Maternal Exposure to Organophosphate Esters during Pregnancy, Maternal Thyroid Function, and Offspring Attention-Deficit Hyperactivity Disorder: Investigation in the Context of Mixtures

Background. Exposures to organophosphate esters (OPEs), common-use plasticizers/flame retardants, are widespread in contemporary human populations. OPEs have been suggested as thyroid disruptors, although inconsistencies exist and research is sparse in vulnerable populations. Particularly during early pregnancy, maintaining normal maternal thyroid function is critical to fetal brain development. Neurodevelopment in children has also been linked with OPEs, specifically more hyperactivity and attention problems. These behaviors are often found in children with attention-deficit hyperactivity disorder (ADHD), however, prenatal OPE exposures have not been evaluated as risk factors for ADHD. Methods. A case-cohort study was nested within the Norwegian Mother, Father, and Child Cohort. Four OPE metabolites were measured from maternal urine collected at 17 weeks’ gestation. We also considered 6 urinary phthalate metabolites, given their potential to co-occur with OPEs. In Aim1, the sub-cohort was used to cross-sectionally investigate the relationship between exposure to common-detect OPEs and phthalates and 6 maternal thyroid function biomarkers in euthyroid pregnant women, using Bayesian Kernal Machine Regression (BKMR) and general linear regression (GLM). In Aim2, a case-cohort analysis was conducted to estimate the risk ratios (RRs) associated with elevated individual and joint exposure(s), using logistic regression and quantile based g-computation, respectively. Mediation through maternal thyroid function and effect measure modification by child sex and polymorphisms in metabolism enzymes were explored. Results. Diphenyl phosphate (DPHP) and di-n-butyl phosphate (DNBP) were commonly detected; while bis(2-butoxyethyl) hydrogen phosphate and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were detected infrequently. In Aim 1, DPHP was inversely associated with total triiodothyronine to total thyroxine ratio in GLM, although the associations near-null in BKMR. In Aim 2, elevated risk of ADHD was observed with pregnancy exposure to greater than sub-cohort median DPHP (RR: 1.38 [95% confidence interval: 0.96, 1.99]) and BDCIPP detection (1.50 [0.98, 2.28]). For DPHP, we observed weak mediation through pregnancy maternal thyroid function and suggestive modifications by polymorphisms and child sex. A quartile reduction in combined exposure to DPHP, DNBP, and phthalate metabolites resulted in an RR of 0.68 [0.64, 0.72].Conclusions. Prenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. Thyroid hormone imbalance may underlie the impact of DPHP.Doctor of Philosoph

A study on modeling nitrogen dioxide concentrations using land-use regression and conventionally used exposure assessment methods

The land-use regression (LUR) approach to estimate the levels of ambient air pollutants is becoming popular due to its high validity in predicting small-area variations. However, only a few studies have been conducted in Asian countries, and much less research has been conducted on comparing the performances and applied estimates of different exposure assessments including LUR. The main objectives of the current study were to conduct nitrogen dioxide (NO2) exposure assessment with four methods including LUR in the Republic of Korea, to compare the model performances, and to estimate the empirical NO2 exposures of a cohort. The study population was defined as the year 2010 participants of a government-supported cohort established for bio-monitoring in Ulsan, Republic of Korea. The annual ambient NO2 exposures of the 969 study participants were estimated with LUR, nearest station, inverse distance weighting, and ordinary kriging. Modeling was based on the annual NO2 average, traffic-related data, land-use data, and altitude of the 13 regularly monitored stations. The final LUR model indicated that area of transportation, distance to residential area, and area of wetland were important predictors of NO2. The LUR model explained 85.8% of the variation observed in the 13 monitoring stations of the year 2009. The LUR model outperformed the others based on leave-one out cross-validation comparing the correlations and root-mean square error. All NO2 estimates ranged from 11.3–18.0 ppb, with that of LUR having the widest range. The NO2 exposure levels of the residents differed by demographics. However, the average was below the national annual guidelines of the Republic of Korea (30 ppb). The LUR models showed high performances in an industrial city in the Republic of Korea, despite the small sample size and limited data. Our findings suggest that the LUR method may be useful in similar settings in Asian countries where the target region is small and availability of data is low

Assessment of environmental injustice in Korea using synthetic air quality index and multiple indicators of socioeconomic status: A cross-sectional study

<div><p>ABSTRACT</p><p>Despite the existence of the universal right to a healthy environment, the right is being violated in some populations. The objective of the current study is to verify environmental discrimination associated with socioeconomic status in Korea, using synthetic air quality index and multiple indicators of socioeconomic status. The concentrations of NO₂ (nitrogen dioxide), CO (carbon monoxide), SO₂ (sulfur dioxide), PM₁₀ (particulate matter with an aerodynamic diameter <10 μm), and O₃ (ozone) in ambient air were integrated into a synthetic air quality index. Socioeconomic status was measured at individual level (income, education, number of household members, occupation, and National Basic Livelihood status) and area level (neighborhood index). The neighborhood index was calculated in the finest administrative unit (municipality) by performing standardization and integration of municipality-level data of the following: number of families receiving National Basic Livelihood, proportion of people engaged in an elementary occupation, population density, and number of service industries. Each study participant was assigned a neighborhood index value of the municipality in which they reside. Six regression models were generated to analyze the relationship between socioeconomic status and overall air pollution. All models were adjusted with sex, age, and smoking status. Stratification was conducted by residency (urban/rural). Moran’s <i>I</i> was calculated to identify spatial clusters, and adjusted regression analysis was conducted to account for spatial autocorrelation. Results showed that people with higher neighborhood index, people living with smaller number of family members, and people with no education lived in municipalities with better overall air quality. The association differed by residency in some cases, and consideration of spatial autocorrelation altered the association. This study gives strength to the idea that environmental discrimination exists in some socioeconomic groups in Korea, and that residency and spatial autocorrelation must be considered in order to fully understand environmental disparities.<i>Implications</i>: This is the first study that provides the possible evidence of the environmental injustice in Korea using air quality index. The findings suggested that air quality index was negatively correlated with several important socioeconomic status measured at either individual or area level. The main implication of this paper, therefore, is to provide another insight to environmental policy makers to consider environmental injustice problem into community intervention for resolving the public health problems by air pollution.</p></div

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

Background: 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. Objective: 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). Methods: 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 (ΣDEHP) 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. Results: 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]. Conclusion: 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

Gestational organophosphate ester exposure and preschool attention-deficit/hyperactivity disorder in the Norwegian Mother, Father, and Child cohort study.

BACKGROUND: Attention-deficit/hyperactivity-disorder (ADHD) is a leading neurodevelopmental disorder in children worldwide; however, few modifiable risk factors have been identified. Organophosphate esters (OPEs) are ubiquitous chemical compounds that are increasingly prevalent as a replacement for other regulated chemicals. Current research has linked OPEs to neurodevelopmental deficits. The purpose of this study was to assess gestational OPE exposure on clinically-assessed ADHD in children at age 3 years. METHODS: In this nested case-control study within the Norwegian Mother, Father, and Child Cohort study, we evaluated the impact of OPE exposure at 17 weeks gestation on preschool-age ADHD. Between 2007 and 2011, 260 ADHD cases were identified using the Preschool Age Psychiatric Assessment and compared to a birth-year-stratified control group of 549 children. We categorized bis(2-butoxyethyl) phosphate (BBOEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) as values&nbsp;&lt;&nbsp;limit of detection (LOD) (BBOEP N&nbsp;=&nbsp;386, BDCIPP N&nbsp;=&nbsp;632), ≥LOD but&nbsp;&lt;&nbsp;limit of quantification (LOQ) (BBOEP N&nbsp;=&nbsp;413; BDCIPP N&nbsp;=&nbsp;75), or above LOQ (BBOEP N&nbsp;=&nbsp;70; BDCIPP N&nbsp;=&nbsp;102). Diphenyl phosphate (DPhP) and di-n-butyl phosphate (DnBP) were categorized as quartiles and also modeled with a log10 linear term. We estimated multivariable adjusted odds ratios (ORs) using logistic regression and examined modification by sex using an augmented product term approach. RESULTS: Mothers in the 3rd DnBP quartile had 1.71 times the odds of having a child with ADHD compared to the 1st quartile (95%CI: 1.13, 2.58); a similar trend was observed for log10 DnBP and ADHD. Mothers with BDCIPP&nbsp;≥&nbsp;LOD but&nbsp;&lt;&nbsp;LOQ had 1.39 times the odds of having a child with ADHD compared to those with BDCIPP&nbsp;&lt;&nbsp;LOD (95%CI: 0.83, 2.31). Girls had lower odds of ADHD with increasing BBOEP exposure (log10 OR: 0.55 (95%CI: 0.37, 0.93), however boys had a weakly increased odds (log10 OR: 1.25 (95%CI: 0.74, 2.11) p-interaction&nbsp;=&nbsp;0.01]. CONCLUSIONS: We found modest increased odds of preschool ADHD with higher DnBP and BDCIPP exposure

Prenatal phthalate exposures and executive function in preschool children

Background Prenatal phthalate exposure has been linked with altered neurodevelopment, including externalizing behaviors and attention-deficit hyperactivity disorder (ADHD). However, the implicated metabolite, neurobehavioral endpoint, and child sex have not always been consistent across studies, possibly due to heterogeneity in neurodevelopmental instruments. The complex set of findings may be synthesized using executive function (EF), a construct of complex cognitive processes that facilitate ongoing goal-directed behaviors. Impaired EF can be presented with various phenotypes of poor neurodevelopment, differently across structured conditions, home/community, or preschool/school. We evaluated the relationship between prenatal phthalate exposure and comprehensive assessment of preschool EF. Methods Our study comprised 262 children with clinically significant/subthreshold ADHD symptoms and 78 typically developing children who were born between 2003 and 2008 and participated in the Preschool ADHD Substudy, which is nested within a population-based prospective cohort study, the Norwegian Mother, Father, and Child Cohort (MoBa). Twelve phthalate metabolites were measured from urine samples that their mothers had provided during pregnancy, at 17 weeks’ gestation. All children, at approximately 3.5-years, took part in a detailed clinical assessment that included parent-and teacher-rated inventories and administered tests. We used instruments that measured constructs related to EF, which include a parent-and teacher-reported Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) and three performance-based tests: A Developmental NEuroPSYchological Assessment (NEPSY), Stanford-Binet intelligence test V (SB5), and the cookie delay task (CDT). The standard deviation change in test score per interquartile range (IQR) increase in phthalate metabolite was estimated with multivariable linear regression. We applied weighting in all models to account for the oversampling of children with clinically significant or subthreshold symptoms of ADHD. Additionally, we assessed modification by child sex and potential co-pollutant confounding. Results Elevated exposure to mono-benzyl phthalate (MBzP) during pregnancy was associated with poorer EF, across all domains and instruments, in both sex. For example, an IQR increase in MBzP was associated with poorer working memory rated by parent (1.23 [95% CI: 0.20, 2.26]) and teacher (1.13 [0.14, 2.13]) using BRIEF-P, and administered tests such as SB5 (no-verbal: 0.19 [0.09, 0.28]; verbal: 0.13 [0.01, 0.25]). Adverse associations were also observed for mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP), although results varied by instruments. EF domains reported by parents using BRIEF-P were most apparently implicated, with stronger associations among boys (e.g., MnBP and inhibition: 2.74 [1.77, 3.72]; MiBP and inhibition: 1.88 [0.84, 2.92]) than among girls (e.g., MnBP and inhibition: −0.63 [−2.08, 0.83], interaction p-value: 0.04; MiBP and inhibition: −0.15 [−1.04, 0.74], interaction p-value: 0.3). Differences by sex, however, were not found for the teacher-rated BRIEF-P or administered tests including NEPSY, SB5, and CDT. Conclusion and relevance Elevated mid-pregnancy MBzP, MiBP, and MnBP were associated with more adverse profiles of EF among preschool-aged children across a range of instruments and raters, with some associations found only among boys. Given our findings and accumulating evidence of the prenatal period as a critical window for phthalate exposure, there is a timely need to expand the current phthalate regulations focused on baby products to include pregnancy exposures