Diphenyl Phosphate Concentrations Research Articles

Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study.

Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; ) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: , 0.17). At delivery, an IQR () increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

Associations between exposure to organophosphate esters and overactive bladder in U.S. adults: a cross-sectional study.

The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to examine the potential link between urinary metabolites of organophosphate esters and OAB. Data from the National Health and Nutrition Examination Survey (NHANES) database of the 2011-2016 cycles were utilized. Four urinary metabolites of organophosphate esters: diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) were included in the study. Multivariate logistic regression and restricted cubic spline (RCS) were used to evaluate the relationship between urinary OPEs metabolites and OAB. Interaction analysis was conducted on subgroups to confirm the findings. A total of 3,443 United States (US) adults aged 20 years or older were included in the study, of whom 597 participants were considered to have OAB. After adjusting for potential confounding factors, we found a positive association between DPHP and the risk of overactive bladder. The risk of overactive bladder increased with increasing DPHP concentrations compared with quartile 1 (quartile 2, OR = 1.19, 95% CI, 0.82-1.73, P = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, P = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, P = 0.002). However, after dividing the participants by gender, only the female group retained consistent results. Additionally, restricted cubic spline analysis revealed a nonlinear dose-response correlation between DPHP and OAB in female participants. In the subgroup analysis based on age, race, body mass index (BMI), recreational activity, smoking status, drinking status, hypertension, diabetes, and stroke, the interaction analysis revealed that the findings were uniform. Our findings indicate that exposure to DPHP could elevate the risk of OAB in US adult females. Further experimental studies are needed to explore the underlying mechanism in the future.

Organophosphate esters, airway inflammation, and lung function among U.S. participants: A nationally representative cross-sectional study from NHANES, 2011–2012

BackgroundHuman beings are widespread exposed to organophosphate esters (OPEs), but little is known about their effects on respiratory health. ObjectivesTo investigate the associations of exposure to OPEs with lung function and airway inflammation among U.S. participants from NHANES, 2011–2012. MethodsA total of 1636 participants aged 6–79 years were included. Concentrations of OPE metabolites were measured in urine and lung function was assessed with spirometry. Fractional exhaled nitric oxide (FeNO) and blood eosinophils (B-Eos), two important inflammatory biomarkers, were also measured. Linear regression was performed to examine the relationships of OPEs with FeNO, B-Eos and lung function. Bayesian kernel machine regression (BKMR) was used to evaluate the joint associations between OPEs mixtures and lung function. ResultsThree of seven OPE metabolites had detection frequencies > 80 %, including diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis-2-chloroethyl phosphate (BCEP). A 10-fold increase in DPHP concentrations were associated with 1.02 mL decreases in FEV1 (β = −0.01, 95 % CIs = −0.02, −0.003) and FVC (β = −0.01, 95 % CIs = −0.02, −0.003), respectively, and the similar, modest decreases were seen for BDCPP. For each 10-fold increase in BCEP concentration, FVC was also reduced by 1.02 mL (β = −0.01, 95 % CIs = −0.02, −0.002). Moreover, the negative associations were only found in non-smokers aged >35 years. The aforementioned associations were confirmed by BKMR, but we cannot definitively identify a constituent driving this association. B-Eos was negatively associated with FEV1 and FEV1/FVC, but not with OPEs. No associations were found of FeNO with OPEs and lung function. ConclusionsExposure to OPEs was associated with modest decrements in lung function, although the observed decrease in FVC and FEV1 is unlikely to be of real clinical relevance for the majority of subjects in this series. Moreover, those associations presented age and smoking status-dependent pattern. Unexpectedly, the adverse effect was not mediated by FeNO/B-Eos.

Exposure of men living in the greater Montreal area to organophosphate esters: Association with hormonal balance and semen quality

Exposure to organophosphate esters (OPEs) is extensive, yet few studies have investigated their association with hormone levels or semen quality. Here, we studied the association between urinary concentrations of OPEs and their metabolites with hormone levels and semen parameters in men (n=117) predominantly in the 20-29years age range who were recruited from the greater Montreal area between 2009 and 2012. Urine, serum, and semen samples were analyzed for OPEs, hormones, and semen quality, respectively. Bis(2-ethylhexyl) phosphate (BEHP), bis(2,4-di-tert-butylphenyl) hydrogen phosphate (B2,4DtBPP), tris(2-chloroisopropyl) phosphate (TCIPP), diphenyl phosphate (DPHP), bis (2-butoxyethyl) phosphate (BBOEP) and di-cresyl phosphate (DCPs) were detected in urine at a frequency≥95%. The highest geometric mean concentration was observed for DPHP (18.54ng/mL) and the second highest was B2,4DtBPP (6.23ng/mL). Associations between a doubling in analyte concentrations in urine and hormone levels and semen quality parameters were estimated using multivariable linear regression. B2,4DtBPP levels were positively associated with total T3 (β=0.09; 95% CI: 0.01, 0.17). DPHP was inversely associated with estradiol (β=-2.56; 95% CI: -5.00, -0.17), and TCIPP was inversely associated with testosterone (β=-0.78; 95% CI: -1.40, -0.17). Concentrations of BCIPP were inversely associated with sperm concentrations (β=-7.76; 95% CI: -14.40, -0.61), progressive motility (β = - 4.98; 95% CI: -8.71, -1.09), and the sperm motility index (β=-9.72; 95% CI: -17.71, -0.96). In contrast, urinary DPHP concentrations were positively associated with the sperm motility (β=4.37; 95% CI: 0.76, 8.12) and fertility indices (β=6.64; 95% CI: 1.96, 11.53). Thus, OPE detection rates were high and exposure to several OPEs was associated with altered hormone levels and semen parameters. The possibility that OPEs affect male reproduction warrants further investigation.

Maternal urinary OPE metabolite concentrations and blood pressure during pregnancy: The HOME study

BackgroundFew studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy. MethodsWe analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP. ResultsICCs of OPEs were 0.17–0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97–9.15). Other OPE metabolites were not significantly associated with HDP. ConclusionMaternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance.

The associations between organophosphate esters and urinary incontinence in the general US population

Organophosphate esters (OPEs) impact health in many ways. Since its relationship with urinary incontinence remains unknown, we aimed to explore their associations in the US general population. We combined the results of urine specimens test and self-reported urinary incontinence conditions from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 among 2666 participants and then conducted linear regression and logistic regression to analyse associations between log2-transformed OPE concentrations and urinary incontinence. We found that 0.92% of men and 15.74% of women complained of mixed urinary incontinence (MUI). The concentrations of diphenyl phosphate (DPHP) were significantly correlated to MUI among women when treated as a continuous variable (adjusted odds ratio (OR) = 1.15; 95% confidence interval (CI), 1.01–1.31; p = 0.0369) and as a categorical variable (adjusted OR = 1.24; 95% CI, 1.03–1.49; p for trend = 0.0245), whereas no positive correlation was found in males. There were no significant associations between the other three OPEs: bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and dibutyl phosphate (DBUP). The association of DPHP with an increased prevalence OR of MUI in women is a public health concern; future prospective studies are needed to explore its potential mechanism.

Variability of urinary organophosphate esters (OPEs) during childhood: The HOME Study

BACKGROUND AND AIM: Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers. Previous research has shown that gestational exposure to OPEs is variable, but no studies have examined the patterns and variability of postnatal exposure to our best knowledge. METHODS: In a prospective birth cohort (HOME Study, Cincinnati, OH, USA), we measured urinary OPE metabolite concentrations three times (16 and 26 weeks of gestation, at delivery) during pregnancy and five times (ages 1, 2, 3, 5, 8 years) during childhood. We log10-transformed creatinine-standardized OPE metabolite concentrations. We calculated Spearman correlation coefficients between postnatal OPE metabolites at each time point. We then used linear mixed models to calculate intraclass correlation coefficients (ICCs) for metabolite concentrations across the five postnatal time points. We further examined the association between three prenatal measures and early childhood (ages 1, 2, 3 years) exposure and subsequent metabolite concentrations at ages 5 and 8 years, including the main effect and the interaction term with the subsequent time points of metabolite measurement using linear mixed models. RESULTS:We detected (2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP) in 79 to 100% of children. The median concentrations (µg/g creatinine) were 0.78-4.76 for BCEP, 4.02-7.42 for BDCIPP, and 2.57-11.48 for DPHP. We found moderate correlations between BCEP and BDCIPP (rs: 0.28-0.49, p 0.001) at all time points. ICCs for metabolites across five postnatal time points, however, indicated poor within-person correlation (0.09–0.25). Prenatal urinary DPHP concentrations were positively associated with postnatal DPHP concentrations at some time points. Positive associations between early (1-3 years) and late childhood concentrations (age 8 years) were found for BCEP and BDCIPP. CONCLUSIONS:We found high within-person variability of OPE exposure within children across the first 8 years of life, suggesting that multiple urine samples are needed to characterize children’s exposures to OPEs. KEYWORDS: Chemical exposures, Endocrine disrupting chemicals, Children's environmental health, Environmental epidemiology

Gestational organophosphate ester exposures and bone mineral density in early adolescence: The HOME Study

BACKGROUND AND AIM: Optimizing bone mineral density (BMD) in adolescence is critical for life-long bone health. Organophosphate esters (OPEs) are synthetic flame retardants and plasticizers that may have osteotoxic effects via endocrine disruption or nuclear receptor agonism. Animal studies suggest that gestation may be a critical period of susceptibility for the impact of OPEs on bone health, but human studies are lacking. We assessed the relation of maternal urinary OPE metabolite concentrations during pregnancy with early adolescent BMD in a prospective birth cohort study. METHODS: We used data from 223 mother-child dyads enrolled in the HOME Study from Cincinnati, OH area, 2003-2006. We measured bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in maternal urine collected at 16- and 26-weeks gestation, and calculated the average of creatinine-adjusted concentrations. We performed dual x-ray absorptiometry in children at age 12 years and calculated height-, age-, sex-, and population ancestry-specific Z-scores for whole body (excluding head), total hip, femoral neck, distal radius, and ultradistal radius areal BMD (aBMD) and spine bone mineral apparent density (BMAD). We estimated covariate-adjusted associations per 2-fold increase in maternal urinary OPE concentrations and assessed effect measure modification by child sex. RESULTS:In adjusted analyses, BDCIPP concentrations were positively associated with aBMD and BMAD Z-scores at most skeletal sites. Z-score differences were between 0.11 and 0.15 and greatest for total hip (β = 0.15, 95% CI: 0.02, 0.29). Associations of DPHP with femoral neck and total hip aBMD differed by child sex. Associations among males were null while DPHP concentrations were inversely associated with femoral neck (β = -0.15, 95% CI: -0.29, -0.02) and total hip (β = -0.15, 95% CI: -0.29, 0.00) aBMD Z-scores among females. CONCLUSIONS:Maternal OPE exposures during gestation may affect early adolescent BMD in a metabolite-, sex-, and bone site-specific manner. KEYWORDS: Chemical exposures, Children's environmental health, Endocrine disrupting chemicals

Organophosphate Ester (OPE) Exposures and Asthma Morbidity Among Urban School-Aged Children in Baltimore City, Maryland

BACKGROUND AND AIM: OPEs are used as flame retardants and plasticizers in many consumer products. Studies suggest OPEs may be linked with respiratory outcomes among children. We aimed to examine associations between OPEs and asthma morbidity among 179 mostly Black children (93%), aged 5-12 years with asthma enrolled in a panel study between 2009-2013¬ in Baltimore City. METHODS: The panel study included up to four seasonal, week-long in-home visits. We collected urine samples on visit-days 4 and 7 (n = 618 samples). We quantified concentrations of 9 OPE metabolites: bis(2-chloroethyl)phosphate(BCEtp), bis(1-chloro-2-propyl)phosphate(BCPP), bis(1-chloro-2-propyl)phosphate(BDCPP), di-benzylphosphate(DBuP), di-benzylphosphate(DBzP), di-o-cresylphosphate(DOCP), di-p-cresylphosphate(DPCP), diphenyl-phosphate(DPHP), and 2,3,4,5-tetrabromobenzoic acid(TBBA). At each visit, participants self-reported asthma symptoms. We calculated Spearman’s rank (continuous) and tetrachoric (binary) correlation coefficients to assess variability of concentrations on days 4 and 7 and intraclass correlation coefficients (ICCs) to assess variability by visit. We assessed associations between metabolite concentrations and asthma symptoms using logistic regression models with generalized estimating equations. We examined BDCPP and DPHP as continuous variables; dichotomized BCEtP, DBuP, and DPCP; and excluded others not frequently detected. We adjusted models for season, visit-day, age, race, sex, BMI, caregiver education, and household income. RESULTS:Detection frequencies were 95% for BDCPP and DPHP, 4.6-31.1% for BCEtP, DBuP and DPCP, respectively and 3% for all other metabolites. OPE concentrations on days 4 and 7 were moderately correlated (rho=0.3-0.6) with low reproducibility across visits (ICC=0.2-0.4). In adjusted models, higher DPHP concentrations were associated with greater odds of self-reported difficulty breathing (odds ratio [OR]: 2.0; 95%CI:1.1-3.6), activity limitation due to asthma (OR:1.6; 95%CI:1.0-2.8), and being bothered by asthma (OR:1.9; 95%CI:1.2-3.2). No associations were observed with other OPEs. CONCLUSIONS:In this predominantly pediatric Black cohort, higher DPHP concentrations were consistently associated with asthma symptoms. We did not observe consistent patterns of association between other OPE metabolites and asthma morbidity. KEYWORDS: Biomarkers of exposure, Respiratory outcomes, Children's environmental health, Environmental disparities, Environmental epidemiology

Characterizing exposures to flame retardants, dioxins, and furans among firefighters responding to controlled residential fires.

Firefighters may encounter items containing flame retardants (FRs), including organophosphate flame retardants (OPFRs) and polybrominated diphenyl ethers (PBDEs), during structure fires. This study utilized biological monitoring to characterize FR exposures in 36 firefighters assigned to interior, exterior, and overhaul job assignments, before and after responding to controlled residential fire scenarios. Firefighters provided four urine samples (pre-fire and 3-h, 6-h, and 12-h post-fire) and two serum samples (pre-fire and approximately 23-h post-fire). Urine samples were analyzed for OPFR metabolites, while serum samples were analyzed for PBDEs, brominated and chlorinated furans, and chlorinated dioxins. Urinary concentrations of diphenyl phosphate (DPhP), a metabolite of triphenyl phosphate (TPhP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), a metabolite of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and bis(2-chloroethyl) phosphate (BCEtP), a metabolite of tris(2-chloroethyl) phosphate (TCEP), increased from pre-fire to 3-hr and 6-hr post-fire collection, but only the DPhP increase was statistically significant at a 0.05 level. The 3-hr and 6-hr post-fire concentrations of DPhP and BDCPP, as well as the pre-fire concentration of BDCPP, were statistically significantly higher than general population levels. BDCPP pre-fire concentrations were statistically significantly higher in firefighters who previously participated in a scenario (within the past 12 days) than those who were responding to their first scenario as part of the study. Similarly, firefighters previously assigned to interior job assignments had higher pre-fire concentrations of BDCPP than those previously assigned to exterior job assignments. Pre-fire serum concentrations of 2,3,4,7,8-pentachlorodibenzofuran (23478-PeCDF), a known human carcinogen, were also statistically significantly above the general population levels. Of the PBDEs quantified, only decabromodiphenyl ether (BDE-209) pre- and post-fire serum concentrations were statistically significantly higher than the general population. These results suggest firefighters absorbed certain FRs while responding to fire scenarios.

Organophosphate Diesters in Urban River Sediment from South China: Call for More Research on Their Occurrence and Fate in Field Environment

Despite numerous studies on the distributions of organophosphate triesters (tri-OPEs) in various environmental compartments, few have investigated organophosphate diesters (di-OPEs) in natural environments. This study was conducted to examine the co-occurrence of tri- and di-OPEs in urban river sediment. The concentrations (range (median); dry weight) of ∑tri-OPE and ∑di-OPE were 17–4400 (330) and 9.0–1200 (130) ng g–1, respectively. The concentrations of diphenyl phosphate (DPHP), bis-(1-chloro-2-propyl) phosphate (BCIPP), bis(2-ethylhexyl) phosphate (BEHP), dibutyl phosphate (DBP), and bis-(butoxyethyl) phosphate (BBOEP) were 1.7–520 (45), 3.2–590 (51), 1.7–100 (22), 0.43–9.6 (1.2), and 0.41–4.4 (0.74) ng g–1, respectively. Positive correlations between the levels of di-OPE and tri-OPE compounds (p < 0.05) together with high concentration ratios of DPHP to TPHP (2.0–96; median 17) and BCIPP to TCIPP (1.6–160; median 5.7) suggested that DPHP and BCIPP were mainly from degradation of TPHP and TCIPP. More studies are needed to illustrate the environmental occurrence, behavior, fate, and ecological risk of di-OPEs.

Short-term temporal variability of urinary biomarkers of organophosphate flame retardants and plasticizers

BackgroundExposure to organophosphate flame retardants and plasticizers (PFRs) is commonly estimated by measuring biomarker concentrations in spot urine samples. However, their concentrations in urine can vary greatly over time due to short biological half-lives and variable exposure, potentially leading to exposure misclassification. In this study, we examined the within- and between-individual and within- and between-day variability of PFR metabolites in spot and 24-hour pooled urine samples during five consecutive days. MethodsWe collected all spot urine samples from 10 healthy adults for 5 days. On one additional day, we collected 24-hour pooled urine samples. Samples were analyzed by solid-phase extraction coupled to high-performance liquid chromatography tandem mass spectrometry. We calculated intraclass correlation coefficients (ICCs) to assess the reproducibility of metabolite concentrations in morning void and spot samples. ResultsFair-to-good reproducibility was observed for serial measurements of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP) and 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) (ICC: 0.396 – 0.599), whereas concentrations of diphenyl phosphate (DPHP) and 2-ethylhexyl phenyl phosphate (EHPHP) were more variable in time (ICC: 0.303 and 0.234). Reproducibility improved significantly when only morning void samples were considered and when concentrations were adjusted for urinary dilution. Collecting 24-hour pooled urine could be a reliable alternative for PFR biomarkers with poor short-term temporal variability. ConclusionsThe between-day variability was minor compared to variability observed within the same day, which suggests that collecting multiple samples could reduce exposure missclassification. Differences in the observed between- and within-individual variance were compound specific and related to both the nature of the exposure (e.g., diet vs other exposure routes, multiple sources) and the individual toxicokinetic properties of the investigated PFRs.

Prenatal organophosphate flame retardant exposure and the odds of small- and large-for-gestational age births

Background: Deviations in normal fetal growth trajectories may predispose infants to adverse outcomes later in life, such as cardio-metabolic disorders and decreased intellectual performance during childhood. Environmental exposures, including commonly used organophosphate flame retardants (OPFRs), have the ability to disturb normal hormonal and metabolic processes during pregnancy; however, associations with fetal growth have been minimally examined in human populations. Methods: Using a pilot case-control study, we investigated the association between 9 OPFRs and the odds of small-for (SGA) and large-for-gestational age (LGA) births. Concentrations of OPFRs were measured in maternal urine collected from three study visits during pregnancy using high performance liquid chromatography-tandem mass spectrometry. SGA (&lt;10th percentile birth weight-for-gestational age, n = 30), LGA (&gt;90th percentile, n = 30), and control (10th - 90th percentile, n = 30) births were selected from the LIFECODES birth cohort study. Odds ratios (OR) and 95% confidence intervals (95% CI) for associations between average OPFR concentrations over pregnancy and SGA and LGA were estimated using multinomial logistic regression. Results: Among the 9 urinary OPFRs measured, only bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPHP) were detected in at least 85% of the participants at each study visit. After adjusting for potential confounders, we observed inverse associations between BDCPP and DPHP concentrations and odds of delivering an LGA baby. For example, a log-unit increase in BDCPP was associated with an OR (95% CI) of 0.37 (0.16, 0.84). All associations between OPFR concentrations and SGA were null. Conclusions: In a pilot study of prenatal OPFR exposure and fetal growth, urinary OPFR concentrations were associated with reduced odds of delivering LGA. While no associations with the SGA group were observed, these findings are consistent with previous observations that OPFRs are associated with lower measures of fetal growth and warrant additional investigation in future work.

Does exposure to organophosphate esters during pregnancy increase the risk of attention-deficit hyperactivity disorder in offspring?

Background. Elevated organophosphate esters (OPEs) during pregnancy has been associated with hyperactivity and attention problems in children. Such behaviors are often found in children with attention-deficit hyperactivity disorder (ADHD). However, no study has investigated OPEs in relation to clinically diagnosed ADHD.Aim. To evaluate associations between prenatal exposure to OPEs and ADHD diagnosis, in a case-cohort substudy of the Norwegian Mother, Father and Child Cohort.Methods. We identified 297 ADHD cases through the Norwegian patient registry and sampled a sub-cohort of 555 participants among the eligible population. Diphenyl phosphate (DPHP), di-n-butyl phosphate (DnBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in urine collected at 17 gestational weeks. Binary exposure indicators were created for DPHP (cutoff: sub-cohort median), DnBP (limit of quantification, LOQ), BBOEP and BDCIPP (limit of detection, LOD). We estimated ORs using logistic regression, adjusting for the season of urine collection, child sex, birth year, maternal depression, maternal ADHD, and phthalate metabolite concentrations. Missing covariates were multiply imputed and estimates were pooled using Rubin’s rules. Effect measure modification by child sex was investigated.Results. DPHP was detected in nearly all samples (98%&gt;LOD), with a higher geometric mean among ADHD cases (0.70 ng/ml) as compared to the sub-cohort (0.52 ng/ml). DNBP was commonly detected as well (6%&lt;LOD; 39% LOD-LOQ; 55%&gt;LOQ), while BBOEP (51%&gt;LOD) and BDCIPP (21%&gt;LOD) were detected less frequently. Children whose mothers had above the median DPHP concentrations during pregnancy were more likely to be diagnosed with ADHD (aOR: 1.41 [95% CI: 1.00, 1.99]). Similar positive associations were observed for BDCIPP (1.47 [0.99, 2.17]), but near-null associations were observed for DnBP (0.93 [0.67,1.30]) and BBOEP (1.05 [0.75, 1.45]). We did not observe strong evidence of modification by child sex.Conclusions. DPHP and BDCIPP exposure during pregnancy may increase the risk of ADHD in offspring.

Prenatal Exposure to Organophosphate Flame Retardants and the Risk of Low Birth Weight: A Nested Case-Control Study in China.

Organophosphate flame retardants (OPFRs), used as flame retardants and plasticizers, have been suggested to impair fetal growth and development in toxicological studies, but epidemiological data are extremely limited. This study was designed to explore whether prenatal exposure to OPFRs was associated with an increased risk of low birth weight (LBW) using a nested case-control design based on the ongoing prospective birth cohort in Wuhan, China. A total of 113 cases and 226 matched controls recruited from this cohort project in 2014-2016 were included. OPFR metabolite concentrations in maternal urine samples collected in the third trimester were determined, and birth outcomes were extracted from medical records. Compared with the lowest tertile of diphenyl phosphate (DPHP) concentrations, pregnant women with the highest tertile of DPHP had a 4.62-fold (95% confidence interval (CI): 1.72, 12.40) significantly increased risk for giving birth to LBW infants, with a significant dose-response relationship (p-trend < 0.01). After stratification by newborn sex, the significant positive association of DPHP levels with LBW risk was merely observed among female newborns. Our results suggest a positive association between maternal urinary DPHP concentrations and LBW risk for the first time, and the effect appears be sex-specific.

Organophosphate esters in a cohort of pregnant women: Variability and predictors of exposure

Organophosphate esters (OPEs) are a group of chemicals used as flame retardants and plasticizers that replaced polybrominated diphenyl ethers in consumer products such as furniture and electronics. To characterize exposure to OPEs during fetal development, we measured urinary OPE metabolite concentrations in women twice during pregnancy (16 and 26 weeks' gestation) and at delivery (n = 357). We also previously quantified house dust OPE parent compound concentrations at 20 weeks’ gestation (n = 317). Diphenyl phosphate (DPHP) had the highest geometric mean urinary concentrations (1.5–2.3 μg/g creatinine), followed by bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 0.75–0.99 μg/g creatinine), and bis(2-chloroethyl) phosphate (BCEP; 0.72–0.97 μg/g creatinine), while dibutyl phosphate (DNBP) had the lowest concentrations (0.25–0.28 μg/g creatinine). Urinary OPE metabolites were moderately correlated with each other at 26 weeks (rs: 0.23–0.38, p < 0.001) while the correlations at 16 weeks and delivery were slightly weaker. Intra-class correlations for urinary metabolites measured at three time points were poor (0.16–0.34), indicating high variability within individuals. Dust concentrations of OPE parent compounds were associated with BCEP, BDCIPP, and DPHP concentrations in urine at some but not all time points. In linear mixed models of urinary OPE metabolite concentrations, household size was inversely associated with BCEP concentrations, and being non-white was associated with lower BDCIPP and DPHP concentrations. Urine samples collected in the summer had the highest OPE metabolite concentrations. This study highlights the need to collect multiple urine samples during pregnancy to define exposure patterns and investigate potential periods of susceptibility.

Uptake, Deposition, and Metabolism of Triphenyl Phosphate in Embryonated Eggs and Chicks of Japanese Quail (Coturnix japonica).

The toxicokinetics of triphenyl phosphate (TPHP) in vivo including the uptake, deposition, and biotransformation into the metabolite diphenyl phosphate (DPHP) is presently reported in embryonated eggs and chicks of Japanese quail. Quail were dosed with TPHP at 3 concentrations by air cell egg injection on embryonic day 0, followed by daily oral dosing after chicks hatched (5 d). Vehicle-only exposed controls were also used. In dosed eggs, only 33% of the TPHP remained 2 d after injection (no hepatic development); after 10 d (post-hepatogenesis), only 2% remained. The estimated TPHP half-lives in the eggs ranged from 1.1 to 1.8 d for the 3 dosed groups. In all exposed eggs and chicks, DPHP significantly increased with dose (0.001 < p < 0.044). It appears that DPHP is an important metabolite in quail, making up 41 to 74% of all metabolites formed in embryonated eggs. In chicks, at medium and high doses, DPHP concentrations significantly exceeded those of TPHP (p ≤ 0.007), making up 67 and 76% of the total burden, respectively. Our findings suggest that rapid TPHP metabolism occurred in chicks and embryonated quail eggs but that this may vary with the age of the embryonated egg and the stage of embryo development, which should be considered when evaluating concentrations of TPHP and DPHP measured in eggs of wild birds. Environ Toxicol Chem 2020;39:565-573. © 2019 Her Majesty the Queen in Right of Canada. Environmental Toxicology and Chemistry © 2019 SETAC.

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring’s behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children’s scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: β = 3.03; 95% CI = 0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: β = 2.49; 95% CI: −0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: β = −3.74; 95% CI = −6.75, −0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals.

The association of urinary phosphorous-containing flame retardant metabolites and self-reported personal care and household product use among couples seeking fertility treatment

BackgroundPhosphorous-containing flame-retardants (PFRs) are widely detected. They are used both as a flame retardant as well as plasticizer.MethodsA subset of 230 women and 229 men were recruited from Massachusetts General Hospital fertility clinic between 2005 and 2015. At each visit, participants completed a questionnaire of personal care product (PCP) and household product (HP) use. Metabolites [bis(1,3-dichloro-2-propyl) phosphate, diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate and bis(1-chloro-2-propyl) phosphate] were measured in urine (1–5 samples; n = 638 women, n = 335 men). Associations were assessed using generalized mixed models, adjusted for SG, age, BMI, smoking, education, and season.ResultsIn women, moisturizer (60%), nail polish remover (77%), and nail polish (134%) use were associated (p < 0.05) with an increase in DPHP concentrations, while ip-PPP concentrations increased 21–27% with conditioner, cosmetics, deodorant, and hair product use. Mouthwash and vinyl glove use were associated with a respective 31% and 92% increase in DPHP among men.ConclusionsOur exploratory analysis suggests PFRs may be used as a plasticizer in consumer products, and nail polish use contributes to internal DPHP exposure. Further research is needed to understand how PFRs are used in these products and how it relates to exposure.

Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology

To evaluate whether urinary concentrations of organophosphate flame retardant (PFR) metabolites are associated with pregnancy loss among women conceiving with assisted reproductive technology (ART). Prospective preconception cohort of subfertile women. Academic hospital fertility center in Boston, Massachusetts. A total of 155 women conceiving 179 pregnancies with ART. None. Mean exposure to each of five PFR metabolites was estimated by averaging the specific-gravity adjusted natural log concentrations from two urine samples collected during the ART cycle of conception. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for biochemical and total pregnancy loss (all losses <20weeks' gestation) by quartiles of PFR metabolite concentrations were estimated using a repeated measures log-binomial model, accounting for multiple pregnancies per woman. Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61-4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64-5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome. Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss. Although this study is uniquely designed to investigate early markers of pregnancy success and maintenance, the small sample size likely contributed to imprecision. Given their increasing use as replacement chemicals for traditional flame retardants, exposure to PFRs may increase, and more studies will be needed to investigate their potential to impact pregnancy and reproduction.