy carboxylic acidic metabolites (methoxyacetic acid [MAA], ethoxyacetic acid [EAA], ethoxyethoxyacetic acid [EEAA], butoxyacetic acid [BAA], phenoxyacetic acid [PhAA], and 2-methoxypropionic acid [2-MPA]) were measured in first morning void urine samples collected from 220 early-pregnancy women, in the mother-child PELAGIE cohort (France). Trained investigators administered the Functional Acuity Contrast Test (FACT) to the 6-year-old children, providing scores for 5 spatial frequencies (1.5-18 cycles per degree (cpd)). We standardized biomarker urinary concentrations on urine sampling conditions. Values below the LOD were imputed based on log-normal distribution, generating five datasets for multiple imputation. Linear regression models were adjusted for potential confounders. RESULTS: GE metabolites were detected in 70-98% of maternal urine samples. Phenoxyacetic acid (PhAA) had the highest median concentration (0.33 mg/L), and 2-methoxypropionic acid (2-MPA) the lowest (0.01 mg/L). Children with higher prenatal PhAA concentrations had poorer FACT scores at various spatial frequencies (fourth vs. first quartile: ß18cpd = -0.90 (95% confidence interval CI = -1.64, -0.16), ß12cpd = -0.92 (95%CI = -1.55, -0.29) and ß1.5cpd = -0.69 (95%CI = -1.19, -0.20)). The 2-MPA log-scale concentration was negatively associated with the FACT score at the 3-cpd stimulus. DISCUSSION: PhAA is the metabolite of ethylene glycol monophenyl ether present in many cosmetics. 2-MPA is the metabolite of an isomer of propylene glycol methyl ether commonly present in household and industrial cleaning products. Although evidence of biological plausibility is lacking, the study suggests adverse impact of ubiquitous prenatal exposure to some GE on visual functioning among children.

Exposure of the French population to bisphenols, phthalates, parabens, glycol ethers, brominated flame retardants, and perfluorinated compounds in 2014-2016: Results from the Esteban study.

BACKGROUND: As part of the French Human Biomonitoring (HBM) programme, the Esteban study described, among other things, biomarkers levels of various chemicals in adults (18-74 years old) and children (6-17 years old). This paper describes the design of the study and provides, for the first time, data on the biological exposure of the general French population to a wide range of contaminants posing a threat to human health which are currently found in domestic environments. METHODS: Esteban is a cross-sectional study conducted on a nationwide sample of the French general population. Exposure biomarkers of six families of contaminants deemed detrimental to adults' and children's health were measured in biological samples collected either at participants' homes by a nurse, or brought to a National Health Insurance examination centre. All participants were randomly selected (2503 adults and 1104 children). The geometric mean and percentiles of the distribution of levels were estimated for each biomarker. Most of the descriptive statistical analyses were performed taking into account the sampling design. RESULTS: Results provided a nationwide description of biomarker levels. Bisphenols (A, S and F), and some metabolites of phthalates and perfluorinated compounds (PFCs) (specifically, PFOS and PFOA) were quantified in almost all the biological samples analysed. Higher levels were observed in children (except for PFCs). Levels were coherent with international studies, except for bisphenols S and F, brominated flame retardants (BFRs) and parabens (with higher levels reported in the USA than in France). CONCLUSION AND PERSPECTIVES: This study is the first to provide a representative assessment of biological exposure to domestic contaminants at the French population level. Our results show that the French general population was exposed to a wide variety of pollutants in 2014-2016, and identify the determinants of exposure. These findings will be useful to stakeholders who wish to advocate an overall reduction in the French population's exposure to harmful substances. Similar future studies in France will help to measure temporal trends, and enable public policies focused on the reduction of those chemicals in the environment to be evaluated.

Exposure to glycol ethers among 6-year-old children in France.

Glycol ethers are an oxygenated solvent family widely present in consumer products. Some of them are recognized reproductive, developmental or hematological toxicants. Although several glycol ether biomonitoring studies have been performed on adults from working or general populations, no studies have hitherto been carried out on children. The aim of our study was to explore the detection of glycol ether metabolites in the urinary samples of 6-year-old children, and if any were found, to describe them. The PELAGIE mother-child cohort included 3421 pregnant women from the general population of Brittany, France, between 2002 and 2006. Our biomonitoring study included a random sample of 110 children from the PELAGIE cohort who had participated in a neurodevelopment evaluation at the age of six. First morning voids were collected from all of the children. Eight urinary glycol ether metabolites were measured using gas chromatography with mass spectrometry. The limit of detection was 0.003 mg/L for all metabolites. Glycol ether metabolites were detected at rates varying from 33.5% of samples for propoxyacetic acid to 100% of samples for phenoxyacetic acid and methoxyacetic acid. The highest median concentration observed was for phenoxyacetic acid (0.141 mg/l). Our study reported the ubiquitous presence of glycol ether metabolites in children's urinary samples. These results call for larger biomonitoring surveys of the general population and study of the potential sources and determinants of these exposures.

Determinants of children's exposure to pyrethroid insecticides in western France.

Pyrethroids are insecticides frequently used in agriculture and in the home; exposure occurs through dietary and non-dietary pathways, including indoor and outdoor environmental contamination. Our objective was to study the potential determinants of pyrethroid metabolite concentrations measured in children's urine samples and in the dust of their homes. Specifically, we measured urinary metabolites from morning spot samples of 245 six-year-old children living in Brittany (France) in 2009-2012 and from dust vacuumed from the floor of their homes. Mothers reported home insecticide use, dietary habits, sociodemographic data; residential and school proximity to agricultural crops was assessed with spatialized data. The metabolites cis-DBCA, trans-DCCA, cis-DCCA, 3-PBA, and F-PBA were detected in 84, 95, 64, 63, and 16% of the urine samples, respectively. Permethrin, cypermethrin, cyfluthrin, deltamethrin, and tetramethrin pyrethroids were detected in 100, 56, 9, 15, and 26% of the dust samples, respectively. Multiple regression analysis suggested diet plays a role in children's exposure, in particular, the food groups "pasta, rice or semolina" (for cis-DCCA and F-PBA), fruit (3-PBA), "breakfast cereals and whole grain bread" (cis-DBCA), and the global proportion of organic food in diet (for cis-DBCA, trans-DCCA). Children with a parent occupationally exposed to pesticides were about 3-times more likely to have higher urinary concentrations of 3-PBA (OR=2.8, 95% CI [1.2; 6.5]). Dust content was correlated mainly with household insecticide use: higher mean concentrations of permethrin (ß=0.8 [0.3; 1.3], in µg/g) and an increased risk of a detectable level of cyfluthrin (OR=4.7 [1.7; 12.9]) were observed in home dust, for indoor use of at least twice a year. Outdoor insecticide use at least once a year was associated with detection in dust of cypermethrin (OR=3.0 [1.3; 6.7]) and tetramethrin (OR=3.7 [1.6; 8.3]). Three positive and one negative correlations (out of 11) between urinary metabolite concentrations and home dust contents of their possible corresponding parent compounds were observed. The strength of this study lies in its concurrent use of biomarkers, environmental measurements, and potential sources of exposure. Its limitations include the use of a single urine sample and imprecise data about pyrethroid use in local agriculture.

Prenatal Exposure to Glycol Ethers and Neurocognitive Abilities in 6-Year-Old Children: The PELAGIE Cohort Study.

BACKGROUND: Glycol ethers (GE) are widely used organic solvents. Despite the potential neurotoxicity of several families of organic solvents, little is known about the impact of GE on the neurodevelopment of infants and children. OBJECTIVES: We investigated the relation between urinary concentrations of GE metabolites in pregnant women and neurocognitive abilities in their 6-year-old children in the PELAGIE mother-child cohort. METHODS: Five GE metabolites were measured in first morning void urine samples of 204 French pregnant women in early pregnancy (< 19 weeks of gestation). Psychologists assessed the neurocognitive abilities of their 6-year-old children with the Wechsler Intelligence Scale for Children IV (WISC) and the Developmental Neuropsychological Assessment (NEPSY). We analyzed the results with linear (WISC) and Poisson regression models (NEPSY), adjusted for potential confounders, including child's stimulation at home. RESULTS: GE metabolites were detected in 90-100% of maternal urine samples. The WISC Verbal Comprehension score was significantly lower for children with the highest tertile of urinary phenoxyacetic acid (PhAA) [ß (third vs. first tertile) = -6.53; 95% CI: -11.44, -1.62]. Similarly, the NEPSY Design Copying subtest score was lower in those with the highest tertile of urinary ethoxyacetic acid (EAA) [ß (third vs. first tertile) = -0.11; 95% CI: -0.21, 0.00]. The other GE metabolites we studied were not significantly associated with WISC or NEPSY scores. CONCLUSIONS: Prenatal urine concentrations of two GE metabolites were associated with lower WISC Verbal Comprehension Index scores and NEPSY Design Copying subscale scores, respectively, at age 6 years. PhAA is the primary metabolite of 2-phenoxyethanol (EGPhE), which is commonly found in cosmetics, and precursors of EAA are frequently used in cleaning agents. Additional research is needed to confirm our findings and further explore potential effects of prenatal GE exposures on neurocognitive performance in children.